Age-Related White Matter Atrophy in the Human Brain WILLIAM MEIER-RUGE, JURG ULRICH, MARCEL BRUHLMANN, AND ELISABETH MEIER Division of Gerontological Brain Research, and Division of Neuropathology Institute of Pathology University of Basel CH-4003 Basel, Switzerland

INTRODUCTION In recent years magnetic resonance imaging detection of white matter changes in elderly patients has increased interest in age-induced white matter changes. In patients without neurologic or psychiatric abnormalities, age is an important predictor for white matter hyperintensities in magnetic resonance imaging.' However, the absence of clear neurologic correlates of white matter hyperintensities suggests that magnetic resonance imaging has limited clinical significance.2 In attempts to gain better understanding of these phenomena morphometric techniques have proved to be the optimal tool for objectifying rnorphologic changes in gray and white matter.' Few reports suggest that aging of the brain involves not only moderate shrinkage of the cortex and other gray matter structures but, and above all, loss of white matter.4.' Geula and Mesulam6 recently reported an agerelated loss in the density of cholinergic nerve fibers in the cerebral cortex, suggesting that atrophy of the white matter might be due to a decrease in the number of nerve fibers. However, as long ago as 1947, Max Burger' postulated that the decline in the volume of white matter could be the result of progressive water loss, reflected in enlargement of the ventricular system. There have been few reports describing morphometric investigations of white matter during normal brain aging.4.5*8-'o Moreover, their results are contradictory, and the studies suffer from methodological inconsistencies. In the investigations described below brains from subjects without neurologic or psychiatric disease were studied in respect of volume changes in cortex and white matter by morphometric investigation of the capillary network, followed by morphometric analysis of the number and density of myelinated nerve fibers, of the extracellular space, and of the total area of nerve fibers in the white matter.

METHODOLOGY Thirty-three brains from neurologically and psychiatrically intact autopsy cases aged between 15 and 93 years were investigated in 3 age groups (15-50 years, 51-70 years, and 71-93 years; FIG. 1). The precentral gyrus, gyrus rectus, and corpus callosum were selected for investigation. The capillary network was stained using a modified alkaline phosphatase reaction on 15-pm native cryostat sections." Nerve fibers were stained with p-phenylenediamine in formalin-fixed tissue and measured stereologically on semithin sections. 260

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The stereological measurements were performed using an Optic-Electronic Image Analyzer (ASBA-Leitz) and a software program designed specifically for the investigation by A. Schweizer (Computer Systems, Basel). This measures the number of capillary segments in randomly selected fields (40 pm?) (N), their total length (L) (by reducing to “skeleton”), and their total diameter (D) (FIG.2). A total of 15 measurement fields were analyzed ( 5 per brain section and area), yielding data on 400-500 capillary segments per brain structure. Mean intercapillary dis-

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FIGURE 1. Age structure of the material used for the measurement of the capillary network in the cortex and white matter of the precentral gyrus, gyrus rectus, and corpus callosum. In the white matter, nerve fibers were measured morphometrically in semithin sections stained with p-phenylenediarnine.

tance ( A AB, pm-?) was quantified using a separate computer program based on concentric dilatations of the capillary segments. It was defined as the radius of the dilated capillaries when total dilatation was 50% of the total surface area of the measurement field (FIG.2). This parameter therefore represents half the mean distance between neighboring capillaries and the geometrical radius of the volume of tissue supplied by them.

ANNALS NEW YORK ACADEMY OF SCIENCES

262

4 0

-

INTERCAPILIARI

DISTANCE [AA0]

DILATED C I U L W Y AREAS SO % OF THE Y A s U n f f i AREA

FIGURE 2. The morphometric parameters used

to

measure the capillary network in the

brain cortex and white matter.

The software program for morphometric study of the white matter measured the following in consecutive steps: extracellular space (pm2), total area of nerve fibers (pm2),number of nerve fibers > 1 pm, and size-category distribution of nerve fibers 1 p m in diameter (FIG.7) and to a lesser extent in nerve fibers with a diameter of 0.4-0.2 pm. (FIG.8).

DISCUSSION The results of morphometric investigation of the capillary network in the cerebral cortex of the precentral gyrus, rectal gyrus, and corpus callosum demon-

FIGURE 3. Methodological principles used for the measurement of nerve fiber parameters in brain white matter.

