ELSEVIER S0197-4580(96)00036-X

Neurobiology of Aging, Vol. 17, No. 4, pp. 535-540, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved

0197-4580/96 $15.00 + .00

MR T 2 Relaxometry in Alzheimer's Disease and Age-Associated Memory Impairment

M. P. L A A K S O , * t K. P A R T A N E N , t H. S O I N I N E N , .1 M. L E H T O V I R T A , * M. H A L L I K A I N E N , * T. H A N N I N E N , * E.-L. H E L K A L A , * P. V A I N I O , t P. J. R I E K K I N E N , SR*$

*Departments of Neurology and ~Radiology, University Hospital and University of Kuopio, CA. L Virtanen Institute P.O. Box 1627, 70211 Kuopio, Finland

Rece ived 3 January 1995; Rev i sed 17 Apri l 1995; Accep ted 6 D e c e m b e r 1995

LAAKSO, M. P., K. PARTANEN, H. SOININEN, M. LEHTOVIRTA, M. HALLIKAINEN, T. H.~NNINEN, E.-L. HELKALA, P. VAINIO AND P. J. RIEKKINEN, SR. MR T 2 relaxometry in Alzheimer' s disease and age-associated memory impairment. NEURO- BIOL AGING 17(,*) 535-540, 1996.--A prolonged MR T 2 relaxation time was proposed to mark the presence and severity of Alzheimer's disease (AD). We studied the value of T 2 relaxometry in diagnosing early AD. T 2 was measured from 54 patients with AD, 25 subjects wilh age-associated memory impairment (AAMI), 18 elderly and 16 young controls. The AD patients had longer T 2 in the right hippoc~mpal head (104 _+ 11 ms) and tail (98 -+ 10 ms) than age-matched controls (95 +- 5 and 92 _+ 9 ms, respectively). This prolongation was not related to age. In the AD group, the T 2 of the left hippocampal head also correlated with the clinical severity. The T 2 of the amygdala did not differ across the groups. Increased T 2 in the temporal and parietal white matter and the thalamus related to increasing age r~Lther than to the diagnostic category. The AAMI subjects had T 2 comparable with those of age-matched controls. Despite the prolongation of T 2 in the AD group the possible diagnostic value was compromized by a substantial overlap between the study groups. We, Lhus, conclude that the T 2 relaxometry is not a reliable method for diagnosing early AD.

Age-associated memory impairment Alzheimer's disease resonance imaging T 2 relaxation time Thalamus

Amygdala Dementia Hippocampus Magnetic

THE hippocampus is known to be damaged in the early stage of AD (17). The volumetric measurement of the whole hippocampus on magnetic resonance imaging (MRI) scans has been documented to be a sensitive indicator of AD, even in mild stages of the disease (18,21,22,24). Most of the simpler linear and planimetric evalua- tions of the hippocampus have, however, been less accurate in differentiating AD patients from controls (9,25), but not all (37).

Recently, Kirsch et al. reported a prolonged hippocampal mag- netic resonance T 2 relaxation time in AD and a correlation be- tween T 2 and the clinical severity of the disease (23). The average hippocampal T 2 was up to 30 ms longer in the AD group than in controls. An ultra low field imager (0.04 T) was used for relax- ometry. In temporal lobe epilepsy, T 2 relaxometry of the hippo- campus, has also been shown to be a helpful tool for detecting hippocampal sclerosis (2,12,19).

We decided to study ~he usefulness of T 2 relaxometry in dis- tinguishing AD patients in the early stage of disease from controls in a large number of stud), subjects. We measured T 2 in the head, body, and tail of the hippocampus, in the temporal and parietal white matter at the corresponding levels, as well as in the amyg- dala and the thalamus. The data of the relaxometry was then cor- related to age and to a history of hypertension and coronary heart disease, and in AD patients to global clinical severity and perfor- mance on memory tests.

In addition to AD patients and two control groups of young and old cognitively intact individuals, we examined a group of nonde-

mented subjects with age-associated memory impairment (AAMI). The AAMI is a controversial entity. The AAMI group consists of elderly people who suffer from objectively and subjectively de- tected memory impairment, but who are not demented. Studies suggest that AAMI is more related to normal aging than it is to Alzheimer's disease (6,32,33). The AAMI category apparently in- cludes a large number of healthy elderly individuals as well as a minor proportion of subjects who are at a high risk for developing dementia.

