The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy

adults
C. DeCarli, MD; D.G.M. Murphy, MD; M. Tranh, BA; C.L. Grady, PhD; J.V. Haxby, PhD; J.A. Gillette, MA; J.A. Salerno, MD; A. Gonzales-Aviles, MD; B. Honvitz, PhD; S.I. Rapoport, MD; and M.B. Schapiro, MD
A r t i c l e abstract-Objectiue: To assess the association of MRI white matter hyperintensities (WMHI) with cognitive performance, cerebral structure, and cerebral metabolism in 51 healthy individuals aged 19 to 91 years without cerebrovascular risk factors. Background: Abnormal white matter signals have been associated with brain atrophy, reduced cerebral blood flow, focal neurologic signs, gait disorder, and poorer neuropsychological test performance. Most studies of WMHI, however, include subjects with hypertension or other identifiable causes of cerebrovascular disease that may have a n independent effect on brain structure and function. To assess brain changes associated with WMHI independent of cerebrovascular risk factors, we determined WMHI volume, brain volume, cerebral metabolism, and cognitive performance for a group of subjects free of medical illness. Regional cerebral metabolism and cognitive domains were also assessed to evaluate the possible role of frontal lobe dysfunction in subjects with WMHI. Design: Cross-sectional study of 51 very healthy subjects aged 19 to 91 years. Methods: WMHI, brain, and CSF volumes were determined by MRI segmentation. Neuropsychological tests were employed to assess multiple cognitive domains. Brain PET. Multivariate relations were tested with stepwise metabolism was determined from 18-fluoro-2-deoxy-~-glucose linear regression. Models included the potential confounders of age and education where appropriate. Results: The distribution of WMHI volume was bimodal, with five subjects having WMHI volumes beyond three SDs from the normally distributed population. A WMHI volume of greater than 0.5% of intracranial volume was considered abnormal. Within the multivariate models, WMHI volumes were significantly predictive of increased ventricular volume, reduced brain volume, and reduced cognitive scores. Subjects with greater than 0.5% WMHI volume also had significantly lower frontal lobe metabolism, significantly higher systolic blood pressure, significantly larger ventricular volume, and significantly lower scores on frontal lobe-mediated neuropsychological tests than age-matched controls. Conclusion: WMHI volume is associated with structural and functional brain changes even within a group of very healthy individuals. WMHI is associated with poorer frontal lobe cognitive function and, when severe, is accompanied by significantly reduced frontal lobe metabolism. Subjects with large WMHI volumes have significantly higher systolic blood pressure, brain atrophy, reduced cerebral metabolism, and lower scores on tests of frontal lobe function than age-matched controls. Large amounts of WMHI are, therefore, pathologic and may be related to elevated systolic blood pressure even when it is within the normal age-related range. NEUROLOGY 1995;45:2077-2084

Cerebral white matter hyperintensities (WMHI) seen with MRI occur with normal aging, and are more frequent in patients with hypertension and cerebrovascular disease.'S2 While WMHI are commonly observed, our understanding of how they affect cerebral structure and function continues to evolve. In the nondemented elderly, abnormal white matter signals have been associated with brain at-

r ~ p h y ,reduced ~-~ cerebral blood f l o ~ ,focal ~ - ~neurologic signs,g gait disorder,l0 and in some9J1J2 but not all13J4studies poorer neuropsychological test performance. WMHI may indicate the presence of ischemic vascular disease when seen in individuals with cerebrovascular risk factors or stroke,15 but the higher frequency of WMHI in healthy individuals over 50 years of age suggests that WMHI may also

From the Laboratory of Neurosciences, National Institute on Aging, and the Epilepsy Research Branch (Dr. DeCarli), National Institute on Neurological Disorders and Stroke, Bethesda, MD. Presented in part a t the 46th annual meeting of the American Academy of Neurology, Washington, DC, May 1994. Received November 22, 1994. Accepted in final form March 10, 1995. Address correspondence and reprint requests to Dr. Charles DeCarli, Laboratory of Neurosciences, Section on Brain Aging and Dementia, National Institutes of Health, Building 10, Room 6 c 414, Bethesda, MD 20892.
