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June 01, 1996; 46 (6) Article

Severity of hippocampal atrophy correlates with the prolongation of MRI T sub 2 relaxation time in temporal lobe epilepsy but not in Alzheimer's disease

A. Pitkanen, M. Laakso, R. Kalviainen, K. Partanen, P. Vainio, M. Lehtovirta, P. Riekkinen, H. Soininen
First published June 1, 1996, DOI: https://doi.org/10.1212/WNL.46.6.1724
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Abstract

We analyzed hippocampal volumes and T sub 2 relaxation times by MRI from 78 control subjects, 24 patients with temporal lobe epilepsy, and 55 patients with Alzheimer's disease (AD).In the epilepsy group, the hippocampal volumes were 27% smaller than in control subjects (p < 0.001). The T2 relaxation times were prolonged (8 to 20 ms compared with control subjects) in the head, body, and tail portions of the hippocampus on the focal side (p < 0.01) and also on the contralateral side (p < 0.05) compared with control subjects. In the epilepsy group, the prolongation of T2 relaxation time correlated inversely with the hippocampal volume (p < 0.05). In the AD group, the hippocampal volumes were 35% smaller than in control subjects (p < 0.01). The T2 relaxation times were slightly prolonged (5 to 6 ms) in the head and tail portions of the right hippocampus (p < 0.01), but the T2 relaxation times did not correlate with the hippocampal volumes. These data show that the degree of prolongation of T2 relaxation time is associated with severity of hippocampal atrophy in temporal lobe epilepsy but not in AD.

NEUROLOGY 1996;46: 1724-1730

Hippocampal atrophy is the most common pathologic finding in human temporal lobe epilepsy (TLE). [1] The underlying histopathologic damage includes loss of pyramidal cells in the CA1 and CA3 fields of the hippocampus proper and loss of interneurons in the hilus of the dentate gyrus. [2] The neuronal loss is accompanied by an increase in glial cells, in particular astrocytes, [3] and by sprouting of the axons of the surviving neurons. [4] When the volume of the hippocampus of patients with drug-refractory epilepsy is measured by MRI volumetry, the hippocampal volume on the focal side is approximately 50 to 85% of that in control subjects. [5-7] The reduction in the hippocampal volume correlates with the loss of hippocampal neurons if this loss is less than 50%. [8] MRI data also showed that T2 relaxation time, which is another quantitative measurement of tissue abnormality in the hippocampal gray matter, was prolonged in the hippocampus in 70% of the patients with drug-refractory TLE. [9] Temporary alterations in T2 relaxation time also occur after status epilepticus [10-14] and generalized seizures. [15] In the epileptic hippocampus, the prolonged T2 relaxation time may result from the increase in water content, gliosis, or drug effects. [9,16]

Significant atrophy of the hippocampus in MRI also occurs in other neurologic diseases such as Alzheimer's disease (AD). [17-21] Based on MRI volumetry, at the early stage of AD the loss in hippocampal volume is 30 to 40%. [17-22] The hippocampal T2 relaxation time was reported to be prolonged in AD by Kirsch et al. [23] Recently, Laakso et al. [24] reported, however, that hippocampal T2 was only mildly elongated. In AD, the underlying histopathologic findings for hippocampal atrophy include loss of pyramidal cells [25] accompanied by an increase in the number of astrocytes and also in microglia and oligodendrocytes as well as by the accumulation of plaques and neurofibrillary tangles. [26,27] Whether the differences in the underlying hippocampal histopathology between the TLE and AD predict different pattern of MRI findings has not been determined.

The molecular and histologic basis of T2 prolongation is poorly understood. Probably, the underlying pathology explaining the radiologic finding differs depending on whether the hippocampal atrophy is associated with the prolongation of T2 relaxation time. It is also unclear whether the prolongation in T2 time is associated with the severity of hippocampal atrophy in epilepsy and how specific the T2 prolongation is for epilepsy. In the present study, we address these questions by measuring the hippocampal volumes and T2 relaxation times in two groups of patients, patients with TLE and patients with AD, with hippocampal pathology. We first studied whether the hippocampal atrophy is accompanied by prolongation of T2 relaxation time and then studied whether the prolongation of T2 time correlates with the magnitude of loss of hippocampal volume in the two groups.

