and sex on the kinetics of intravenously administered L-phenylalanine. Clin Chem 1982;28:204-206.

32. Rose DP, Cramp DG. Reduction of plasma tyrosine by oral con- traceptives and oestrogens: A possible consequence of tyro- sine aminotransferase induction. Clin Chim Acta 1970;29:49-53.

33. Westwood A, Raine DN. Heterozygote detection in phenyl- ketonuria. Measurement of discriminatory ability and interpre- tation of the phenylalanine loading test by determination of the heterozygote likelihood ratio. J Med Genet 1975;12:327-333.

34. Rampini S, Anders PW, Curtius HCh, Marthaler TH. Detec- tion of heterozygotes for phenylketonuria by column chroma- tography and discriminatory analysis. Pediatr Res 1969;3:

35. Saraiva JM, Seakins JWT, Smith I. Plasma phenylalanine and tyrosine levels revisited in heterozygotes for hyperphen- ylalaninemia. J Inherit Metab Dis 1993;16:105-109.

36. Leeming RJ, Blair A, Green A, Raine DN. Biopterin deriva- tives in normal and phenylketonuric patients after oral load of

287-297.

L-phenylalanine, L-tyrosine and L-tryptophan. Arch Dis Child 1976:51:771-777.

37. Dhondt JL, Farriaux JP. Relationships between phenylala- nine and biopterin metabolism. In: Wachter H, Curtius HCh,

Pfleiderer W, eds. Biochemical and clinical aspects of pteri- dines. Berlin: Walter de Gruyter, 1982;1:318-328.

38. Dhondt JL, Lerox B, Farriaux JP, Largilliere C, Leeming RJ. Dihydrobiopterin biosynthesis deficiency. Eur J Pediatr 1983;

39. Alas T, Be1 Y, Cabello ML, et al. Improved identification of heterozygotes for phenylketonuria using blood neopterin and biopterin. J Inherit Metab Dis 1993;16:457-464.

40. Danks DM, Schlesinger P, Firgaira F, et al. Malignant hyper- phenylalaninemia-clinical features, biochemical findings and experience with administration of biopterins. Pediatr Res

41. Tanaka K, Yoneda M, Nakajima T, Miyatake T, Owada I. Dihydrobiopterin synthesis defect: an adult with diurnal fluc- tuations of symptoms. Neurology 1987;37:519-522.

42. Knappskog PM, Flatmark T, Mallet J , Liidecke B, Bartholome K. Recessively inherited L-dopa-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum Mol Genet 1995:4;1209-1212.

43. Liidecke B, Dworniczak B, Bartholome K. A point mutation in the tyrosine hydroxylase gene associated with Segawa’s syn- drome. Hum Genet 1995;93:123-125.

141:92-95.

1979;13:1150-1155.

Volume loss of the hippocampus and temporal lobe in healthy elderly persons

destined to develop dementia J.A. Kaye, MD; T. Swihart, BS; D. Howieson, PhD; A. Dame, BA; M.M. Moore, BS; T. Karnos, BA;

R. Camicioli, MD; M. Ball, MD; B. Oken, MD; G. Sexton, PhD

Article abstract-Objective: To determine initial locus and rate of degeneration of temporal lobe structures (total lobe, hippocampus and parahippocampus) in preclinical dementia. Background: Postmortem studies suggest that the earliest changes in Alzheimer’s disease are neurofibrillary tangle formation in hippocampus and adjacent cortex. MRI volume analysis of temporal lobe structures over time in subjects prior to developing dementia may allow the identification of when these processes begin, the rate they develop, and which areas are key to symptom development. Methods: 30 nondemented (NOD), healthy, elderly individuals enrolled in a prospective study of healthy aging evaluated annually over a mean of 42 months. Twelve subjects with subsequent cognitive decline were assigned to the preclinical dementia group (PreD). All 120 annual MRI studies analyzed by volumetric techniques assessed group differences in temporal lobe volumes and rates of brain loss. Results: NOD as well as PreD subjects had significant, time-dependent decreases in hippocampal and parahippocampal volume. Rates of volume loss between the groups did not significantly differ. PreD cases had significantly smaller hippocampi when asymptomatic. Parahippocampal volume did not differ between PreD and NOD cases. Significant time-dependent temporal lobe atrophy was present only in PreD. Conclusions: Hippocampal and parahippocampal atrophy occurs at a similar rate regardless of diagnostic group. Those who develop dementia may have smaller hippocampi to begin with, but become symptomatic because of accelerated loss of temporal lobe volume. Temporal lobe volume loss may mark the beginning of the disease process within six years prior to dementia onset. NEUROLOGY 1997;48:1297-1304