November 1995 NEUROLOGY 45 2077

Transmission images were obtained for attenuagional metabolism and cognitive domains to evalution correction. p < 0. The Wechsler Adult Intelligence Finally.29Frontal lobe-mediated tasks included the mance on tests of frontal function results from a digit symbol subtest of the WAIS.21The clinical and pathologic findand pixel intensities three or more SDs above the mean ings of WMHI on MRI are. a seven-section machine with a transverse resolution of 6 sociations between WMHI volumes. Arterial blood samples were dinal study of healthy aging at the Laboratory of Neurodrawn throughout the procedure for measurement of be a normal age-related p h e n ~ m e n o n . heart or cerebrovascular disease. The Wechsler verbal and performance sums of ropsychological test performance suggests frontal scaled scores were used instead of I& to avoid the conlobe dysfunction.3 F i r s t . Cleveland. cerebral metabolism. global associations with WMHI volumes. No WMHI in normal aging often include subjects with subject received medication within 2 weeks of evaluation. The double-echo pixel intenbrain abnormalities i n approximately two-thirds of sity histogram was modeled as a gaussian distribution patients studied.5-tesla imager (Picker Instruments.used volumes calculated as a percentage of total intracranial a qualitative rating of abnormal white matter. however.83. and a pixel intenropathologic studies of leukoaraiosis on CT find sity histogram recalculated. resulting of 19 and 91 years were selected from an ongoing longituin a total of 14 sections. ~ comparisons were performed on brain.3. or substance abuse were excluded. hyAxial images were analyzed using a double-echo sequence (TR 2. There have been consistent differences i n echo of the double-echo sequence to determine cerebral cerebral structure a n d cognitive performance when and hemispheric CSF and brain volumes. and WMHI functional expression.19~20 gion of interest (ROI) analysisz6 was applied to detert i v i t y of MRI t o d e t e c t WMHI m a y lessen the mine the volumes of the cerebral ventricles.000/20/80) according to previously pubpertension is associated with brain atrophy and relished method^. 'Subjects ~ with chronic medical illnesses including hypertension.25 WMHI volumes calculated by this method comparison across imaging modalities a n d may be are significantly correlated (r = 0. a n d neuropsychological test scores for each of these neuropsychological tests were used in the analysubject allowed us to examine the regional versus ses. Neuropsychology.3O the FAS word list generation task. and visuospatial ogy of this effect has yet t o be determined. Interrater reliabilities for this method have been egoric ratings of WMHI m a y not allow for valid published. All volumes were determined by ab1e. ~ Lack of definite conclusions regarding the pathophysiology and clinical significance of WMHI m a y reflect differences in b o t h subject selection and 2078 NEUROLOGY 45 November 1995 . A reSecond. disruption of complex cogniTest. hypertension. to use quantitative measures to assess a conwere placed in the imager with their eyes covered. The emissubjects with WMHI. All images pathophysiologic significance of WMHI when comwere filtered to exclude radiofrequency inhomogeneities.16-20 even i n tions were obtained from the foramen magnum to the subjects w i t h mild disease and w i t h o u t signifivertex. most s t ~ d i e s l .31and the Trail tive systems. MRI of the brain was performed on fect b r a i n s t r u c t u r e a n d function independent of a 0. Sweden). Catheters were t u r e . and cognitive perforplaced in a radial artery for drawing blood samples and mance i n the absence of cerebrovascular risk facin an antecubital vein for injecting the isotope. Subjects. Neu~ matter pixels of the second echo image. p a r e d w i t h a b n o r m a l w h i t e matter signals s e e n and segmentation analysis was performed on the first with CT. Acquisition of quantitative MRI. et all1 argue that the cognitive impairment induced Memory function was