Methods.

Patients.

Measurements of the hippocampal volumes and T2 relaxation times were performed in three study groups: control subjects, patients with TLE, and patients with AD. The same observer (M.L.) who was unaware of patient group and the laterality of seizure focus analyzed all images.

The control group included 76 subjects (28 men, 48 women) with a mean age of 59.7 +/- 19.9 years. The younger control subjects were interviewed and the older control subjects were also tested neuropsychologically [28] to exclude neurologic diseases.

The patient group with TLE included 24 patients (12 men, 12 women) with a mean age of 39.4 +/- 10.4 years. Three patients were newly diagnosed, and 21 had drug-resistant chronic TLE. All patients included in the study had unilateral hippocampal sclerosis assessed by visual analysis of MRI and concordant unilateral EEG focus. In MRIs, we assessed hippocampal atrophy, loss of defined internal morphological structure, increased T2-weighted signal, and decreased T1-weighted signal. The diagnosis of hippocampal sclerosis was made if the hippocampus was atrophied or there was evidence of morphologic abnormality and signal abnormality of the hippocampus. In 17 patients, the EEG focus was defined by ictal registration. Eleven patients had focus on the right and 13 had focus on the left. The etiology for epilepsy was cryptogenic in 11 patients and remote symptomatic (vascular, hypoxic, traumatic, or infectious) in 13 patients. Twenty-two patients were on antiepileptic medication at the time of imaging.

The patient group with AD included 55 patients (28 men, 27 women) fulfilling the criteria of probable AD. [29] Their mean age was 69.9 + 8.3 years. The patients had mild to moderate dementia. They were undergoing diagnostic examinations or had recently been diagnosed. The comprehensive diagnostic workup was described previously in detail. [24]

MRI volumetry.

The method used to measure the hippocampal volumes was described previously. [28] Briefly, the subjects were scanned with a 1.5-T Magnetom (Siemens, Erlangen, Germany) by using a standard head coil and a tilted coronal three-dimensional gradient echo sequence (MP-RAGE: TR 10 ms, TE 4 ms, TI 250 ms, flip angle 12 degrees, FOV 250 mm, matrix 256 times 192, 1 acquisition). This gave 128 T1-weighted partitions with a slice thickness of 1.5 to 1.8 mm, which were oriented at right angles to the long axis of the hippocampus. The "hippocampal volume'' included the volumes of the dentate gyrus, hippocampus proper, and subicular complex (for details see [28]). The boundaries of the region of interest were outlined by a tractball-driven cursor on computer images that included the whole rostrocaudal extent of the brain region. The number of voxels within the region was calculated by using an in-house program developed for a standard work console. The intraobserver variability for the hippocampal volumes was 6.7%. [28]

T sub 2 relaxometry.

The method used for T2 relaxometry was similar to that described by Jackson et al. [9] T2 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. The interslice gap was 2.0 mm. The tilting angle was oriented at a right angle to the longitudinal axis of the hippocampus.

The T2 maps were generated by a computer program that fitted a single exponential 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 T2 relaxation time was thus calculated for each pixel, and an image was then constructed in which pixel intensity corresponded to the calculated T2 relaxation time. The T2 images thus generated were magnified by factors 2.3 to 2.5.

Mean hippocampal T2 was measured within the anatomical boundaries of the hippocampus by placement of the largest possible circular region of interest with a minimum of 8, but typically 30 to 50, pixels (40 to 60 mm3) within the anterior, middle, and posterior sections corresponding to the head, body, and tail of the hippocampus, respectively. Boundaries where partial volume effects might occur were avoided.

To study the stability of T2, we made five repeated measurements of a normal volunteer within a 12-month period. The mean coefficient of variation in different locations of the hippocampus was 2.6% (range 1.3 to 3.7%).

Statistical analysis.

The hemispheric difference between the volumes of the hippocampus (Delta HC) was calculated as the volume of the structure on the right minus the volume on the left. The hemispheric ratio (rHC) was calculated as the volume of the structure on the right/volume on the left. The Delta T2 and rT2 were calculated accordingly.

