clinical history, brain metabolism, and neuropsychological function in alzheimer's disease

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. Postmor- tem studies attempting to relate clinical findings to brain disorder have found most cell loss occurring in the temporal and frontal lobes and, in severe Alz- heimer's disease (AD), in the parietal lobes as well

With the recent development of positron emission tomography (PET) using fluorine 18-labeled fluoro-2- deoxy-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 AD and that dramatic reductions in overall cerebral metabolism occur in late, severe AD.

Because of the heterogeneous course and symp- tomatology of AD, descriptive criteria for each patient and age-matched control subject must be satisfied before metabolic results from PET can be correlated with

[ 5 , 61-

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 age- matched 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 ade- quately 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.

From the "Section on Brain Aging and Dementia, Laboratory of Neurosciences, National Institute on Aging, and the +Nuclear for publication Feb 19, 1985.

Received June 15, 1984, and in revised form Feb 1, 1985. Accepted

Medicine Department, Clinical Center, National Institutes of Health, Berhesda, M D 20205. Address reprint requests to Dr Curler, Depmment of Neurology,

Naval Medical Command. National CaDital Region. Bethesda, MD I

20814.

298

TabIe 1. Description of Seven Patients with Alzheimer’s Disease ~ ~ ~ ~~ ~

Duration Severity Test Scores Dominant EEG Patient Age (yr), of Illness Background No. Sex (yr) MMSE BMICT BDS MS HS Neurological Signs Frequency (Hz)

1 2

65, M 81, F

4 3

24 26 2.5 19 23 2.5

123 104

2 1

Snout reflex Snout reflex, rooting reflex,

fine tremor of fingers Mild tremor Dy sdiadochokinesia Snout, palmomental

reflexes

10-1 1 18-24

3 4 5

49, M 67, F 57, F

2 3 2.5

20 21 6.5 15 22 . . . 13 20 8.5

119

108 . . .

2 3 3

10-11 6-7 3-7

Meana 6 7

63.8 67, M 73, F

2.8 6 6

18.2 22.4 5.8 5 9 9.5

. . . 9 10.5

113.5 33 . . .

2.2 2 Snout reflex, grasp

Snout, palmomental reflexes

3-5 4-6 . . .

Meanb Group

mean

70 65.6

6 3.7

. . . 9 10.0 16.0 18.6 6.7 97.4 2.1 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

Lateral Ventricle Patient Memory Deterioration Reflexes Cortical Enlargement on No. Deficits Disorientation Aphasia Apraxia of Personality (Snout, Grasp) Atrophy CT Scanning

1 + . . . . . . . . . . . . + . . . + 2 + . . . . . . . . . . . . + + + + + + 3 + + . . . + . . . . . . . . . + + (L > R) 4 + . . . + + + + + + . . . + + + + 5 + + . . . . . . + + + + + + 6 + + + + + + + + + + + + + + + + + 7 + + + + + + + + + . . . + + + + + + + + + + = mild; + + = moderate; + + + = severe; CT = computed tomography; L = left; R = right.

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 Examina- tion 1137, the Blessed Dementia Scale, the Blessed Memory Information Concentration Test 141, and the Mattis Demen- tia Scale 1221 (Table 1). In order to exclude other causes of dementia, all patients were evaluated for a vascular disorder

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 ap- proved 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 concen- trations of 18FDG and glucose in the plasma. Brain radioac- tivities (in microcuries per gram) were calculated with a cali- bration 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, 1 11 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 11 I), 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 syn- opses 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 Blood Pressure Heart Rate Height Weight (gm/dl)/ (mm (mm Glucose Anxiety No. (mm Hg) (beatdmin) (m) (kg) Hct (%) PH Hg) Hg) ( g d d l ) Ratinga

Mean Arterial Hgb PaCo2 Pa02

1 96.6 56 1.73 91.0 15.3144.7 7.39 43 77 79 * 0.11 0

3 110 68 1.82 86.8 15.8145.7 . . . . . . . . . 100 t 1.1 1

5 78 72 1.45 46.9 14.3/41.4 . . . 90 t 0.17 3 6 92.6 56 1.54 54.7 14.9/41.9 . . . . . . 0 7 95 96 52.0 12.9136.9 . . . 84 t 0.16 3

2 66 62 1.56 48.1 15.0/43.4 7.38 35 108 73 4 0.11 1

80 0.09 3 4 88 56 1.56 51.9 13.8/40.0 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mean 89.5 66.6 1.61 61.6 14.6/42.0 7.39 39 92.5 84 1.6

“Anxiety score: 0 = minimal to 3 = intense.