assessed by the Wechsler Memby WMHI is nonspecific. sion imaging was begun after a 45-minute uptake period. and then a bolus of 5 mCi of 18-fluoro-2ate the possible role of frontal lobe dysfunction i n deoxy-o-glucose was injected intravenously. psychiatric disorders. effects reerator-guided tracing techniques previously published.28the Porteus Maze multifocal. ~ . Subjects tors. neurologic. Neufunction. PET imaging was performed on a ScanThe purpose of this study was to examine the asditronix PC1024-7B tomograph (Uppsala." reconcile the differences counting the number of pixels identified within a given between WMHI detected by MRI and leukoaraiosis region and multiplying by the pixel voxel size (approxiseen on CT by suggesting that a threshold level of mately 6. CSF. National Institute on Aging.27all statistical ~ . if one agrees that WMHI adversely affect Scale (WAISlz8was administered to 47 of the 51 subjects the brain structure or f u n ~ t i o n .22x23 Some authors6. Catvolume. but partial. Third. history s t u d y methods. and laboratory ~ c r e e n i n g . brain s t r u c mm and an axial resolution of 10 mm. PET Making Test. To correct for individual differences in WMHI severity o n MRI must be p r e s e n t before head size on measures of brain volume. OH). ' . ears tinuous versus a threshold effect of WMHI on brain occluded.^^. the greater sensicantly more WMHI.7 mm3). parts A and B. PET imaging. more v a r i were considered WMHI.25After image subjects with leukoaraiosis on CT brain images are segmentation of brain from CSF was performed. Two interleaved images were obtained parallel to and 10 Methods.32Raw score values for each studies. but continuous.^^ Eighteen 7-mm-thick contiguous secduced cerebral metabolism of glucose.001) with opinsensitive t o subtle.~ J l Jpathophysiol~ to evaluate general intellectual. a n d to measure specific remask. The sum of scaled scores was combined as the indicator of tributed in the periventricular white matter. parallel to an estimated orbitomeatal line. the presence or extent of WMHI. verbal. Boone general intelligence.11J2 b u t WMHI are diffusely disfounding effect of age correction on the I& measure. Cerebrovascular risk factors can afQuantitative MRI. Fifty-one subjects between the ages to 100 mm above the inferior orbitomeatal line. Each subject underwent rigorous medical.sciences. National Institutes of Health. a n d that poorer perforory Scale. ~ ." vealed by quantitative measures. For example. and heads held in place by a thermoplastic structure a n d function. published r e p ~ r t s l ~ of ~ ' ~ ' of ~ head trauma. brain matter pixels of the first echo image were added to brain compared w i t h those without l e u k o a r a i o ~ i s .

With increasing volume of WMHI. Demographics. Age-related correlations are summarized in table 1. and cerebral metabolism. these WMHI were in the centrum semiovale superior and lateral to the body of the lateral ventricles. Stepwise linear multiple regression was used to test the independent predictive value of WMHI volume on brain volumes. temporal.1% of the intracranial volume.1 0 . and central CSF volume was examined in a model that included age as the other predictor variable. WMHI volume was predicted using suspected risk f a c t o r s ' ~ ~ of. plasma radioactivity and glucose concentration. Distribution of white matter hyperintensity (WMHZ) volumes expressed as percent of intracranial volume. which is more than * * three SDs from the mean of the other 46 subjects. Solid black line is a gaussian f i t to the data. The amount of independent variance for each predictor variable and the total variance of the model are given for each analysis. there were small WMHI within the subcortical white matter distinct from the lateral ventricle margins. and diastolic blood pressure. Regression analyses.0 1 0. The values within each vertical bar denote the decade of life for the number of subjects indicated.5%. immediate and delayed Wechsler verbal memory scores. Average intelligence for the subjects was a WAIS I& of 125 rt 12. Regional