Cognitive impairment in the elderly is highly preva- lent and is estimated to approximately double every five years after the age of 65.l This makes elderly

persons over 85 years of age particularly vulnerable to dementia. In an individual patient, it has been diffi- cult to determine whether mild memory complaints

From the Departments of Neurology (Drs. Kaye, Howieson, Camicioli, Ball, and Oken; and Mr. Swihart, Ms. Moore, and Ms. Karnos), Pathology (Dr. Ball), and Surgery and Medicine (Dr. Sexton), Oregon Health Sciences University; and the Portland Veterans Affairs Medical Center (Drs. Kaye and Howeison, and Ms. Dame), Portland, OR. Supported by grants from the Department of Veterans Af’fairs, the National Institute on Aging, the National Institutes of Health (AG08017), the Medical Research Foundation of Oregon, and the Alzheimers Research Alliance of Oregon. Received July 19, 1996. Accepted in final form November 14, 1996. Address correspondence and reprint requests to Dr. Jeffrey A. Kaye, Department of Neurology, CDW2, Oregon Health Sciences University, 3181 Sam Jackson Park Road, Portland, Oregon 97201.

Copyright 0 1997 by the American Academy of Neurology 1297

or examination-demonstrated memory deficits are the clinical manifestations of early dementia or part of a more benign aging process. In patients with the earli- est signs of dementia there is a predictable rate of progression to dementia of approximately 31% over two years.2 The underlying pathoanatomic substrate of these age-associated impairments is commonly local- ized to medial temporal lobe systems attributed to be critical for retrieval or recall of new information. Dis- ruption of this system is most prominently seen in the clinicopathologic entity called Alzheimer’s disease (AD).

In AD, pathologic studies have repeatedly demon- strated the predominant presence of lesions of neu- rons in the hippocampal system and adjacent cortex. This has led to the suggestion that the medial tem- poral lobe and particularly the hippocampus may be the primary and initial sites of injury in the disease, creating an early “hippocampal” demer~t ia .~.~ These retrospective studies have the inherent limitation of assessing the brain in individuals who were either identified during life as already demented or who were incidentally discovered to have the pathology associated with AD, but were historically thought to be cognitively intact. Thus, these studies make it difficult to determine the initial loci of pathologic change and their relationship to the trajectory of cognitive decline.

The ability to determine the earliest preclinical sites and rates of change of the clinicopathologic pro- cess of cognitive decline is particularly important in determining whether the initial changes are similar to aging, but differ only in the starting reserve upon which the pathologic process develops. Alternatively, if there is a separate locus and rate of decline that sets apart those destined to become clinically de- mented, then an early, preclinical identification of the onset of disease would be identified. From a clin- ical standpoint, the presymptomatic detection of ear- liest loci of damage would provide a unique tool to determine if putative treatments for AD altered the underlying disease process. Identified sites of early damage would also be useful for screening asymp- tomatic candidates such as members of genetically at-risk pedigrees for future preventative therapies.

Although prospectively studied incident cases are the ideal population to answer this question, there are methodologic difficulties in identifying suitable cases. Despite cognitive failure and dementia being relatively prevalent in the elderly population over 65 years, large numbers of subjects are required to identify incident cases in a prospective fashion. This sample size problem is confounded by the increasing prevalence of comorbid conditions that may affect the aging brain and cognition, thus clouding the at- tribution of changes to age alone. One approach to overcoming these difficulties is to study healthy pop- ulations at high risk for developing dementia. Among these populations are the oldest old, those 85 years of age or older, who have an approximate inci- dence of dementia of up to 27% per year, depending 1298 NEUROLOGY 48 May 1997

on the severity of dementia d e t e ~ t e d . ~ - ~ In those over age 84 years in the Oregon Brain Aging Study (OBAS),8-10 a longitudinal study of healthy brain ag- ing, we observed a 40% cumulative incidence of cog- nitive impairment after a mean follow-up period of 42 months. We took advantage of this high incidence group to study preclinical changes in brain volume by serially evaluating the brain MRI of all OBAS subjects who have had at least three annual scans while enrolled in the OBAS. An abstract of this work has been presented.ll