Hgb = hemoglobin; Hct = hematocrit; PaCO, = partial pressure of arterial carbon dioxide; PaOz = partial pressure of arterial oxygen

300 Annals of Neurology Vol 18 No 3 September 1985

Table 4. Wechsler Adult 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 65 Mild 119 111 114 105 2 81 Mild-moderate 110 77 84 70 3 49 Mild-moderate 12 1 97 100 93 4 67 Moderate 114 65 78 53 5 57 Moderate 97 75 89 59 Mean ? SD‘ 63.8 . . . 112 2 11 85 5 9 93 5 10 76 % 9 6 67 Severe 119 57 63 55 7 73 Severe 121 . . . . . . Meane 70 . . . 120 . . . . . . . . . Controls 63.3 120 c 7

d d . . . d

. . . 134 c 6 135 5 5 128 ? 10 (n = 9) (mean 2 SD)

‘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 . Wechsler Memory 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 65 Mild 11 1 12 2 2 81 Mild-moderate 8 0 0 0 3 49 Mild-moderate 1 0 2 0 4 67 Moderate 11 1 0 0 5 57 Moderate 5 0 1 0 Mean -+ SDb 63.8 . . . 7.2 c 3 0.4 c 0.6 3.0 2 2 0.4 c 0.6 6 67 Severe 2 0 0 0 7 ’ 73 Severe . . . . . . , . . . . . Meand 70 . . . . . . . . . . . . . . . Controls 63.3 . . . 21.4 2 4.2 16.8 ? 3.3 11.7 -+ 2.3 8.8 ? 2.9

c C C C

(n = 9) (mean 2 SD)

“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 tenta- tive 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 Il l 7/01; DOA: 121 1 0182) The patient, an 81-year-old, right-handed woman living in a residential care facility, had a 3-year history of progressive memory dysfunction. Her son had first noted uncharacter- istic 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 IQ 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. Cur- rently 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. Al- though 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 syntacti- cally 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 1 I1 182) 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-

iar and new surroundings and became reluctant to make de- cisions. 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. Re- sults 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 whole- body 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: 1 I3 1/83) The patient is a 57-year-old, right-handed woman with a 3- year 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. Be- cause 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 pro- cess.

The patient’s premorbid intelligence is estimated to have been in the average range [33]. Her neuropsychological tests revealed a marked deficit of recent memory and a moderate deficit of remote memory. H e r performance on tests of cor- tically mediated cognitive functions (e.g., visuospatial construction, language, abstract reasoning, immediate memory)


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 on 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: 1011 2/82; died 9130l84) The patient was a 73-year-old, right-handed woman with a 6- year 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.

Neuropsychological evaluation 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 AD 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 AD 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 AD group as compared with controls. On 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 AD 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 AD 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 AD 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


Table 6. Cerebral Metabolic Rates for Glucose in Alzbeimerk Disease Patients and Age-Matched Controlsa

Regional Cerebral Metabolic Rate for Glucose (mg . 100 gm-' . min-')

Controlsb AD (mild-mod)' AD (severeid mm Above Bran Regon IOMkne Left Right Left Lght Left Lght

Hemisphere Frontal lobe

Superior frontal gyrus

Midfrontal ~ Y N S

Inferior frontal gym

Cingulate gyms Orbitofrontal gyrus Precentral ~ Y N S

Paracentral lobule

Postcentral gyrus Parietal lobe

Superior parietal gyms

Inferior parietal gYns

Precuneus Occipital lobe

Cuneus Calcarine Lingual Retrosplenial

gray matter Temporal lobe

Superior temporal

Inferior middle temporal gyrus

Inferior temporal gyms

Hippocampal region Anterior medial

temporal gyrus Caudate nucleus Thalamus Lenticular nucleus h u l a cortex Cere bullum Centnun semiovale

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 . . . 70-100 55-70 70-100

45-70

65-80 . . .