metabolic rates were obtained by averaging values in the circular regions that fell within anatomically recognized areas of the frontal. neuropsychological performance.5%. but not diastolic.0 1.4 0.0 and 0.9 1. The distribution of subject values is displayed in figure 1. blood pressure were significant independent predictors of WMHI volume. The remaining five subjects had volumes greater than 0. Forty-six subjects had WMHI volumes between 0.5 0.1 HYPERINTENSITY VOLUME (YOintracranial volume) Figure 1. Visual inspection of t h e MRIs showed t h a t the smaller WMHI volumes were located at the genu of the frontal and occipital horns of the lateral ventricles.8 0.age ~ and systolic and diastolic blood pressure.11 0. verbal sum of scaled scores from t h e WAIS. Statistics. Mean blood pressures were 124 * 14 mm Hg systolic and 78 * 9 mm Hg diastolic. WMHI values for these subjects appear normally distributed with a mean of 0.34 PET data were analyzed using a template composed of circular ROIs that were 8 mm in diameter (48 mm2).10%.6 0.7 0. Table 2 summarizes these findings.35 Whole-brain cerebral metabolic rate of glucose was calculated by averaging regional cerebral metabolic rate of glucose from cortical and subcortical gray matter regions. There were 25 women and 26 men. Since brain volumes were highly correlated with age. Betweengroup comparison of patients with large WMHI volumes and age-matched controls w a s performed w i t h t h e Wilcoxon signed rank test. The regression slope and upper and lower 95% confidence intervals were determined for the 46 subjects with WMHI volume less than 0. Significant age-related differences were found for each variable except the general measure of intelligence. cerebral brain volume. Age effects. a n d parietal lobes. In both cases. Regional cerebral metabolic r a t e s for glucose were calculated using a m ~ d i f i c a t i o n of ~~ t h e operational equation of Sokoloff et al. I n two subjects with the largest volumes of WMHI. Age and systolic.3 0.0 to 1. Men had significantly more educational achievement and significantly higher mean WAIS I& scores. Age-related differences were examined with Pearson correlation coefficients. Ordinal numbers within vertical bar segments indicate subjects' decade of life. Figure 2 displays the age-related differences in WMHI volumes. The volume of WMHI ranged from 0. with a mean age of 52 * 20 years a n d mean educational achievement of 16 2 years.SUBJECT NUMBER NORMAL DISTRIBUTION pq 0. there was spread of hyperintense signal around the body of t h e lateral ventricles. Both age and WMHI volume contributed sigNovember 1995 NEUROLOGY 45 2079 .4% of intracranial volume. FAS scores. Results. Subdivisions indicate the number of subjects by decade of age. the association between WMHI volume. Stepwise linear regression was used to evaluate the independent predictive value of multiple variables in the regression model. MRZ measures. The ROIs were spaced evenly throughout t h e cortical a n d subcortical regions.14 ( I ) U 0 U W 8 m I 6 0.2 0. Gray solid bars are total number of subjects at each interval WMHI volume.

First. WMHI volume.01).46 R = -0.5% of intracranial volume were removed from analysis. and cerebral metabolism as mg of glucosd100 g braidmin. educational achievement.23 R = -0. Blood pressure is expressed in mm Hg. The neuropsychological tasks where WMHI volume was a significant independent predictor were used as the dependent variables in multiple regression models that included age.8 - R= 0. and time on the Trail Making Task B.2 Blood pressure (47 subjects) Systolic Diastolic Brain volumes (51 subjects) Cerebral volume Central CSF volume WMHI volume PET rCMRglc (42 subjects) Global gray Frontal Parietal Temporal Cognition (49 subjects) General IQ* WAIS Verbal? WAIS Performance? Wechsler Immediate Verbal Memory Wechsler Delayed Verbal Memory Wechsler Immediate Visual Memory Wechsler Delayed Visual Memory WAIS Digit Symbol Porteus Maze FAS Word List Trail Making.0001 p < 0.0001 3t l Y= -0.0001 0 9 : > z 0.13 R = -0.0001 p > 0. and were