Methods. Subjects. Thirty nondemented (NOD) healthy elderly subjects were evaluated as part of the OBAS.gJo These consecutively enrolled subjects were selected from OBAS for this study for having had at least three or more consecutive MRI brain scans annually (mean scan number, four). All subjects were at least 84 years old at entry. All subjects were of European ancestry except for one who had Native American ancestry. Subjects were required to be functionally independent and to score 512 on the instru- mental activities of daily living section of the Older Amer- icans Resources and Services Multidimensional Functional Assessment and Questionnaire (OARS).’* Further entry criteria were scores of zero on the Clinical Dementia Rat- ing Scale,I3 224 on the Mini-Mental Status Examination (MMSE),14J5 511 on the Cornell Depression Scale,16 and 5 10 on the Geriatric Depression S~a1e . I~ There could be no history of major medical illnesses including diabetes, hy- pertension (seated blood pressure I 160/95 mmHg), an- gina, cardiac arrhythmia, chronic pulmonary disease, can- cer, major affective disorder, transient ischemic attacks, stroke, major head injury (loss of consciousness >15 min- utes) or other neurologic disease. Subjects were excluded if they had a prior history of cardiac or coronary artery sur- gery. There was no history of drug or alcohol abuse. Sub- jects took no medications with the following exceptions: vitamins, aspirin, thyroid hormone (with sustained euthy- roidism for one year before study) and estrogen. Subjects had never sought evaluation for cognitive or behavioral impairment and considered themselves mentally fit.

Twelve preclinical dementia (PreD) cases were identi- fied as those OBAS subjects who initially satisfied all the above inclusion and exclusion criteria, but who had clini- cally deteriorated as evidenced by a CDR score 20.5 or a MMSE score <24 on two consecutive semi-annual evalua- tions; two cases, each with one CDR score of 0.5, were conservatively included in this group because they died before a second consecutive 0.5 evaluation could be demon- strated. Clinical status was substantiated by a clinical evaluation including a collateral interview of a t least one person who had close contact with each case. Specific diag- noses for cognitive failure were made according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders As- sociation (NINCDS-ADRDA) criteria for probable or possi- ble AD18 and the California Criteria for probable or possi- ble ischemic vascular dementia.lQ

All subjects underwent an an- nual evaluation which included a Personal and Family History Questionnaire for collection of demographic data and medical history. The subjects’ education (highest level obtained), occupation and economic status,20 living ar-

Evaluation procedures.

rangement, health status, and self-reported memory status were determined and later verified by subject examination as well as by a collateral source. All subjects gave informed consent to participate in the project.

History and physical examinations were performed within two weeks of each MRI evaluation. At entry, a structured interview was conducted in which the medical history was reviewed and an assessment of the subjects’ mental status and mood state was made. The MMSE and the Neurobehavioral Cognitive Status Examination were administered,21,z2 and a quantitative, coded, neurologic ex- amination was p e r f ~ r m e d . ~ Individuals returned within one week for neuropsychological testingz0 and an MRI of the brain. Six months after each annual evaluation, a follow-up visit was completed during which the subjects’ health status was updated, the MMSE was administered and a CDR score was assigned after the collateral source interview.

MRI procedures. Scan protocol. MRIs were performed with a 1.5-T magnet. The imaging protocol used for each study consisted of continuous slice, multiecho, multiplanar image acquisition, with 4 mm-thick coronal slices, a 24 cm2 field of view using a 256 X 256 matrix, with two as the number of excitations (NEX). The brain was visualized using the following sequence: multiecho coronal sequence, TR = 3000 msec, TE = 30 and 80 msec. TI-weighted sagit- tal images centered in the midsagittal plane were used to orient the coronal plane. All brains were imaged with this protocol except the first nine scans acquired in the first year, which had a 2.5 mm gap. The coronal plane was determined as the plane oriented perpendicularly to a line drawn from the lowest point of the splenium to the lowest point of the genu of the corpus callosum on the midsagittal image. Analysis of the MR images was performed with computer-assisted techniques utilizing a program called REGION, developed for use with any Macintosh 6800X series computing equipment (Apple Computer, Cupertino, CA).