The data were analyzed using SPSS-PC+ V.4.1 software (Chicago, IL). The T2 relaxation times were analyzed by using MANOVA for repeated measures by group (control subjects, focus on the right, focus on the left, AD) times region (head, body, and tail of the hippocampus) times side (right, left). If the data met the assumptions of the test (Mauchly sphericity test p < 0.05), the univariate approach was used; if not, we used the multivariate approach and the Pillais test to show the significances. Accordingly, MANOVA for repeated measures by group times gender times side was used to analyze the volumetric data. In the post-hoc analysis, we used Duncan test to determine which groups differed from each other. Student's paired t test was used to analyze side differences within a group. Correlations were tested using linear regression analysis and two-tailed Pearson's correlation test. The results are expressed as mean +/- SD. The level of statistical significance of differences was set at p < 0.05.

Results.

Hippocampal volumes in different patient groups.

The volumes of the right and left hippocampi, Delta HC and rHC in different groups of patients, are summarized in Table 1. Men had larger hippocampal volumes than women regardless of group (gender times side interaction [F = 5.3 df 1, p < 0.05]; group times gender interaction [F = 0.1, df 1, p < 0.05]). The hippocampal volumes were smallest on the focal side in the epilepsy group (group times side interaction [F = 47.7, df 3, p < 0.0001]) Table 1. Results from the post-hoc analysis of volumetric data are summarized.

View this table:

Table 1. Volumes of the right and left hippocampus (HC), volumetric difference between the right and left hippocampus (Delta HC), and the right/left hippocampal ratio (rHC) in different patient groups

In control subjects, the right hippocampus was 7% bigger than the left (p < 0.001). The volumes of the hippocampi, Delta HC or rHC, did not correlate significantly with age.

In all patients with TLE, the volumes of the hippocampi were smaller than in the control subjects (right 72% of that in control subjects, left 71%; p < 0.05). In patients with TLE and focus on the right, the volume of the right hippocampus varied between 1,326 and 3,811 mm3, which was 70% of that on the contralateral side (p < 0.001) Table 1, 60% of that in the control subjects (p < 0.01), and 71% of that in patients with focus on the left (p < 0.01). The volume of the left hippocampus was also reduced, being 89% of that in the control subjects (p < 0.05). In patients with TLE and focus on the left, the volume of the left hippocampus varied between 1,047 and 2,735 mm3, which was 63% of that on the contralateral side (p < 0.01) Table 1, 57% of that in the control subjects (p < 0.01), and 64% of that in patients with focus on the right (p < 0.01). The volume of the right hippocampus was also smaller than that in the control subjects (85%; p < 0.05).

In patients with AD, the volume of the right hippocampus varied between 1,004 and 4,280 mm3 Table 1. The mean volume of the right hippocampus was 68% of that in the control subjects (p < 0.01) and 80% of that in epileptic patients with focus on the left (p < 0.01). The volume of the left hippocampus varied between 1,112 and 3,550 mm3. The mean volume of the left hippocampus was 64% of that in the control subjects (p < 0.01) and 72% of that in epileptic patients with focus on the right (p < 0.01). The right hippocampus was 13% larger than the left (p < 0.001).

T sub 2 relaxation times in different patient groups.

The T2 relaxation times were prolonged, in particular, in the epilepsy group, and the clearest T2 prolongation was found in the head of the hippocampus (group times side [F = 17.8, df 3, p < 0.001]; group times region [F = 4.0, df 6, p < 0.001]). Results from the post-hoc analysis are summarized below. For a table showing the T2 relaxation times in the different patient groups, see the Note at the end of this article.