included in the model with WMHI volumes to predict neuropsychological test scores. .59 R = 0.21 10 .9'10-3X 0.0001 p z 0. .200- I p > 0.1 p > 0. WMHI White matter hyperintensity.1 p < 0. .001 p p p p Figure 2. cerebral volumes a s percent of intracranial volume.1 < 0.55 R = 0. I I 50 90 AGE (years) p < 0. however.0- p < 0.73 P c 0.19 R = 0. Since it is plausible that brain volume and cerebral metabolism could also influence neuropsychological performance.001 p < 0.60 p < 0. continued to be a significant independent predictor of general intelligence.23 R = -0.0001 p < 0.62 R = -0. After removing subjects with large WMHI volumes. Part B j : ] WMHI > 0. global gray m a t t e r 2080 NEUROLOGY 45 November 1995 metabolism. Age explained all significant independent variance in the four PET measures of cerebral metabolism (table 1).Table 1.64 R = -0. Black full circles are subjects within the 95% confidence intervals of the gaussian distribution shown in figure 1. 30 40 I . and times on Trail Making Task A and B.01 > 0.01 -0.61 R = -0. 60 . We examined the notion of a threshold effect of WMHI volume in two ways.69 R = -0. .6- R = -0.50 R = 0.02 R = 0. . Age-relatedcorrelations 1.E 0. Systolic blood pressure also was no longer a significant predictor of WMHI volume after subjects with large WMHI volumes were removed from the analysis. The regression slope and statistical significance reflect these subjects. . nificant independent predictive value.1 w 1.59 R = -0. central CSF volume. Regional cerebral glucose metabolism was predicted using age a n d WMHI volumes. 20 . Age and educational achievement are both strong predictors of neuropsychological performance. and regional gray matter metabolism. another series of regression models was tested. WMHI remained the only significant predictor of time on Trail Making Task A.0001 zs > 2c . WMHI volume and global gray matter metabolism were the significant predictors of Wechsler immediate visual memory.0001 < 0.57 R = -0. Part A Trail Making. Age-related differences in white matter hyperintensity (WMHZ) volume expressed as percent of intracranial volume.0001 < 0. The other variables predicted no more than 10% of the variance in any model and were always entered after WMHI volume.0001 < 0.0001 < 0. Educational achievement and WMHI were the significant predictors of general intelligence scores.41 R = -0.41 R = -0. All models were significant ( p < 0. 70 80 . * Sum of verbal and performance scaled scores t WAIS sum of scaled score. Threshold effect.55 p p p p < 0. digit symbol. WMHI volumes explained greater than 40% of the variance in the Trail Making Tasks and more than 20% of the variance in the visual memory tasks.1 p < 0.64 R = 0. Data from subjects with WMHI volumes greater than 95% confidence limits of the gaussian distribution are plotted as open circles.08 + 3. . . brain volume. WMHI volume explained significant independent variance in both brain volumes and neuropsychological scores.5% 0 R = 0. . WMHI volume and age were the significant predictors of Wechsler delayed visual memory. immediate and delayed visual memory scores. Wechsler immediate and delayed visual memory scores. all subjects with WMHI volumes greater than 0. and the regression analyses where WMHI was previously a significant independent predictor were repeated. the significant relations between WMHI volume. .001 < 0. and central CSF volumes were lost. brain volume.1 p > 0. whereas WMHI and central CSF volumes were the significant predictors of time on Trail Making Task B.24 R = -0. WMHI volume was a significant independent predictor of general intelligence scores.