SUBJECTS AND METHOD

We examined a total of 113 subjects: 54 patients (27 women, 27 men; mean age +_ SD, 70 _+ 8 years) fulfilling the NINCDS- ADRDA criteria of probable AD (29), 25 subjects (18 women, 7 men; 70 -+ 4 years) fulfilling the National Institute of Mental Health criteria of AAMI (6), 18 old controls (10 women, 8 men; 74 _+ 2 years), and 16 young controls (7 women, 9 men; 26 _ 7 years). The AD, AAMI, and old control groups did not differ significantly in age or gender.

The ethics committee of Kuopio University and University Hospital approved the study. All subjects provided their informed consent for participation in the study following an explanation of the study protocol.

The AD group The AD patients were evaluated in diagnostic examinations or

had been recently diagnosed in the Neurological Department of

1 To whom requests for reprints should be addressed.

535

536 LAAKSO ET AL.

Kuopio University Hospital. They underwent the following exami- nations: general physical and clinical neurological examination; assessment of clinical severity using Mini-Mental Status Exami- nation (MMSE) (11) and Clinical Dementia Rating scale (CDR) (16); an extensive battery of laboratory tests to exclude secondary causes of dementia; comprehensive neuropsychologic testing; EEG and event-related potentials; single photon emission com- puted tomography-scan; and MRI of the brain. All patients scored less than four in the modified ischemic scale (36). According to the CDR scale, 5 AD patients had questionable dementia [0.5], 34 had mild [1], and 15 had moderate [2] dementia. The mean MMSE _+ SD for AD patients was 22 + 4. Seventeen AD patients had a history of coronary heart disease and 10 had well-controlled hy- pertension.

The Controls

The AAMI group and the old controls were examined similarly. The investigation included clinical neurological examination, neuropsychological testing, EEG, event-related evoked potentials, and MRI. The young controls were healthy students or staff mem- bers volunteering for the study. Four AAMI subjects and one old control had coronary disease and four AAMI subjects and four old controls had hypertension.

Neuropsychological Tests

Verbal memory was examined with the list learning test using shopping items (14). A yes or no recognition of the words in the list was asked after a 30-min delay filled with other psychometric tests. We also used the story recall test with the Boston approach (30). The recall of the story was tested immediately and after a 30-min delay. Visual memory was tested immediately and after a 30-min delay by using the Heaton Visual Reproduction test (27)

MRI Imaging Technique and Measurement of T 2

The subjects were scanned with a 1.5 T Magnetom (Siemens, Erlangen) using a standard head coil. MRI measurements were done blind to the clinical data of the subjects. The method used for T 2 relaxometry was similar to that described by Jackson et al. (19). T 2 maps were calculated in each of four oblique coronal 8 mm sections from 16 images obtained at echo times of 22 to 262 using a Carr-Purcell-Meiboom-Gill sequence (CPMG). The interslice gap was 2.0 mm. The tilting angle was oriented at a right angle to the longitudinal axis of the hippocampus (Fig. 1A). The T 2 maps were generated by a computer program that fitted a single expo- nential to the signal intensity data of corresponding pixels from all 16 echoes after ensuring that there were no motion artifacts visible in the source images. The T 2 relaxation time was, thus, calculated for each pixel and an image was then constructed in which pixel intensity corresponded to the calculated T 2 relaxation time (Fig. 1B and C). The T 2 images thus generated were magnified by the factor of 2.3-2.5.

Mean hippocampal T 2 was measured within the anatomic boundaries of hippocampus by placement of the largest possible circular region of interest (ROI) with minimum 8, but typically 30-50 pixels (40-450 mm3), within the anterior, middle, and pos- terior sections corresponding to head, body, and tail of the hippo- campus, respectively. Boundaries where partial volume effects might occur, were avoided. Similarly the ROIs were placed on the amygdala (100 pixels, 125 mm 3, shown in anterior section in 98% of cases), the thalamus (100-150 pixels, 125-190 mm 3, in the posterior section in 83% of cases), and the temporal (50-70 pixels, 63-88 mm 3) and parietal (200 pixels, 250 mm 3) white matter in each of three sections from caudal to rostral (Fig. 1B and C).

A B

12

FIG. 1. (A) Sagittal scout image showing the alignment of the acquisition planes for T 2 maps. (B) T 2 map showing the regions of interest placed on the tail of hippocampus, thalamus and parietal and temporal white matter. (C) T 2 map showing the regions of interest placed on the head of hippo- campus, amygdala, and the parietal and temporal white matter.

Because the values do not represent basically any distinct anatomic locations, the relaxation times of temporal and parietal white mat- ter are presented in this article as average relaxation times of the anterior, middle, and posterior sections.