Four regions of interest (ROI) were analyzed: supratentorial intracranial cavity volume, temporal lobe tissue volume (without the hip- pocampal body or parahippocampal gyrus regions), para- hippocampal gyrus volume, and body of hippocampus vol- ume. Left and right sides of bilateral structures were analyzed separately. After all slices were analyzed, total pixel count for each ROI in the entire brain was deter- mined by summing the corresponding pixel count for each slice. Pixel count was converted to volume by multiplying the ROI cross-sectional area by the slice thickness.

The hippocampal and parahippocampal regions for all subjects were determined, by the same analyst, by outlin- ing the structures with a cursor directly on a computer display. To insure the least variable and the most reliable measurements of hippocampal volume, we restricted our analysis to the body of the hippocampus. The body of hip- pocampus was defined on the slice beginning at the level of the red nucleus and ending with the superior c0llicu1us.~~ The parahippocampal gyrus region was the first gyrus identified after the collateral sulcus. The intra-rater reli- ability of these measurements performed five times on five randomly chosen scans was: hippocampal body intraclass correlation coefficient = 0.90; parahippocampus intraclass correlation coefficient = 0.92. Five postmortem brains

Region of interest analysis.

were selected for individuals over 90 years of age to com- pare hippocampal premortem MRI volume with post- mortem volume, neuron, and neurofibrillary tangle counts using standardized morphometric technique^.^^ The mean age of this group was 97.5 2 3.6 years. The mean interval from MRI to death was 19 I 19 months. The correlation coefficients for the premortem hippocampal volume and post-mortem volume were 0.61. The postmortem volume correlation with neuron counts was 0.77, and with neurofi- brillary tangle counts, 0.63.

The intracranial (supratentorial cavity) volume was de- fined as all non-bone pixels beginning with the first slice in which the frontal poles were present and ending at the occipital pole. At the base of the brain, brainstem struc- tures were excluded from supratentorial structures by manually tracing those pixels to be excluded according to atlas-based rules. The temporal lobe volume was defined as all brain-assigned pixels beginning at the temporal pole and extending posteriorly to the slice where the temporal horn of the lateral ventricle formed the trigone. The lat- eral, inferior, and medial borders of the middle and poste- rior temporal lobes were easily discriminated by the adja- cent cerebrospinal fluid. On slices where temporal lobe was contiguous with or connected to adjacent brain (e.g., tem- poral stem), the temporal lobe was isolated by manually tracing a defining border based on strict, consistent rules. On these slices, a line was drawn from the most inferior and medial point of the vertical Sylvian fissure across to the transverse or choroidal fissure, and then connected to the outline of the CSF-bound medial temporal lobe.

The total supratentorial intracranial volume and tem- poral lobe volumes were determined with an automated technique called recursive segmentation built into the REGION analysis program. Within each slice, tissue types of interest are coincidentally sampled on the spatially reg- istered multiecho images by selecting a predetermined number of sample points (five) comprised of a 3 x 3 pixel sample within four tissue types: bone, brain (gray and white matter), CSF, and high signal intensity areas within the white matter.

The recursive segmentation is completed automatically by successively applying a discriminant function to the established tissue type sample intensities and “peeling” away or isolating regions of the image. Bone is first identi- fied and then stripped from the image leaving the intracra- nial contents for analysis. Subsequent discriminant func- tions are used to isolate brain and CSF. The discriminant procedure is repeated until all areas of interest within each given slice have been identified. The inter-rater reli- ability of the technique performed by three operators on the same set of five brain scans was: intracranial volume intraclass correlation coefficient = 0.98; temporal lobe in- traclass correlation coefficient = 0.97.