Gyrus p r u c m t r a l I s white u t t e r

c 0

b

Gyrum rocturn COrteX

FIGURE 4. Cross-correlation between age and the number of capillary segments in the corpus callosum, gyms precentralis, and gyrus rectus (A = 21-50 years; C = 71-100 years), showing an increase in capillary density with increasing age, particularly in the corpus callosum and subcortical white matter. The median value ( + ) is at the center of the circles.

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265

strate that age-induced atrophy is more a question of the white matter than of the ~ o r t e x . ~ . ’ I?t. takes ’ ~ the form of a drawing together of the capillary network and is the result of the loss of myelinated nerve fibers and expansion of the extracellular space. This increase in extracellular space in the white matter may be the reason

TABLE 1. Age-Dependent Morphometric Changes in Capillary Parameters in

Cerebral White Matter and Cortex Age Group (Group Mean) Parameter Corpus callosum Number of capillary segments/40 pm? Capillary length/pm’ Intercapillary distance (pm-?) Gyrus precentralis White matter Number of capillary segments/40 pm? Capillary length/pm2 Intercapillary distance (prn-?) Gyrus precentralis Cortex Number of capillary segments/4O pm? Capillary length/pm? Intercapillary distance (pm-’) Gyrus rectus White matter Number of capillary segrnentd40 pm? Capillary length/pm’ Intercapillary distance (pm-’) Gyrus rectus Cortex Number of capillary segmentd40 pm? Capillary lengthlpm’ Intercapillary distance (urn-?)

2 1-50 years (36.9 ? 10.7)

51-70 years (62.8 t 4.9)

71-100 years (78.7 t 6.6)

384.3

379.2

104.2

457.1 t 102.5

69.54 t 4.24 131.49 ? 21.66

80.03 t 1.34 118.62 2 14.92

2

85.0

63.46 t 2.25 135.32 12.90

*

117.7

468.1 2 114.6

69.22 ? 0.41 123.57 t 19.98

75.86 2 4.12 126.18 2 19.34

84.21 t 2.51 114.99 t 13.38

298.2

1495.8 t 290.8

1570.7 k 479.6

257.88 t 12.51 50.20 t 5.78

249.05 t 4.20 50.44 t 9.47

435.2 t 119.2

1513.1

2

234.12 t 6.24 50.73 t 7.45

480.6

2

175.6

423.6

2

492.5

2

?

209.2

66.73 k 6.14 115.95 t 25.12

76.66 ? 1.32 116.91 t 25.91

1225.9 2 421.4

1332.2

?

191.37 ? 7.21 60.87 t 15.73

224.46 56.58

2 15.11 ?

237.0 9.78

529.9 t 118.5 77.01 104.9

k ?

5.12 11.25

1272.2 t 359.0 203.58 58.22

?

2

17.77 12.24

for the increasing fluctuation in brain volume in old age, which may explain the considerable variation observed in CT scan. Considering that the volume of a myelinated nerve fiber is much greater than that of the nerve cell itself, it is obvious that nerve cell loss causing only moderate cortical atrophy will be significant at the level of the white matter.9 Thus, white

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FIGURE 5. Cross-correlationbetween age and intercapillary distance in the corpus callosum (A = 21-50 years; B = 51-70 years; C = 71-100 years), gyrus precentralis, and gyrus rectus (A = 21-50 years; C = 71-100 years). The median value ( + ) is at the center of the circles.

An age-dependent decrease is apparent in the corpus callosum and subcortical white matter, but not in the cortex.

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MEIER-RUGE el al.: WHITE MATTER ATROPHY

FIGURE 6. Morphometrically derived results for extracellular space and total nerve fiber area in the corpus callosum and precentral gyrus as a function of age.

n/um*

Corpus callosum

Gyrus precentralis

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35

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60

85

35

60 85 Age

FIGURE 7. The decline in total nerve fiber area in white matter of the precentral gyrus and corpus callosum is accompanied by a decrease in the number of myelinated nerve fibers larger than I p m in diameter.

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ANNALS NEW YORK ACADEMY OF SCIENCES

matter atrophy may be important as an indirect indicator of nerve cell loss in the cortex and brain stem ganglia.