45-65 30-45 15-30 45-70

. . . 30-45

15-30

5-15

20-35 20-35

35-55 40-50 35-55 40-60 0-15

70-90

4.53 f 1.15 5.32 2 1.32 5.65 2 1.46 5.53 f 1.59 5.34 f 1.50 5.95 f 1.67 5.40 2 1.51 5.61 2 1.77 5.56 2 1.43 5.55 ? 1.40 4.73 f 1.14 5.92 f 1.56 5.50 2 1.56 5.92 f 1.35 5.42 f 1.34 5.65 f 1.36 5.28 2 1.61 5.61 2 1.43

5.09 2 1.34

6.44 f 1.56 5.36 1.33 5.98 f 1.36 5.43 f 1.36 4.60 f 1.44 5.52 f 1.50

4.33 t 1.05 4.94 2 1.13

4.25 f 1.10

3.63 f 0.93

4.37 f 1.25 3.66 f 0.84

5.30 f 1.53 5.29 f 1.62

5.80 f 1.42 4.37 2 1.05 2.69 f 0.67

5.75 t 1.65

4.60 2 1.17 4.20 2 0.48 4.35 t 0.61 5.36 f 1.31 4.57 f 0.80 4.83 t 0.65 5.59 2 1.42 4.44 t 0.79 4.70 t 1.02 5.41 2 1.46 4.45 f 0.80 4.77 2 0.88 5.33 2 1.49 4.86 2 0.75 4.96 -t 0.79 6.01 f 1.51 4.17 2 0.97' 4.65 2 1.03' 5.54 f 1.58 4.34 f 1.26 4.67 t 1.27 5.69 f 1.79 4.46 f 1.20 4.94 t 1.28 5.58 f 1.54 4.63 f 1.22 4.94 t 0.95 5.55 f 1.40 5.33 2 0.62 5.33 2 0.62 4.82 f 1.21 4.29 f 0.84 4.56 t 0.36 6.05 2 1.52 5.35 f 0.69 5.27 t 0.88 5.80 2 1.63 5.48 f 0.58 5.70 t 0.43 5.92 f 1.35 5.26 f 0.75 5.26 t 0.75 5 51 f 1.42 4.43 f 0.98 4.62 t 1.25 5.76 f 1.42 5.12 2 0.89 5.35 t 1.20 5.53 f 1.63 5.81 f 0.47 5.88 t 0.64 5.65 f 1.55 3.97 f 1.04' 4.31 t 1.42'

5.29 f 1.44 4.26 f 1.25 4.45 t 1.39

6.36 f 1.51 5.36 2 1.62 5.34 2 1.74 5.39 2 1.33 5.15 f 0.82 5.26 t 0.92 5.94 f 1.39 5.59 2 1.44 5.71 t 1.57 5.45 2 1.33 4.99 2 0.79 4.96 t 0.85 4.84 f 1.57 4.55 f 0.46 4.59 t 0.77 5.52 f 1.50 5.48 f 1.51 5.48 i 1.15

4.41 t 1.09 3.69 f 0.73 3.98 t 0.64 5.04 f 1.28 3.72 2 0.96 4.02 f 0.95

4.30 f 1.19 3.61 2 0.06 3.79 t 0.83

3.48 f 0.71 2.23 f 1.OG' 3.05 f 0.63'

4.35 f 1.26 4.60 + 0.44 4.93 f 0.62 3.74 f 0.83 3.62 f 0.32 3.77 f 0.62

5.29 f 1.62 5.34 t 0.72 5.25 2 1.10 5.38 f 1.62 5.28 f 0.46 5.38 f 0.58 5.77 f 1.66 5.81 * 0.61 6.08 f 0.89 5.98 f 1.55 5.09 2 0.85 5.54 t 0.94 4.52 f 1.11 4.43 t 0.59 4.35 2 0.38 2.54 2 0.57 2.44 f 0.49 3.00 f 0.84

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'

2.21 f 0.27

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'

2.10 f 0.35' 2.54 f 0.42'

2.43 2 0.49'

2.39'

3.74 2 0.37' 2.36 2 0.92

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

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'

2.26 f 0.13

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'

2.63 t 0.22' 2.04 2 0.27'

2.05 f 0.16'

1.11'

3.53 f 0.41' 2.09 2 0.46

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

"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 = inferior orbitomeatal; mod = moderate.