Statistical Analysis. Group characteristics a t entry were compared with t tests. Rates of change were calcu- lated by a linear regression analysis to determine a slope for each individual subject. These subject slopes were then combined to produce a mean group rate of change or slope. The group slopes were compared with an unpaired t test. Data was analyzed for volumes both with and without adjustment for intracranial cavity volume (dividing the region of interest volume by the intracranial cavity vol- ume). All statistical results were essentially identical; un-

May 1997 NEUROLOGY 48 1299

Table 1 Demographic characteristics of subjects

Age at entry Female (%)

Socioeconomic status

Education (years)

Duration of dementia diagnosis (months)

Duration of follow-up (months)

NOD n = 18

86.8 -+ 1.9*

55.6

45.6 t- 15.4

13.6 t 3.4

0

42.3 t 15.5

PreD n = 12

90.4 i 5.2

58.3

49.8 t 17.6

14.6 5 3.8

12.1 i 12.0

46.2 i 10.2

* Mean 2 SD; differs significantly from PreD group.

corrected values are given in the results section, unless noted. In order to determine which brain volumes best predicted group membership, a discriminant function anal- ysis was performed.

Results. Subject characteristics. Clinical and demo- graphic characteristics of the subjects are described in ta- ble 1. Because three of the PreD cases were centenarians, the groups significantly differed in age. All analyses were performed first with and then without the centenarians in the data set. There were no significant differences detected in any analysis as a result of including the centenarians. The subjects otherwise did not differ with respect to educa- tional level, socioeconomic status or duration of follow-up. There were statistically significant cognitive test score dif- ferences at entry which are of interest to the interpretation of the cerebral volume data presented in table 2. However, no subject met criteria for dementia at entry (all initially functioned independently, scored 0 on the CDR and above 25 on the MMSE). The PreD group showed consistent small declines in summary scores of cognitive screening and functional assessment tests at follow-up. The current dementia diagnoses of the 12 PreD subjects are: probable AD (n = 7), possible AD (n = 5) .

The total intracranial volume was not significantly different between groups (ta- ble 3) . Within groups there were no significant differences between the left and right hippocampal and temporal lobe volumes (see table 3) . The left parahippocampal volume

MRI region of interest analysis.

Table 2 Cognitiue and behavioral characteristics of subjects

was significantly larger than the right in both the NOD and PreD groups.

All subsequent analyses of volumes are described for left and right sides combined. Analysis of the differences in hippocampal volume demonstrated significant differences between groups in absolute volume at entry as well as at the final evaluation point (figure, A).

There were significant decreases in hippocampal vol- ume over time, but the rates of loss or slopes were essen- tially parallel. On the other hand, the parahippocampal volumes were not significantly different between groups at entry. Like the hippocampus, the rates of decline or slopes showed significant time-dependence which were not signif- icantly different between groups (figure, B). The initial temporal lobe volume was significantly different between the two groups (figure, C) when this region was corrected for intracranial volume ( p < 0.01), with a less striking difference when analyzed uncorrected ( p < 0.06). The NOD subjects showed no significant change in volume over time. The PreD group demonstrated a significant loss of volume over time.

In order to determine which volume best predicted fu- ture group membership, a discriminant function analysis was performed, entering those volumes that were signifi- cantly different between groups (initial hippocampal and temporal lobe volumes and the rate of change in temporal lobe volume) and age. All were significant predictors of subsequent dementia: hippocampal volume at entry (F = 14.5, p = 0.0007), temporal lobe volume at entry (F = 7.7, p = 0.0005), age (F = 7.6, p = 0.0013) and the rate (slope) of temporal lobe volume loss (F = 4.2, p = 0.0006). The initial hippocampal and temporal lobe volume in this model correctly classified 80% of all cases. Assuming a linear rate of volume loss in the PreD group of 1.3% per year, the PreD group are projected to have had approxi- mately the same mean temporal lobe volume as the NOD group six years prior to longitudinal study entry.