In control subjects, the T2 relaxation times measured in the head, body, or tail of the hippocampus did not differ from each other. The length of T sub 2 was similar in the right (head 97.6 +/- 7.9 ms, body 94.8 +/- 7.2 ms, tail 93.7 +/- 7.6 ms) and left (head 97.9 +/- 7.7 ms, body 93.8 +/- 8.1 ms, tail 94.2 +/- 8.7 ms) hippocampi. T2 relaxation time, Delta T2, nor rT2 correlated with age. In all patients with TLE, the T2 relaxation times were prolonged bilaterally in the head (right 108.5 +/- 11.0 ms, left 107.3 +/- 12.8 ms), body (right 108.0 +/- 14.7 ms, left 104.8 +/- 11.1 ms), and tail (right 101.7 +/- 11.7 ms, left 99.2 +/- 9.3 ms) of the hippocampus compared with the control subjects (p < 0.05). On the left, the T2 relaxation times were also elongated in the body (p < 0.05), and on the right, in the head and body (p < 0.05) compared with patients with AD. In patients with TLE and focus on the right, the T2 relaxation times of the head (111.4 +/- 11.8 ms), body (115.5 +/- 11.3 ms), and tail (107.5 +/- 12.6 ms) of the right hippocampus were prolonged compared with the contralateral side (100.3 +/- 7.6 ms, 97.7 +/- 7.2 ms, 94.5 +/- 6.4 ms, respectively) (p < 0.05). They were also longer than those in the control subjects (p < 0.01), patients with AD (p < 0.01), and epileptic patients with focus on the left (p < 0.01). In patients with TLE and focus on the left, the T2 relaxation times in the head (115.1 +/- 13.3 ms), body (111.9 +/- 9.9 ms), and tail (104.0 +/- 9.6 ms) of the left hippocampus were also longer than those in the control subjects (p < 0.01) or in patients with AD (p < 0.01). The T2 relaxation time of the tail of the left hippocampus was prolonged compared with the contralateral side (95.9 +/- 7.5 ms) (p < 0.05).

In patients with AD, the T2 relaxation times of the head (103.4 +/- 11.0 ms), body (96.3 +/- 8.2 ms), and tail (98.5 +/- 9.7 ms) of the right hippocampus did not differ from that on the contralateral side (100.1 +/- 10.6 ms, 96.2 +/- 8.6 ms, 96.1 +/- 9.7 ms, respectively). On the right, the T2 measured in the head and tail portions of the hippocampus were slightly prolonged compared with the control subjects (p < 0.01).

Correlations between the hippocampal volumes and the T sub 2 relaxation times in different groups of patients.

The correlations between the hippocampal volumes and T2 relaxation times in different portions of the hippocampus (head, body, tail) are summarized in Table 2. The correlations between the Delta HC and Delta T2 (head, body, and tail) and rHC and rT2 (head, body, and tail) are shown in Figure 1.

View this table:

Table 2. Correlation between hippocampal volume and T2 relaxation times in different portions of the hippocampus (HC)

Figure

Figure 1. Top row: Correlations between the right-left differences in the hippocampal volumes (Delta HC) with the right-left differences in the T2 relaxation times (Delta T2) in different patient groups. The Delta T2 s were calculated from three levels of the hippocampus (head, body, and tail). Bottom row: Correlations between the right/left ratios in the hippocampal volumes (rHC) with the right/left ratios in the T2 relaxation times (rT2) in different patient groups. The rT2 s were calculated from three levels of the hippocampus (head, body, and tail). Note that in the epilepsy group, the decrease in Delta HC (smallest Delta HC was in patients with focus on the right and largest with focus on the left) correlated with the increase in Delta T2 (largest Delta T2 in patients with focus on the right and smallest in patients with focus on the left) of the head, body, and tail of the hippocampus. The decrease in rHC (smallest rHC was in patients with focus on the right and largest with focus on the left) also correlated with the increase in rT2 (largest rT2 was in patients with focus on the right and smallest with focus on the left) of the head, body, and tail of the hippocampus. Thin solid line = control subjects; thick solid line = epilepsy; dashed line = AD. AD = Alzheimer's disease; r = Pearson's correlation coefficient.

In control subjects, on the right, the increase in hippocampal volume was slightly positively correlated with the prolongation of the T2 in the head, body, and tail of the hippocampus Table 2. On the left, a slight positive correlation was found between the increase in the volume of the hippocampus and the prolongation of the T2 in the head Table 2. No correlation was found between Delta HC and Delta T2 (head, body, tail) or between rHC and rT2 (head, body, tail) Figure 1.