0 Controls IP age=6 lyr 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 se- uere AD, 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 AD 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 AD were characterized primarily by an impairment surrounding recent events. This was noted in Patients 1 to 3 by their inability to synthesize or incor- porate 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 Pa- tient 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

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 right- left 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 de- bilitations 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

AD 1.231.


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 AD group. Our findings may show similar absolute values of rCMRglc as our number of subjects with AD 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 AD 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 mm 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 AD. (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 in- compatibility 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.


Table 7. Q Values in Alzheimer's Disease Patients and Age-Matched Controls'

Regional Cerebral Metabolic Rate for Glucose (mg . 100 gm-' . min-')

Controlsb AD (mild-mod)' AD (severe)d mm Above

Brain Region IOMLine Left Rght Left Right Left Right

Frontal lobe Superior frontal gyms

Midfrontal g y ~ s

Inferior frontal gyrus

Cingulate gyrus Orbitofrontal gyrus Precentral gyrus

Paracentral lobule

Postcentral g y ~ s Parietal lobe

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 g Y N S

Hippocampal region Anterior medial

temporal gyrus Caudate nucleus Thalamus Lenticular nucleus h u l a cortex Cerebellum Centnun semiovale

. . . 80- 100 60-80 35-60 65-90 45-65 50-70 35-50 35-70 20-35 70-100 55-70 80-100 ... 70-100 55-70 70-100

45-70

65-80 . . . 45-65 30-45 15-30 45-70

. . . 30-45

15-30

5-15

20-35 20-35

35-55 40-50 35-55 40-60

0-15 70-90

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

1.12 f 0.11

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

0.96 t 0.13 1.10 f 0.15

0.94 f 0.16

0.82 f 0.14

0.97 f 0.21 0.82 f 0.13

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

1.18 f 0.10 1.08 f 0.20 1.13 f 0.12 1.13 f 0.14 1.08 f 0.12 1.19 f 0.15 1.05 2 0.27 1.10 f 0.27 0.99 f 0.27 0.97 f 0.27 1.18f 0.11 1.05 f 0.22 1.12 f 0.21 1.19 f 0.38 1.16 f 0.21 1.16 f 0.12 1.14 f 0.13 1.16 t 0.08 1.30 f 0.20 1.19 f 0.16 1.27 2 0.12 0.98 f 0.25' 1.09 f 0.21' 0.93 t 0.15' 0.89 t 0.16' 1.20 f 0.10 1.01 f 0.25' 1.08 f 0.19' 1.17 f 0.25' 1.03 f 0.12 1.25 f 0.12 1.06 f 0.26 1.16 t 0.17 1.07 f 0.08' 1.04 f 0.18' 1.22 f 0.12 1.08 f 0.27 1.15 f 0.13 1.20 f 0.18 1.12 f 0.13 1.22 f 0.09 1.25 f 0.10 1.25 f 0.10 1.30 t 0.22 1.30 f 0.22 1.07 t 0.17 1.02 f 0.25 1.08 f 0.13 1.05 t 0.19 1.05 f 0.15 1.29 f 0.14 1.26 f 0.13 1.24 f 0.16 1.16 f 0.28 1.11 -+ 0.30 1.27 f 0.13 1.24 f 0.09 1.29 f 0.15 1.37 1.35 1.27 f 0.11 1.23 f 0.21 1.23 f 0.21 1.27 f 0.05 1.27 f 0.05 1.21 f 0.12 1.03 f 0.16' 1.07 f 0.23' 0.84 f O . l l e 0.83 f 0.18' 1.23 f 0.12 1.20 f 0.15 1.25 f 0.22 1.18 f 0.22 1.17 f 0.30 1.20 f 0.16 1.31 f 0.01 1.33 f 0.01 1.18 1.14 1.20 f 0.15 0.93 f 0.21' 1.00 f 0.28' 0.71 f 0.18' 0.67 f 0.22'

1.16 f 0.13 0.98 +. 0.19' 1.02 f 0.25' 0.78 f 0.02' 0.80 t 0.03'

1.38 f 0.16 1.24 +- 0.31 1.24 f 0.35 1.13 f O.Ole 1.13 f 0.1G' 1.20 f 0.17 1.20 & 0.10 1.23 t 0.13 1.30 f 0.14 1.26 f 0.13 1.32 f 0.19 1.29 f 0.25 1.32 f 0.29 1.44 t 0.13 1.38 f 0.18