59 1.29$ 0.42$ G r e a t e r than 0.05. larger central CSF volumes.2 f 1.4 1.4 1.80 f .9) for the subjects with normal WMHI volumes. and a mean WMHI area of 3. The high frequency of large WMHI volumes in N ove mbe r 1995 NEUROLOGY 45 2081 . t h e presence of large WMHI volumes was associated with significantly higher systolic blood pressure. 1 46 f 1 15 i 2 37 + 84 66 f 29 153 709 6.5% w i t h 1 ' 7 subjects matched by mean age and age range with WMHI volumes less than 0.11 128 11 78 f 8 79 f 3.02 - * - - 0.24 147 139 87 14 77 * 2. By way of comparison to Boone et al.37$ (60-81) WMHI" Systolic BP Diastolic BP Cerebrum" Central CSF* General IQ'i WAIS Verbal$ WAIS Performance$ Wechsler Immediate Verbal Memory Wechsler Delayed Verbal Memory Wechsler Immediate Visual Memory Wechsler Delayed Visual Memory WAIS Digit Symbol Porteus Maze FAS Word List Trails A time (sec) Trails B time (sec) Global gray matter rCMRglc Frontal lobe rCMRglc Parietal lobe rCMRglc Temporal lobe rCMRglc 0. 10. and Trails B time. were present in approximately 10% of the study population. 8 p < 0. The amount of independent variance explained by each predictor variable of the model is shown in the middle columns.251 0. * Volume expressed as percent intracranial volume.45$ 0. quantitative MRI.99 * 0. and PET metabolism are summarized in table 3.0s 124 i 20 77 i 9 47 f 14 20 3 Age Cerebrum Central CSF 0. and significantly lower global gray matter and frontal lobe metabolism. we examined the magnitude of the differences in our brain and neuropsychological measures for subjects with large WMHI volume by comparing the five subjects with WMHI volumes g r e a t e r t h a n 0.1 f 0.33t 0.3 f 0. brain volume.24% as compared with 0.29$ 0. FAS word list generation. 134 to 167 mm Hg). In our second analysis.7 to 6. The mean WMHI volume for subjects with large WMHI volumes was 0.9) for the five subjects with large WMHI volumes.4 5. Measures of blood pressure.161 - 0.02 0. WMHI volume was a significant independent predictor of smaller brain volumes and lower cognitive performance scores in otherwise very healthy subjects.5%WMHI volum e 5 74 i 14 (54-91) 0. Subjects with large WMHI volumes had significantly higher mean systolic blood pressure (range.41f 0.36$ 0.36$ * NS NS 19 *5 17 i 2 10 * 2 9*3 53 f 9 14 i 3 46 9 38 * 9 75 + 26 7. Mean values for age. and significantly lower global gray matter and frontal lobe glucose utilization.ll these values correspond to a mean WMHI area of 12.9 6.05.04 - 0.87 f 0. In addition. and cerebral metabolism of glucose for the five subjects with large WMHI volumes and 17 age-matchedcontrols Age-matched c ontrols Number Age (range) 17 69 i 6 W M H I vol ume Systolic BP Diastolic BP 0. 0.8 cm2 (range.47% 0. even in subjects for whom blood pressures are in the normal range. In the right column is the total variance explained by the model. significantly lower scores on Wechsler immediate and delayed visual memory. neuropsychological scores.5 vol ume 0.28t 6 i 5s 0.001. Multiple linear regression analyses Predicted variables Predictor vari abl es R e s ults Table 3.8 8.56i: The predicted variables are shown in the left column.9 2 4 cm2 (range.10* 0. Wilcoxon's rank sum.30% * * Neuropsychological test results * * WMHI Age General IQ WAIS Verbal WAIS Performance Wechsler Immediate Verbal Memory Wechsler Delayed Verbal Memory Wechsler Immediate Visual Memory Wechsler Delayed Visual Memory WAIS Digit Symbol Porteus Maze FAS Word List Trails A time Trails B time 0.8 135 f 14 85 9 50 f 9 23 i 4 0.29f * Education 0. blood pressure.02 0.04 0.06* WMHI 0.5%.35f B r a i n volumes WMHI vol ume 0.11% for the age-matched controls.0 3. Within this small group.12t * * * 0. * p < 0. 0.0 + 0.Table 2.01 Age 0. Large WMHI volumes.5% of intracranial volume. but only in those subjects greater t h a n 50 years of age.01. significantly larger central CSF spaces.19 0.2 i 0.52$ NS 0.02 0.7 * WMHI White matter hyperintensity. cognition. and individual regional cerebral metabolic r a t e of glucose for the global gray matter a n d frontal lobe metabolism are displayed in figure 3.04 0. lower neuropsychological test scores.45f 0.05 0.19% 0.07* 0.54% 0. * Discussion. i p c 0.07" 0. f p < 0.27$ 0.17t 0.04 0.02 0.0 8.8% -+ 0. BP Blood pressure.3 to 18. defined as greater than 0.9 - - 0.42% 0.36 7. ? IQ = verbal sum of scale scores + performance sum of scale scores % Sum of scale score (no age correction). We found that the volume of WMHI is positively associated with higher systolic blood pressure.29t 0.9 * 0.8 0.0 2.