In order to study the stability of T 2, we did five repeated mea- surements of a normal volunteer within a 12-month period. The mean coefficient of variation was in different locations of the hippocampus and the amygdala 2.6% (range from 1.3-3.7%), in the thalamus 6.6% (6.4-6.8%), in the temporal white matter 6.8% (6.3-7.2%), and in the parietal white matter 3.4% (3.0-3.8%).

Statistical Analysis

The data were analyzed by utilizing SPSS-PC+ V.4.1 software. Analysis of variance (ANOVA) with Duncan post hoc analysis was used to compare the means over the study groups. For those T2 times that were significantly different across the study groups, ANOVA adjusted for presence of hypertension and coronary heart disease was performed. Correlations between T 2 and age, and in the AD group, between hippocampal T 2 and MMSE scores and memory test scores were calculated using two-tailed Pearson's correlation test. The hippocampal T 2 for AD patients classified by the CDR scale were tested by using ANOVA and Duncan posthoc analysis. The results are expressed as mean + standard deviation (SD). The level of statistical significance of differences is p < 0.05.

RESULTS

Table 1 presents the results of the relaxometry. ANOVA showed significant differences in relaxation times of the right hip- pocampal head (p < 0.01) and tail (p < 0.05) over the study groups; AD patients differed from OC (head) and from OC and AAMI (tail). For T 2 of the right hippocampal head that showed the most clear significant difference, the 95% confidence intervals of the

M R T 2 R E L A X O M E T R Y IN A L Z H E I M E R ' S D I S E A S E 537

T A B L E 1

T 2 RELAXATION TIMES (ms) FOR ALZHEIMER PATIENTS (AD), SUBJECTS WITH AGE-ASSOCIATED MEMORY IMPAIRMENT (AAMI), OLD CONTROLS (OC), YOUNG

CONTROLS (YC)

Region (n) AD AAMI OC YC ANOVA p

HHR(98) 1 0 4 - + l l t 100-+ 9 95-+ 5 97-+ 9 ** HH L (99) 101 + 10 98 -+ 7 95 + 6 98 -+ 10 NS H B R ( l l 3 ) 96-+ 8 96-+ 6 93-+ 7 96-+ 9 NS HBL(112) 96-+ 9 93_+ 8 94-+ 6 95-+10 NS H T R ( l l l ) 98-+10:~ 94-+ 8 92-+ 9 96-+ 6 * H T L ( l l l ) 96-+10 92-+10 97-+ 7 94-+ 9 NS A R ( l l l ) 97-+10 99-+ 7 97_+ 9 96-+ 8 NS A L ( l l l ) 96-+12 96-+ 7 92-+ 9 96-+ 8 NS 'I'V~M R (94) 80 -+ 6 80 _+ 4 80 -+ 7 76 -+ 5 NS TWM L (94) 81-+ 6§ 80+_ 4 82-+ 6§ 77-+ 5 * PWM R (95) 92 -+ 13§ 90 _+ 5§ 93 -+ 16§ 82 +- 4 ** PWML(95 ) 93-+12§ 90_+ 5§ 92-+11§ 82-+ 5 * T R(94) 82-+ 7§ 82-+ 7§ 81-+ 7 77-+ 4 * T L(78) 84-+ 9§ 82-+ 8§ 82-+ 8 77-+ 4 *

Results are mean -+ SD. HH = hippocampal head; HB = hippocampal body; HT = hippocampal tail; A = amygdala; TWM = temporal white matter; PWM = parietal white matter; T = thalamus; R = right; L = left. ANOVA over the study groups, *p < 0.05, **p < 0.01; Duncan? differs from OC, ~t differs from OC and AAMI, § differs from YC at the 0.05 level.

m e a n s were 95 .7 -101 .2 has for AD, 90 .6 -96 .8 m s for A A M I , 87 .4-95 .9 m s for OC, and 92 .9 -99 .3 ms for YC groups. The T 2 o f a m y g d a l a did not differ be tween the groups. The average T 2 o f CSF of 14 m e a s u r e m e n t s f r om lateral ventr icles was 2214 _+ 544 m s .

In A D patients , the T 2 o f left h ippocampal head correlated s ignif icant ly with the M M S E scores (r = -0 .44 , p < 0.01) (Fig. 2). Table 2 and Fig. 3 show tllat T 2 for the A D pat ients of C D R stages 0,5, 1, and 2 and for O C 6iffered s ignif icant ly in the h ippocampa l head and tail; the A D pat ients with modera te demen t i a differed f rom OC and A D pat ients with mi ld disease. In A D patients, the relaxat ion t imes did not correlate to m e m o r y test scores (data not shown) .