1.09 f 0.27 1 .082 0.14 1.08 f 0.13 1.16 f 0.16 1.09 f 0.05 1.22 f 0.16 1.27 & 0.28 1.27 f 0.28 1.38 t 0.15 1.38 f 0.15

1.21 f 0.17 ~1.16 -C 0.06 1.16 f 0.07 1.35 f 0.07 1.33 t 0.14

0.98 t 0.14 0.87 2 0.18 0.93 f 0.07 0.75 f 0.19' 0.93 f 0.01 1.12 f 0.18 0.87 -C 0.18' 0.93 f 0.12' 0.90 & 0.06' 0.73 f 0.1G'

0.95 f 0.18 0.86 * 0.14 0.89 f 0.08 0.86 f 0.10 0.73 f 0.01'

0.80 f 0.13 0.50 f 0.23' 0.68 f O.lle 0.79 0.37

0.97 2 0.21 1.09 2 0.16 1.16 t 0.13 1.34 f 0.26' 1.26 f 0.26 0.84 f 0.14 0.87 2 0.18 0.89 f 0.11 0.82 f 0.25 0.74 f 0.09

1.15 f 0.13 1.25 f 0.07 1.22 f 0.16 1.35 f 0.01' 1.42 f 0.05' 1.17 f 0.15 1.24 f 0.10 1.26 f 0.07 1.39 f 0.16' 1.29 f 0.05' 1.26 f 0.13 1.36 f 0.09' 1.42 f 0.12' 1.48 f 0.05' 1.50 f 0.01 1.31 f 0.13 1.19 f 0.16 1.28 f 0.12 1.32 f 0.16 1.30 f 0.04 1.01 f 0.21 0.99 f 0.17 0.97 f 0.03 1.14 f 0.25 1.17 t 0.17 0.56 0.17 0.58 * 0.13 0.71 f 0.21 0.38 0.38

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

- 2 0 (controls (1 age=llyrl

AD C i age=64yr mild moderate form1

0 AD IF age=70yr seve:e tormi

Rt) FRONTAL

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 sensitiv- ity 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 distin- guished 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).

PARIETAL TEMPORAL OCCIPITAL

Fig 3. Mean lobar Q values are shown for patients with both ihe mild to moderate and severe forms of Alzheime~s disease (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 dq- ferent 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


neurotransmitter substances [S, 91, including neu- ropeptides [24] , is required before a patient exhibits the associated cognitive changes found in AD. Re- duced 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 physiolog- ical aspects, and diagnostic history.

References 1.

2.

3.

4.

5 .

6.

7.

8.

9.

10.

11.

12.

Alzheimer A: Uber eine eigenartige Erkrankung der Hirnrinde. Alg 2 Psychiatr 64:1460-1480, 1907 American Psychiatric Association Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Dis- orders, ed 3. Washington, DC, American Psychiatric Associa- tion, 1980, pp 124-126 Ball MJ: Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients: a quantitative study. Acta Neuropathol (Bed) 42:72-80, 1978 Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry

Brun A, Englund E: Regional pattern degeneration in Alzheim- er’s disease: neuronal loss and histopathological grading. Histo- pathology 5:549-564, 1981 Brun A, Gustafson L Distribution of cerebral degeneration in Alzheimer’s disease: a clinico-pathological study. Arch Psychiatr Nervenkr 223:15-33, 1976 Chase TN, Foster NL, Fedio P, et al: Regional cortical dysfunction in Alzheimer’s disease as determined by positron emission tomography. Ann Neurol 15:S170-S174, 1984 Coyle JT, Price DL, DeLong M R Alzheimer’s disease: a disorder of conical cholinergic innervation. Science 2 19:1184-1190, 1983 Davies P Studies on the neurochemistry of central cholinergic systems in Alzheimer’s disease. In Katzman R, Terry RD, Bick KL (eds): Alzheimer’s Disease: Senile Dementia and Related Disorders. (Vol 7, Aging). New York, Raven, 1978, pp 453- 459 buara R, Grady C, Haxby J, et al: Human brain glucose utilization and cognitive function in relation to age. Ann Neurol

Duara R, Margolin RA, Robertson-Tchabo EA, et al: Cerebral glucose utilization, as measured with positron emission tomography, in 21 resting healthy men between the ages of 21 and 83 years. Brain 106:761-775, 1983 Ferris SH, DeLeon MH, Wolf AP, et al: Regional metabolism and cognitive deficits in aging and senile dementia. In Samuel D, Algeri S, Gershon S, et al (eds): Aging of the Brain (Vol 22, Aging). New York, Raven, 1983, pp 133-142

1141797-811, 1968

16:702-i13, 1984

13.