" supporting the idea We conclude t h a t WMHI occur even in very that a threshold size of WMHI may be necessary for healthy individuals. In agreement with previous s t ~ d i e s . especially about the horns of the lateral tension. Reduced pressure may operate along a continuum. The significant associaWMHI also occur as part of the aging process indetion between WMHI volume and neuropsychological pendent of the effects of elevated blood pressure. sensitive than other brain measures. will be necessary to assess completely the untoward effects of large WMHI volumes on brain structure and function.41 Damage to these fasciculi. structural. brain structure." we noted our cohort is surprising given that our subjects were WMHI to occur primarily adjacent to the cerebral free of cerebrovascular risk factors. brain structure. lower neuropsychological scores. Although present in only five or 0. other . however. such as cerebral amyloid a n g i o ~ a t h y .40 That Figure 3. and lower ceredisease or further cognitive impairment. large WMHI volumes had a dismore sensitive t o the untoward effects of WMHI proportionate impact on systolic blood pressure. However. These included the commonly recognized Trail Making Tasks A and B. which were driven primarily by subhowever. neuropsychological tests may be more WMHI volumes were converted to area measures. While frontal lobe metabolism and impaired frontal lobe this finding was present primarily in a small group neuropsychological performance indicate preferenof older subjects with large WMHI volumes. Similar to Boone et al. we must interpret these findings cautiously. The complex cogniis unclear and was not tested directly. especially vulblood pressure and WMHI volume is also consistent nerable due to t h e i r length a n d proximity to with the relation between systolic blood pressure WMHI. and and stroke.5% of the intracranial volume). confluent WMHI in subcorwas a significant independent predictor of WMHI tical white matter distinct from periventricular volume suggests t h a t the effect of systolic blood WMHI were not seen i n our subjects. tests of frontal lobe function were predominantly affected. Among the neuropsychological tests employed. and cerebral metabolism. however. working memory as opposed to temporal lobe-mediMean WMHI volumes and cerebral metabolism for the ated memory function. predictor of WMHI volume. Given the 1 2082 NEUROLOGY 45 November 1995 . x-axis) as compared with association is between WMHI and frontal lobe 17 age-matched controls (<0. could explain the metabolic. This seems the mean area of WMHI for each subject with a unlikely given that lower neuropsychological scores large WMHI volume was greater than 10 cm2. and possibly 0 GLOBAL GRAY MATTER rCMRglc + FRONTAL GRAY MATTER rCMRglc longitudinal assessment.~ ~ relations. but also the Wechsler 0 immediate and delayed visual memory tasks. trum semiovale.5% of intracranial volume). ~ ~ jects with large WMHI volumes. than the structural and metabolic effects of WMHI. tive systems of the frontal lobes may possibly be For our subjects. Large.small number of subjects with large WMHI volumes in our study. Larger subject cohorts. frontal lobe function. even when in the normal range for age. When Alternatively. the imtial impairment of frontal lobe neural circuitry. including hyperventricles. our finding that systolic blood ventricles. Cerebral metabolic rate of glucose (CMRglc) of WMHI volume accounted for more variance in the global and frontal lobe gray matter for subjects with immediate version of the Wechsler memory task large white matter hyperintensity (WMHI) volumes than in the delayed version also implies that the (>0. and occasionally extending into the cenpressure. WMHI are assosubjects. large amounts of WMHI appear pathologic ciated with higher systolic blood pressure. subjects with large WMHI volumes had significantly reduced frontal lobe glucose utilization.05% of intracranial volume.13J4 similar to that of Boone et al.19~20The significant relation between systolic occur. The pact on brain structure and function was similar to long association superior-longitudinal fasciculi pass that seen in patients with well-controlled hypertenadjacent to the lateral ventricles where WMHI sion. relation between systolic blood pressure and WMHI systolic blood pressure was no longer a significant and the relation between WMHI. and are not always found in association with WMHI. When large (greater than 10 cm2 clinical expression.l test performance was continuous as opposed to the The frequency or impact of other causes of WMHI. brain atroand may identify subjects at risk for cerebrovascular phy.42-44 tinuous untoward effect of blood pressure on the The relation between WMHI volume and neucerebrum. This suggests t h a t and cerebral metabolism.36further supporting the notion of a conneuropsychological consequences of WMHI. When subjects with the largest WMHI ropsychological test performance differed from the volumes were removed from the analysis.~~ found that WMHI volume was a significant independent predictor of neuropsychological scores. Consistent with impaired two groups are summarized in table 3. We believe the Wechsler visual memory test accesses frontal function by utilizing working memory that is located primarily in the frontal lobes. ~ we ~~'.