SUMMARY Aging of the brain involves not only appreciable shrinkage of the cortex and other gray matter structures but above all loss of white matter. This could be due to a decline in the number of myelinated fibers or to a loss of water. To assess the role played by each of these factors we studied brains from 33 neurologically intact subjects at autopsy representing three different age groups: 15-50, 51-70, and 71-93 years. The precentral gyrus, gyrus rectus, and corpus

1.0-0.8 pin

0.8-0.6 pm

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0.4-0.2 pm

0.2-0.1 pm

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35 60 85

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FIGURE 8. Age-related changes in the percentage size class distribution of nonmyelinated nerve fibers smaller than I p m in diameter in the corpus callosum.

callosum were selected for investigation, with staining for alkaline phosphatase on native cryostat sections to visualize the capillary network, and staining for myelin on semithin sections for nerve fiber visualization. Atrophy was objectified by measuring the number of capillaries, the intercapillary distance, and capillary length, since the capillary network remains constant throughout normal life. A mean difference of 16-20% was found, representing white matter atrophy, between the oldest and youngest age-groups. The cortex of the corresponding gyri, on the other hand, showed a difference of less than 6%. Morphometric investigation of sections stained for myelin showed that the brains with a mean age of 78.7 6.6 years had 10-15% fewer myelinated fibers. This was only partly offset by an increase in the volume of extracellular space. Our findings show that the age-related decline in brain volume is much more a question of white matter atrophy than of brain cortex atrophy. White matter

*

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atrophy could be an indirect indicator of nerve cell loss, since the volume of a nerve cell is much smaller than its myelinated fiber. REFERENCES 1.

2. 3. 4.

9. 10.

11.

12. 13.

SULLIVAN. P., R. PARY,F. TELANG.A. HINDRIFAI& G. S. ZUBENKO. 1990. Risk factors for white matter changes detected by magnetic resonance imaging in the elderly. Stroke 21: 1424-1428. B. C. P. LEE, L. A. SAINT-LOUIS & M. D. F. ZIMMERMAN, R. D., C. A. FLEMING, DECK.1986. Periventricular hyperintensity as seen by magnetic resonance: Prevalence and significance. Am. J. Neurol. Res. 7: 13-20. MEIER-RUGE, W. 1988. Morphometric methods and their potential value forgerontological brain research. Interdiscip. Top. Gerontol. 25: 90-100. MEIER-RUGE, W., 0. HUNZIGER, U. S C H U L Z , H.-J. TOBLER& A. SCHWEIZER. 1980. Stereological changes in the capillary network and nerve cells of the aging human brain. Mech. Age. Dev. 14: 233-243. MEIER-RUGE, W. 1982. Age-induced changes of subcortical white matter. A morphometric investigation. Arch. Suisses Neurol. Neurochir. Psychiatr. 133: 249-250. 1989. Cortical cholinergic fibers in aging and AlzheiGEULA.C. & M. M. MESULAM. mer's disease: A morphometric study. Neuroscience 33: 469-481. BURGER,M. 1947. Die Alternsveranderungen des Gehirns und Nervensystems. I n Altern und Krankheit. Max Burger, Ed.: 118-126. George Thierne. Leipzig. 1980. Variation with age in MILLER,A. K. H., R. L. ALSTON& J. A. N. CORSELLIS. the volumes of grey and white matter in the cerebral hemispheres of man: Measurements with an image analyser. Neuropathol. Appl. Neurobiol. 6 119-132. ANDERSON. J. M., B. M. HUBBARD, G. R. COGHILL & W. SLIDDERS. 1983. The effect of advanced old age on the neurone content of the cerebral cortex. J. Neurol. Sci. 5 8 235-244. WENDER. M., H . HUDUK-HANTKE, A. GONCERZEWICZ & H. WYGLCADALSKA-JERNAS. 1988. Morphometry of myelin in the aging human brain. Neuropatol. Pol. 26: 9-18. MEIER-RUGE, W., W. BIELSER.JR., K. H. WIEDERHOLD & M. MEYENHOFER. 1971. Incubation media for routine laboratory work on enzyme histotopochemistry. Beitr. Pathol. 144: 409-43 I . HAUG,H. 1990. Morphometric evaluations of the aged human brain. Changes in the volume of various grays, in the neuronal composition and ultrastructure. (Proc. Xth Int. Congr. Neuropathol. Kyoto) Neuropathol. Suppl. 631-634. S. & T . MATSUZAWA. 1985. Age-related brain atrophy: A study with computed TAKEDA, tomography. J. Gerontol. 40: 159-163.

Age-related white matter atrophy in the human brain.

Aging of the brain involves not only appreciable shrinkage of the cortex and other gray matter structures but above all loss of white matter. This cou...
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