T2 (ms) in left hlppocamp•l head 140

120

100

8O

60

40

20

0 12

• •

• • • v w • e

• • •

r : -0 .44, p<O.01

I I I I I I I I

14 16 18 20 22 24 26 28 30

MMSE •core

FIG. 2. Correlation between T 2 relaxation times of the left hippocampal head and Mini-Mental Status Examination scores (MMSE) in Alzheimer patients.

The T 2 o f the temporal white mat ter on the left was signifi- cant ly pro longed in A D and OC groups ( A N O V A / D u n c a n , p < 0.05) and the parietal re laxat ion t imes in all old groups were pro- longed compared to y o u n g controls (p < 0.05). The T 2 o f the tha lamus was also s ignif icant ly pro longed in the A D and A A M I groups on both sides (p < 0.05) than in the YC group. In A A M I , the T 2 in the s tructures s tudied did not differ s ignif icant ly f rom old controls.

The d i f ferences in re laxat ion t imes r ema ined s igni f icant in A N O V A adjus ted for a his tory o f hyper tens ion and coronary hear t disease. W e found no s ignif icant correlat ions be tween age and h ippocampa l T 2 (Fig. 4). Thus , the prolongat ion o f the T 2 in hip- pocampa l head and tail in A D pat ients was not expla ined by age or presence o f vascular diseases . In contrast , T 2 in the tempora l and parietal white mat ter was s ignif icant ly related to age in the whole s tudy popula t ion and in n o n d e m e n t e d subjects (AAMI , OC, YC), with r rang ing f rom 0.27 to 0.45 (p < 0.01) (Fig. 5). Therefore , increased T 2 in cortical white mat te r is expla ined by age rather

T A B L E 2

HIPPOCAMPAL T 2 RELAXATION TIMES (ms) FOR ALZHEIMER PATIENTS STRATIFIED ACCORDING TO THE CLINICAL DEMENTIA RATING (CDR)

Region CDR 0.5 CDR 1 CDR 2 OC ANOVA p

HH R 107-+15I" 101-+10 109-+ 11:~ 95 -+ 5 ** HH L 96-+ 6 98 + 10 108-+ 10§ 95 -+ 6 ** HB R 98 _+ 8 95 -+ 8 100 -+ 9 93 -+ 7 NS HB L 94 -+ 10 97 -+ 9 96 -+ 7 94 -+ 6 NS H T R 98 -+ 9 97 -+ 8 101 -+ 131" 92 -+ 9 * HT L 99 -+ 10 93 -+ 7 102 -+ 12§§ 97 -+ 7 *

Results are mean __. SD. HH = hippocampal head; HB = hippocampal body; HT = hippocampal tail; R = right; L = left. ANOVA over the study groups. *p < 0.05, **p < 0.01; Duncan p < 0.05, ? differs from OC;

differs from CDR 1 and OC; § differs from CDR 0.5, CDR 1 and OC; §§ differs from CDR 1.

538 LAAKSO ET AL.

T2 (ms) in left hippocampal head 140

120

100

80

60

40

20

0

!

CDR 0.5 1 2

Alzheimer AAMI OC YC

FIG. 3. Scattergram ofT 2 relaxation times of the left hippocampal head for Alzheimer patients (AD) with questionable (0.5), mild (1), and moderate (2) dementia according to the Clinical Dementia Rating scale, subjects with age-associated memory impairment (AAMI), old controls (OC), and young controls (YC). ANOVA/Duncan; *p < 0.05, AD patients with moderate disease differed from those with mild disease and from AAMI, OC, and YC groups.

T2 (ms) in right h ippocampal head 140

120

100

80

" edp • •

• Ib •

• " " I L e , A

° • • •

r=0.15, p>0.05

60 J I I I i I i 10 20 30 40 50 60 70 80 90

Age (years)

• AD " AAMI " OC * YC

FIG. 4. Correlation between age and T 2 relaxation times of the right hip- pocampal head.

T2 (ms) in right parietal white matter

140

120

100

80

6 0 i i

10 20 30 90

• ml

.

t

r=0.43, p<0.0001

I I I r [

4 0 5 0 6 0 7 0 8 0

Age (years)

• AD " AAMI " OC * YC

FIG. 5. T 2 relaxation times of the fight parietal white matter correlate significantly with age.

than by the diagnostic category or by a history of hypertension and coronary heart disease.