In the whole epilepsy group, the prolongation in the hippocampal T2 relaxation time (head, body, or tail) correlated with the decrease in the hippocampal volume on the right Table 2. Also on the left, the prolongation in the hippocampal T2 relaxation time (head, body) correlated with the decrease in hippocampal volume Table 2. The increase in Delta T2 correlated with the decrease in Delta HC of the head, body, and tail of the hippocampus Figure 1. The increase in rT sub 2 also correlated with the decrease in rHC of the head, body, and tail of the hippocampus Figure 1.

In patients with AD, the increase in the T2 of the body of the hippocampus on the left correlated slightly with the increase in the hippocampal volume Table 2. No correlation was found between the Delta HC and Delta T2 (head, body, tail) or rHC and rT2 (head, tail). A slight positive correlation was found between the rT2 and rHC in the body of the hippocampus Figure 1.

Discussion.

Previous histopathologic analysis of experimental and human epilepsy suggests an association between the number of seizures and the severity of neuronal damage in the epileptic brain. [7,30,31] Furthermore, the severity of the neuronal damage evaluated histologically correlates with the severity of the loss in volume measured by MRI volumetry in vivo. [8] Thus, MRI volumetry provides one method for determining the progression of neuronal loss in the epileptic brain in vivo. The loss of hippocampal volume may reflect the loss of neurons, but additional markers are needed to identify other neuropathologic aspects of the epileptic hippocampus, such as gliosis and axonal sprouting. In this study, we found that in patients with TLE, but not in patients with AD, the prolongation of the hippocampal T2 relaxation time correlates with the loss of hippocampal volume. This finding probably reflects differences in the underlying neuropathology of the hippocampal atrophy that occurs in these two diseases.

All our patients with TLE had visually assessed hippocampal sclerosis. In the MRI volumetry, we found the hippocampal volume on the focal side to be about 60% of that found in control subjects. Our results agree with previously published data from patients with drug-refractory epilepsy and a history of febrile seizures or infection. [5,6] In our study population, the volume of the contralateral hippocampus was reduced by 10 to 15% compared with control subjects, even though the EEG seizures had unilateral onset. This finding is in agreement with previous histologic, [32] volumetric MRI, [33] T2 relaxometry, [9,34,35] and MRI spectroscopy [36] data that showed damage in the contralateral hippocampus in a subgroup of patients with drug-refractory TLE.

To get information on whether T2 is abnormal focally or diffusely in the atrophied epileptic hippocampus, we measured the T2 relaxation times separately in the head, body, and tail of the hippocampus. The T2 relaxation times were prolonged by 10 to 20 ms throughout the rostrocaudal axis of the hippocampus on the side of the focus. The T2 relaxation time was also prolonged in the rostral portion of the contralateral hippocampus in cases where the primary focus was on the left. This agrees with our volumetric data, which indicated mild structural damage on the contralateral side. The prolongation of T2 relaxation times was most clear in the rostral portion of the hippocampus. This is in record with a previous histologic study that showed that the hippocampal damage was most severe in the anterior portion of the hippocampus. [37] Furthermore, we found a correlation between the degree of volume loss and the prolongation of T2 relaxation time. For example, in the correlation analysis between the left hippocampus and the T2 relaxation time measured from the head of the left hippocampus, the patients with the mildest damage to the left hippocampus (i.e., patients with the focus on the right) had the shortest T2 times. The patients with the most severe hippocampal damage on the left (i.e., patients with the focus on the left) had the longest T2 times. This suggests that the progression of pathologies underlying the loss of hippocampal volume and the prolongation of T2 relaxation time are associated.

In patients with AD, the hippocampal volumes were reduced symmetrically by about 35% compared with the control subjects. These data agree with the findings of previous studies. [17-20] The T2 relaxation times were slightly increased (5 to 6 ms) in the head and tail of the right hippocampus compared with control subjects. The increase in T2 was less than in the study of Kirsch et al., [23] who reported a 30-ms increase in the hippocampal T2 relaxation time in patients with AD and that the prolongation correlated with the severity of cognitive impairment. In the study of Kirsch et al., [23] however, only 13 AD patients were examined and 0.04-T MRI was used for imaging, which may partly explain the differences in findings. We found that the magnitude of T2 prolongation is smaller in patients with AD than in patients with TLE and found no correlation between the severity of hippocampal atrophy and the prolongation of T2 time, even though the range of hippocampal volumes and T2 relaxation times in AD was similar to that in control subjects or patients with epilepsy. This is probably related to the differences in the pathology underlying the hippocampal damage in AD and epilepsy.