Discussion. We demonstrated that in a group of prospectively evaluated, healthy elderly there is a constant rate of hippocampal and parahippocampal volume loss regardless of whether one goes on to develop dementia. The percentage volume loss of the hippocampus and of the parahippocampus were al- most identical, suggesting that the medial temporal

NOD PreD

Visit one Alyear Visit one Ahear

MMSE (max. score = 30) 28.4 5 1.5 -0.1 i 0.6 26.9 % 2.0* -0.6 t- 0.St

NCSE modified (max. score = 85) 78.4 i 4.9 -0.4 i 1.5 73.6 t 7.6* -2.1 2 1.71 ADL ( m a . score = 18)

IADL (max. score = 14)

0.1 i 0.2 0.0 t- 0.1 0.0 ? 0.0

0.0 i 0.0 0.0 5 0.1 0.4 t- 1.0

0.3 t 0.4t

0.6 2 l.Ot

-0.3 i 0.6 Cornell 1.3 t 1.9 0.2 2 0.7 2.5 2 1.4

* Significantly differs from mean of healthy group at entry, p < 0.05. t Change is significantly different compared to healthy group, p < 0.03.

MMSE = Mini-Mental Status Examination; NCSE modified = Neurobehavioral Cognitive Status Examination, modified; ADL = activi- ties of daily living; IADL = Instrumental Activities of Daily Living; Cornell = Cornell Depression Scale.

1300 NEUROLOGY 48 May 1997

Table 3 Brain volumes

Intracranial Hippocampus Parahippocampus Temporal lobe volume

NOD Initial scan Left 0.66 2 0.09 1.72 f 0.33 52.81 2 5.74

Right 0.68 2 0.1 1.62 f 0.26 53.11 t 4.39

Total 1.34 t 0.26 3.35 t 0.47 105.92 t 8.88 1140.13 ? 102.5

Volume change per yr Left -0.017 t 0.025 -0.025 ? 0.045 -0.1 2 1.14

Right -0.011 t 0.027 -0.113 ? 0.304 0.13 t 1.99

Total -0.028 t 0.047 -0.072 2 0.081 0.01 t 1.67 3.04

% -2.09 -2.16 0 0.27

PreD Initial scan Left 0.59 t 0.09* 1.64 t 0.3 48.29 f 9.13

Right 0.57 t 0.06* 1.51 t 0.29 49.33 f 9.87

Total 1.16 t 0.1* 3.15 f 0.46 97.62 i 17.43 1138.45 5 155.31

Volume change per yr Left -0.014 t 0.013 -0.044 2 0.040 -0.465 i 1.55

Right -0.014 t 0.018 -0.035 f 0.051 - 1.02 ? 2.16

Total -0.027 t 0.023 -0.092 i 0.073 -1.236 2 1.431 0.94

% -2.33 -2.92 - 1.27t 0.08

Volumes are absolute value in cm3 (unadjusted for intracranial size). All volume changes were significant over time ( p < 0.01) except for temporal lobe volume in the NOD group.

* Significantly differs from mean of NOD group a t entry. For left hippocampus, p < 0.048; right hippocampus, p < 0.0014; total hip-

t Change is significantly different compared to NOD group, p < 0.05. pocampi, p < 0.0018.

lobe volume changes reflect a constant aging-related rate of deafferentation of the entorhinal cortex. De- spite these constant rates of volume loss in medial temporal lobe structures, in those destined to de- velop dementia, there were clear differences in the rate of volume loss in the remainder of the temporal lobe.

Because hippocampal and temporal lobe volumes were significantly different at entry between the NOD and PreD groups, but temporal lobe volume changed significantly over time only in the PreD group, we suggest that it is the superimposition of increasing loss of temporal association cortex upon a critically atrophic hippocampus that results in the emergence of clinical dementia in the oldest old. This observation is in keeping with recent clinical- pathologic correlations reported by Morris et al.25 in very early AD, as well as with the models of Braak and Braak26 and of Fewster et al.,27 suggesting the "spread" of Alzheimer pathology through the tempo- ral association cortex with progressive stages of dis- ease severity. Further supporting the relative pres- ervation of non-hippocampal temporal lobe in normal aging are several cross-sectional MRI studies of sub- jects across the adult age spectrum which have shown little or modest loss of total temporal lobe volume in control populations up to 80 years of age.28-30 The virtual absence of extrahippocampal vol- ume loss in our healthy elderly likely reflects the relatively short 42 month time span over which we

assessed these subjects, an interval that may be too brief to detect small volume decreases.