DISCUSSION

We found a significant prolongation of T 2 in the right hippo- campal head and tail that was not explained by high age or pres- ence of vascular disorders. In AD, the global clinical severity correlated with T 2 of the left hippocampal head. The prolonged T 2 was seen in AD patients with moderate disease, whereas values for those in the mild stage were comparable to those of controls. No significant side-to-side differences were discovered, nor was there any segmental pattern of T 2 values in the three anatomical regions of the hippocampus. The T 2 in temporal and parietal white matter, as well as thalamus, seemed to reflect aging rather than diagnostic category. Even though differences in Z 2 w e r e found, the diagnostic value was compromised by considerable overlap between the study groups. Interestingly, most of the overlap, in terms of the confidence intervals, came from the YC group, and the least from the OC group. This unexpected finding may be random or then reflect vulnerability of the method to interference of some kind. Possible sources that affect the relaxation behavior are discussed below. The mean T 2 of atl the regions of the hippocampus in normal controls groups was comparable to those reported by Kit- sch et al. and Jackson et al. (19,23).

In addition to the prolongation of T 2 in hippocampus reported by Kitsch et al., a visually increased hippocampal T 2 signal in AD has been reported (10). On the other hand, when measured at 7 T in vitro, T 2 did not indicate the presence or severity of AD or vary

MR T 2 RELAXOMETRY IN ALZHEIMER'S DISEASE 539

between hippocampal subfields (15). T~ values measured at 0.08 T were reported to be similar for presenile AD patients and controls in the study of Christie et al. (5).

The T 2 (spin-spin or transverse relaxation) is dependent on numerous factors, such as observation frequency, temperature, mo- bility of observed spin, ancl presence of large molecules, paramag- netic ions and molecules, or other outside interference. In most tissues one component, usually water (or CSF), dominates the relaxation behavior. In the presence of two components with dif- ferent relaxation propertie,;, the quantitative interpretation is even more complicated (34).

Many pathologic conditions are known to produce alterations in factors that account for the observed relaxation behavior of tissues. The most importar~Lt of these is the presence of CSF in the region. There are many possible reasons for this such as hippo- campal fissure and/or unc, al sulcus, developmental cyst (4), in- creased CSF in atrophying region, lacunae, and edema. Another common cause of prolonged T 2 is gliosis or glioma (3). In AD, the chronic inflammation resulting from the accumulation of amyloid is known to produce microgliosis and astrocytosis (28). The T 2 arising from microgliosis and astrocytosis might be difficult to interpret: the signal of astrocytosis might increase the overall sig- nal whereas T 2 might be shortened due to iron in microglia, senile plaques, or neurofibrillary tangles in the hippocampus (1, 8, 26). Further possibilities are normal variations between subjects and within one individual, anct variations caused by anatomical posi- tion or machine drift (13), pharmaceuticals (21), hamartoma, vas- cular malformations, nonspecific calcification, scarring (3), flow artifacts, volume averaging, observer variation, poor image qual- ity, or differences in imaging parameters. It is noteworthy that T 2 of the hippocampal body did not show differences between the groups. This might be due to the fact that, when using proper

tilting, the body does not curve. In fact, it may be possible, that when measuring more irregularly shaped atrophied head or tail, partial volume averaging of CSF might occur. However, because the underlying sources of the T 2 are not yet determined, it is also possible that the T 2 signal arises from factors that are independent of those producing the atrophic changes.

The contradictory results of our study compared to the study of Kirsch et al. might be partly explained by our larger sample size and the fact that most of the patients in the present study had mild dementia. Prolongation of the hippocampal T 2 was not seen until in moderate dementia showing that the measurement of hippocam- pal T 2 does not help in diagnosing mild AD. Also, in the present study we used a 1.5 T imager compared to a 0.04 T imager used in the study by Kirsch et al. A 1.5 T imager has a better signal- to-noise ratio. Thus, it is possible that a low signal-to-noise ratio would result in noisy T 2 maps. Consequently, it might be easier to avoid CSF in the measured ROI at high field. The field strength should not affect the interpretation of T 2 as much as it would affect that of T] (34). Methodologically, the CPMG sequence used in our study is adequate (35). In this study, the overlap between the groups was substantial and we, thus, conclude that the T 2 relax- ometry of the hippocampus or other structures studied here is not reliable in diagnosing AD at its early stage. It remains to be ex- plored whether T 2 is prolonged in vascular dementia, where hip- pocampal sclerosis, leukoencephalopathy, and multiple lacunae are found (7), or in more rare dementias, where, for example, Lewy bodies and gliosis constitute the major pathologic findings.

ACKNOWLEDGEMENTS

This study was supported by the Medical Research Council of the Academy of Finland and the North-Savo Fund of the Finnish Cultural Foundation.

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