The neuropathologic findings in the hippocampus of patients with TLE include the loss of pyramidal neurons and interneurons, gliosis, and sprouting of the axons of the surviving neurons. [38] Prolongation of T2 occurs in conditions with excess numbers of glial cells. [39] There is also evidence that in the epileptic hippocampus, prolongation of the T2 correlates with the density of glial cells. [40] Because the T2 was not prolonged in the presumably gliotic hippocampus of patients with AD included in the present study, the question arises: Is the gliosis in AD different from that in epilepsy? In AD, gliosis includes the accumulation of astrocytes, microglia, and oligodendrocytes. [25,41,42] In epilepsy, the astrocytes rather than microglia or oligodendrocytes are the most dominant type of glial cells described so far. [3,38,43] The microglia contains the iron-binding protein, ferritin. [44] Iron is also found in another iron-binding protein, lactotransferrin, which is associated with glia, neurofibrillary tangles, and senile plaques in the hippocampus of patients with AD. [45] A recent MRI study demonstrated increased iron in the caudate and globus pallidus of AD patients. [46] Iron decreases the T2 relaxation time in in vitro conditions. [47] There is also an inverse correlation between the concentration of iron and the length of T2 relaxation time in several regions of the human brain. [47-50] In AD, the accumulation of iron-containing proteins in the hippocampus may compensate for the prolongation of T2 relaxation time associated with gliosis.

In AD, the neuronal loss is accompanied by gliosis and by the accumulation of plaques and tangles. If the plaques and tangles were to decrease the T2 relaxation time, one would expect the T2 times in AD to be even shorter than in the control subjects. However, this was not found in the present or previous studies. [23,24] Furthermore, in a recent study with 7-T MR microscopy, the T2 relaxation time did not correlate with the size of the hippocampus or the numbers of plaques or tangles in AD. [51] In addition, about 10% of the patients with TLE had diffuse type of senile plaques in the hippocampus. [52] Thus, the data available provide evidence that some factor other than the number of plaques and tangles underlies the prolongation of T2 relaxation time.

Another explanation for the prolonged T2 relaxation time in the epileptic hippocampus could be related to seizure-induced edema. A recent report described T2 hyperintensity bilaterally in the occipital and parietal white matter (the hippocampus was not studied) after a single seizure or a small number of seizures lasting from 30 seconds to several minutes. [15] The edema secondary to the seizure-caused disruption in the blood-brain barrier was suggested to cause the increased T2. Our study population consisted mainly of drug-refractory patients. Thus, we cannot exclude the possibility that seizure-induced damage to the blood-brain barrier in the medial temporal lobe region may explain the prolongation in T2. However, we included one newly diagnosed patient in the study who had been seizure-free for 1 year. This patient had hippocampal atrophy, and the T2 relaxation time was clearly prolonged (120 ms), which suggests that, at least in this case, edema was not the major factor causing the prolongation of T2. Also, no significant correlation was found between the hippocampal T2 relaxation time and the frequency of seizures in the study of Grunewald et al. [53] The sprouting of the axons of surviving neurons (e.g., sprouting of granule cell axons or mossy fibers to the inner molecular layer of the dentate gyrus) and the antiepileptic medication [54] could also contribute to the prolongation of T2 in the epileptic hippocampus.

To summarize, the decrease in the hippocampal volume correlated with the prolongation in T2 relaxation time in patients with TLE but not in patients with AD. In TLE, the measurement of T2 relaxation time together with the hippocampal volume may provide new noninvasive tools for studying the severity and progression of hippocampal damage during the patient's lifetime.

Note.

Readers can obtain a table consisting of 2 pages from the National Auxiliary Publication Service, c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163-3513. Request document no. 05270. Remit with your order (not under separate cover), in U.S. funds only, $7.75 for photocopies or $4.00 for microfiche. Outside the United States and Canada, add postage of $4.50 for the first 20 pages and $1.00 for each 10 pages of material thereafter, or $1.75 for the first microfiche and $.50 for each fiche thereafter. There is a $15.00 invoicing charge on all orders filled before payment.

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