The data suggest that medial temporal lobe atro- phy is a necessary, but not sufficient condition for the development of dementia. The current data do not more precisely pinpoint the locus of change within the temporal lobe outside of the hippocampus and parahippocampus. Future studies are evaluating the role of individual divisions within the temporal association cortex or other regions that may accu- mulate AD pathology prior to onset of dementia symptoms.

Many cross-sectional comparisons have shown, as ours has, that hippocampal volume is significantly smaller in established dementia or AD patients when compared to NOD control s u b j e ~ t s . ~ l - ~ ~ Similar differences in volume between AD patients and con- trol subjects are reported for other regions of the medial temporal lobe (amygdala, parahippocam- pus)32,35,36 or the total temporal lobe volume.35,3s,39 Our current data is the first longitudinal, multipoint assessment of temporal lobe volumes reported in asymptomatic subjects, at high risk to develop de- mentia (the oldest old), who have also been followed until the stage of developing dementia.

Previous longitudinal structural imaging studies have relied on shorter time periods of observation and have compared subjects who already fulfill crite- ria for dementia or cognitive impairment with age- matched control subjects. Most of these studies have

May 1997 NEUROLOGY 48 1301

A) Hippocampal Volume - 1.7 7 m 5 1.6 1 v

No D -- --

- _ -- -I ---

- - - - -_ - -__ " 1.0 PreD !& 0.9

0.8' ' ' ' ' " " 1 2 3 4 5

EVALUATION

C) Temporal Lobe Volume -

- - W

- - - _ _ _ _ _ _ _ _ - - - - - - - - - - _ 105 3 9 - - - _ _ _ _ - _ _ - - - - - - _ - _

1 2 3 4 5

EVALUATION

used CT and thus have been unable to directly as- sess the hippocampal or parahippocampal volumes. Nevertheless, these studies are consistent with our data. For example, in a CT study of 32 subjects with memory complaints and minimal cognitive impair- ment, perihippocampal CSF volume ratings were an excellent predictor of subsequent dementia develop- ing in 23 of these subjects 4 years later.40 In younger AD patients with moderately severe dementia when compared to age matched control subjects, Shear et al.41 demonstrated that the greatest rate of change was in the Sylvian fissure CSF volume, as seen on CTs obtained a mean of 2.1 years apart. Jobst et al.42 demonstrated marked rates of decline of temporal lobe width on CT obtained annually with some AD patients followed for up to four years. The ability of these techniques to discriminate between demented and nondemented individuals, although good, is vari- able and may reflect the indirect assessment of dis- crete anatomic regions, the use of change scores or a limited number of assessment points, the stage of dementia relative to the time of scan, the age of subjects at entry, and diagnostic heterogeneity of the groups . 4 2 9

Aside from these few longitudinal CT studies of the medial temporal lobe, there have been numerous cross-sectional volumetric studies of AD patients compared to control subjects where the hippocam- 1302 NEUROLOGY 48 May 1997

6) Parahippocampal Volume - -$ - 4.5 -1

4-1 No 0

PreO 2.5 -

2 ' I " " " " 1 2 3 4 5

EVALUATION

Figure. Brain volume change over time in subjects cogni- tively stable (NOD) and in subjects who developed demen- tia (PreD). Initial hippocampal and temporal lobe volumes were significantly different between groups. The rate of change (slope) of temporal volume (C), but not hippocam- pal or parahippocampal volumes (A, B), was different be- tween groups.

pus, amygdala, or temporal lobe itself has been found to be significantly smaller in the demented group. These studies have consistently shown a cor- relation of the severity of dementia with the volume of interest implying that there may be detectable atrophy even at the earliest stage of disease. Whether this atrophy precedes the onset of clinical symptoms of dementia had not been directly ad- dressed prior to our present study. However, Golomb et al.44 showed that hippocampal atrophy ratings were significantly associated with mild memory im- pairment in NOD elderly. They speculated whether those subjects with hippocampal atrophy might go on to develop dementia. In a study comparing 16 sub- jects without memory complaints to 16 subjects meeting National Institute of Mental Health (NIMH) Workgroup criteria for age-associated memory im- pairment Soininen et al.46 did not find sig- nificant group differences in hippocampal or amyg- dala volumes. However, they did notice less hippocampal asymmetry in the AAMI group as well as smaller amygdala volumes in a subgroup of AAMI subjects with the lowest visual memory scores. None of these studies assessed the rest of the temporal lobe to determine if early extra-temporal lobe atro- phy was present in the memory failure groups. Follow-up study will be needed to determine whether these subjects will develop dementia.