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50. University of Wisconsin School of Medicine. DeCarli C. Diaz JF. Rapoport SI. and abnormal white matter signals. the laminin isoform in skeletal muscle. has been identified in classic CMD patients. Sadoshima S. and in turn is linked to the subsarcolemmal actin-based cytoskeleton via the dystrophin-glycoprotein complex (DGC). Since merosin is also expressed in the nervous system and has biologic activities on neurite outgrowth and Schwann cell migration. Sunada and Campbell). Rapoport SI. Bennett H. Luxenburg JS. Ichiya Y. heterogeneous disorders. Handbook of mental health a n d aging. Lotz. although abnormal brain white matter signals are occasionally observed on MRI. Brain 1989. Howard Hughes Medical Institute. 1990. University of Iowa College of Medicine. Laragh JH.C. R. Yao H. merosin is a native ligand for dystroglycan linking the extracellular matrix and dystrophin.^-^^ Merosin has diverse biologic functions.7 Hence. it is typically associated with brain structural a n ~ m a l i e sand ~ .P. MD. Accepted in final form March 10. San Diego: Academic Press. The significance of age-related enlargement of the cerebral ventricles in healthy men and women measured by quantitative com1992. Kaye JA. Patterns of performance in healthy aging. Iowa City. 1992:201-228.I4The absence of merosin could disrupt this critical link and cause From the Howard Hughes Medical Institute and the Department of Physiology and Biophysics (Drs.P. 49. Grady CL. even though brain white matter abnormalities are occasionally observed on CT or MRI. MD. Supported in part by the Muscular Dystrophy Association. Corbett AJ. Treatment of age-related cognitive dysfunction: pharmacological and clinical evaluation. Rust. 44. Thus. Sloane RB. T. merosin binds a-dystroglycan. Haxby JV. Cerebral blood flow and oxygen metabolism in patients with vascular dementia of the Binswanger type. In: Birren JE.21:1694-1699. Department of Physiology and Biophysics. J Am Geriatr SOC 46. Recently. Campbell. Fujishima M. 1995. Cognitive dysfunction following subcortical infarction. Hypertension: pathophysiology. Hachinski VC. Kevin P.48:1022-1025. IA 52242. In: Racagni G. Raffaele KC. Haxby JV. PhD. MD. The most frequent form in the Caucasian population is classic (occidental) CMD. 43. Madison. eds. Typical presenting signs include hypotonia and arthrogryposis.51:999-1007. deficiency of merosin. Lotz. including mediation of cell attachment and promotion of neurite outgrowth and Schwann cell migration. 1995. polymicrogyria. Arch Neurol 1994. Edgar. 2084 NEUROLOGY 45 November 1995 . Int Acad Biomed Drug Res. e t al.DeCarli C. is an investigator of the Howard Hughes Medical Institute. Iowa City. 48. We report here two patients with merosin-negative CMD presenting extensive brain abnormalities characterized by cortical anomaly. and Rust). prevalent in Japan. Campbell. NEUROLOGY 1995. New York Raven Press. Address correspondence and reprint requests to Dr. Dev Neuropsychol 1991. Arch Neurol 1991. WI. B. 47. IA and the Department of Neurology (Drs.6 Clinical manifestations of CMD in the Occidental population usually are limited to skeletal muscle without CNS symptoms.45:2084-2089 Congenital muscular dystrophy (CMD) is an autosoma1 recessive disease of muscle presenting in the first few months of life and is characterized by dystrophic changes on muscle There are several forms of CMD with heterogeneous etiologies. MD. K. these cases have been termed “classic” or “pure” CMD.Crouzel C. characterized by exclusive muscle involvement. In skeletal muscle. and management. Edgar. merosin deficiency could disrupt the attachment of muscle cell to the extracellular matrix and lead to muscle cell necrosis. Stroke 1990.7:99-113. The predominant histopathologic feature of muscle is extensive connective tissue pr~liferation.13In skeletal muscle.2:69-79. Kuwabara Y. Merskey H.112:931-951. Merosin-negative congenital muscular dystrophy associated with extensive brain abnormalities Y. Brenner BM. eds. ~ was recently mapped to chromosome 9q3 1-33.40:225-231. Age-associated memory impairment. PhD Article abstract-Congenital muscular dystrophies (CMDs) are autosomal recessive. Cerebral metabolism in aging and dementia. Received January 4. 45. puted x-ray tomography. Improved recognition of leukoaraiosis and cognitive impairment in Alzheimer’s disease.S. Cohen GD. One form that has become established as a single disease entity is Fukuyama-type CMD. Kos S. 400 EMRB.S. Sunada. and K.~ We have identified a particular subset of classic CMD that is characterized by complete absence of merosin (laminin M chainL8 Merosin is the predominant homologue of laminin A chain in the basal laminae of striated muscle and Schwann cell^. 1992. Friedland RP.P. Mendlewicz J. Koss E. diagnosis. University of Iowa College of Medicine.Schapiro MB. an extracellular 156-kDa dystrophin-associated glycoprotein. deficiency of merosin could affect the development of the nervous system. Basel: Karger. Local brain haemodynamics and oxygen metabolism in cerebrovascular disease. Rapoport SI.