14.

15.

16.

17.

18.

19.

20.

Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198, 1975 Foster NL, Chase TN, Fedio P, et ak Alzheimer’s disease: focal cortical changes shown by positron emission tomography. Neu- rology (Cleveland) 33:961-965, 1983 Foster NL, Chase TN, Mansi L, et al: Cortical abnormalities in Alzheimer’s disease. Ann Neurol 16:649-654, 1984 Frackowiak RSJ, Pozzillic C, Legg NJ, et al: Regional cerebral oxygen supply and utilization in dementia: a clinical and psyclio- logical study with oxygen-15 and positron tomography. Brain

Friedland RP, Budinger TF, G a n z E, et al: Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with [18)fluorodeoxyglucose. J Com- put Assist Tomogr 7:590-598, 1983 Hachinski VL, Iliff LO, Zilkha E, et al: Cerebral blood flow in dementia. Arch Neurol 32:632-637, 1975 Hagberg R, Ingvar D: Cognitive reduction in presenile dementia related to regional abnormalities of the cerebral blood flow. Br J Psychiatry 128:209-222, 1976 Huang SC, Phelps ME, Hoffman EJ, et al: Noninvasive deter- mination of local cerebral metabolic rate of glucose in man. Am

1041753-778, 1981

J Physiol 238:E69-E82, 1980 2 1. Kuhl DE, Metter EJ, Riege WH, Phelps ME: Effects of human

aging on patterns of local cerebral glucose utilization determined by the [‘8F]fluorodeoxyglucose method. J Cereb Blood Flow Metab 2:163-171, 1982

22. Mattis S: Mental status examination for organic mental syn- drome in the elderly patient. In Bellak L, Katasu T (eds): Geriatric Psychiatry: A Handbook for Psychiatrists and Primary Care Physicians, Vol 7. New York, Grune & Stratton, 1976, pp 77-121

23. Mayer-Gross W, Slater E, Roth M: Clinical Psychiatry, ed 3. London, Balliere, 1969

24. Rossor MN: Neurotransmitters in CNS disease: dementia. Lan- cet 2:200-204, 1982

25. Roth M, Tomlinson BE, Blessed G: Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects. Nature 209:109-110, 1966

26. Rumsey JM, D w a R, Grady C, et al: Brain metabolism in autism: resting cerebral glucose utilization rates as measured with positron emission tomography (PET). Arch Gen Psychiatry (in press)

27. Schlageter NL, Horwitz B, Creasey H, et al: Measured gray matter cerebral metabolic rate for glucose (CMRglc) and cerebral atrophy are not correlated in a healthy aging population (abstract). Neurology (Cleveland) 35(suppl 1):232, 1985

28. Schwartz M, Creasey H, Grady CL, et al: Computed tomographic analysis of brain morphometrics in 30 healthy men, aged 21 to 81 years. Ann Neurol 17:146-157, 1985

29. Snedcor GW, Cochran WG: Statistical Methods. Ames, IA, Iowa State University Press, 1980

30. Tomlinson BE, Blessed G, Roth M: Observations on the brains of demented old people. J Neurol Sci 11:205-242, 1970

31. Wechsler D: A standardized memory scale for clinical use. J

32. Wechsler D: The Measurement and Appraisal of Adult Intelli- gence, ed 4. Baltimore, Williams & Wilkins, 1958

33. Wilson RS, Rosenbaum G, Brown G, et al: An index of premorbid intelhgence. J Consult Clin Psycho1 46:1554-1555, 1978

34. Yamaguichi F, Meyer JS, Yamamoto M, et al: Noninvasive regional cerebral blood flow measurements in dementia. Arch Neurol37:410-418, 1981

35. Zola-Morgan S, Squire LR, Mishkin M: The neuroanatomy of amnesia: amygdala-hippocampus versus temporal stem. Science

Psycho1 19187-95, 1945

2 18: 1337-1339, 1983


clinical history, brain metabolism, and neuropsychological function in alzheimer's disease

Documents