Our data suggest that gross volume decreases in- dicative of pathologic changes associated with de- mentia can be observed several years before the on- set of clinical signs. The PreD group showed small but significant declines at follow-up in summary scores of cognitive screening and functional assess- ment tests, suggesting that the volume differences at entry were due to an ongoing, subclinical, cognitive decline and not an unrecognized bias of the two groups. Further, this difference suggests that like the volume changes identified on MRI, these individ- uals were already subclinically affected, despite be- ing fully independent and passing rigorous measures widely used to exclude the presence of dementia. Since both groups were free of vascular disease or risk factors for vascular disease, these results are not explained by the development of ischemic vascu- lar dementia. At this early stage the majority of these patients fulfill criteria closest to probable AD. Thus far, only three of these subjects have come to autopsy, a number too small from which to draw any meaningful clinicopathologic conclusions.

Although MRI volumetry is an indirect method of assessment of the neuronal status of brain struc- tures with aging, our data, as well as others, demon- strate that the method correlates well with neuron density or neurofibrillary tangle counts.47 Thus, the changes observed are likely to reflect ongoing and progressive histopathology in cases developing de- mentia. Because these techniques may be used as a surrogate of biological activity, they may find utility for monitoring disease activity longitudinally in liv- ing subjects. They may further be useful in identify- ing early cases of dementia for studies of treatment effects, as well as in identifying high risk popula- tions such as the oldest old for primary prevention trials. Once a treatment has begun, critical regions dependent on the stage of disease can then be as- sessed to detect therapeutic slowing of the disease process.

Acknowledgments The authors are grateful to F. Miller, D. Clark, and G. Murdoch for neuropathologic assistance; S. Lehman and D. Wasserman for longitudinal assessments; and R. Guariglia for database manage- ment.

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Predictors of time to institutionalization of patients with Alzheimer’s disease:

The CERAD experience, Part XVII A. Heyman, MD; B. Peterson, PhD; G. Fillenbaum, PhD; and C. Pieper, DrPH

Article abstract-We studied the time to institutionalization (or death as the first event) in 727 white patients with Alzheimer’s disease (AD) enrolled in the Consortium to Establish a Registry for Alzheimer’s disease (CERAD). At the time of analysis, 417 patients had been admitted to nursing homes and 32 others had died without previous institutionaliza- tion. The major predictors of time to first event were sex, age, marital status (men only), and severity of dementia at entry into the study, as measured by activities of daily living, the Mini-Mental State Examination, and the Clinical Dementia Rating scale. The overall median time from enrollment in the study to first event was 3.1 years. For unmarried men, the median time was significantly less (2.1 years) than for either married men or for married or unmarried women, all of whom had medians greater than 3 years. In an analysis of survival time following institutionalization, we found that men survived a median of 2.1 years, compared with 4.5 years for women. This nationwide study of AD largely confirms earlier studies that reported on smaller numbers of cases from local catchment areas and included patients with various types of dementia. NEUROLOGY 1997;48:1304-1309

There have been a number of studies in the past decade reporting the factors predicting admission to nursing homes among elderly persons with Alzhei-

mer’s disease (AD) or other dementing disorders.’“ As expected, the predictive factors are complex, and include not only clinical and demographic character-

From the Divisions of Neurology (Dr. Heyman), Biometry (Drs. Peterson and Pieper), and the Center for the Study of Aging and Human Development (Drs. Fillenbaum and Pieper), Duke University Medical Center, Durham, NC. Supported by NIA Grant AG06790. Received October 7, 1996. Accepted in final form October 31, 1996. Address correspondence and reprint requests to Dr. Albert Heyman, Box 3203, Duke University Medical Center, Durham, NC 27710.

1304 Copyright 0 1997 by the American Academy of Neurology