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Original Contribution |

Association of White Matter Hyperintensity Volume With Decreased Cognitive Functioning:  The Framingham Heart Study FREE

Rhoda Au, PhD; Joseph M. Massaro, PhD; Philip A. Wolf, MD; Megan E. Young, BA; Alexa Beiser, PhD; Sudha Seshadri, MD; Ralph B. D’Agostino, PhD; Charles DeCarli, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Boston University School of Medicine, Boston, Mass (Drs Au, Wolf, and Seshadri and Ms Young); Department of Biostatistics, Boston University School of Public Health (Drs Massaro and Beiser); Department of Mathematics and Statistics, Boston University (Drs Massaro and D’Agostino); and Department of Neurology and Center for Neuroscience, University of California, Davis, Sacramento (Dr DeCarli).


Arch Neurol. 2006;63(2):246-250. doi:10.1001/archneur.63.2.246.
Text Size: A A A
Published online

Objective  To examine the relationship between white matter hyperintensity (WMH) volume on magnetic resonance images and cognitive tests in a large, population-based sample.

Methods  Quantitative magnetic resonance imaging and neuropsychological evaluations were performed in 1820 dementia- and stroke-free participants from the Framingham Offspring Cohort. The WMH volume relative to total cranial volume was computed; WMH volumes more than 1 SD above the age-predicted mean were defined as large. Adjusting for age, sex, education, height, and Framingham Stroke Risk Profile, we examined the relationship between WMH and 3 cognitive factors derived from a neuropsychological test battery (verbal memory, visuospatial memory and organization, and visual scanning and motor speed) and 3 individual measures of new learning, abstract reasoning, and naming.

Results  Compared with those with no or little WMH volume, participants with large WMH volume performed worse on the cognitive factors of visuospatial memory and organization (P = .04) and visual scanning and motor speed (P = .01), as well as on new learning (P = .04), but not on verbal memory (P = .52).

Conclusions  In this younger community-based population of nondemented individuals, those with large WMH volume, as compared with those with less or no WMH volumes, performed significantly worse in cognitive domains generally associated with frontal lobe systems and, to a lesser extent, the medial temporal area. Further study will clarify whether large WMH volume and associated cognitive impairment lead to future risk of stroke or dementia.

Imaging research finds that white matter hyperintensities (WMHs) occur in individuals presumed free of neurologic disease,1,2 as well as those with stroke3,4 and dementia.57 The cause of WMH, however, remains a matter of debate; it may be associated with ischemic disease, as supported by positive associations with cerebrovascular risk factors,812 or representative of nonspecific brain changes that reflect a variety of processes including normal aging, cerebrovascular disease, and Alzheimer disease.13

Although the cause of WMH remains unclear, accumulating evidence suggests that the clinical manifestations result in poorer performance in executive functioning, particularly among subjects who were not demented.1417 Generally, limited sample sizes as well as subject sampling bias attenuate the significance of these findings.

In the population-based Cache County comparison study of nondemented, mild cognitive impairment, Alzheimer disease, and neuropsychiatric groups, Bigler et al14 found a significant relationship between WMH and cognitive performance but were unable to draw conclusions because of heterogeneity in the data. In the Rotterdam Scan Study, de Groot et al18 reported that psychomotor speed was more strongly associated with WMH than was memory. Inferences of their findings to the general population, however, may be limited by the absence of definitive measures of executive function and use of a semiquantitative measure of WMH rather than a quantitative measure.

Each of these population-based studies was restricted to the study of older individuals, limiting our understanding of the full impact of WMH in earlier life. Data from the Atherosclerosis Risk in Communities study19,20 suggest that WMH may be a consequence of cerebrovascular risk factors that manifest at an early age.

Thus, although the prevalence and potential cognitive consequences of WMH are well documented, previous research has major methodologic limitations, such as insufficient sample size, different magnetic resonance (MR) imaging measuring techniques, and biased subject sampling, including emphasis on the assessment of older individuals. The Framingham Offspring Study involves a community-based cohort whose ages span 6 decades and who have been longitudinally studied for cardiovascular risk and the development of clinical stroke and dementia for more than 30 years. This relatively young, large study population provides an unprecedented opportunity to detect subtle, but significant, relationships between WMH and cognitive performance associated with normal aging.

STUDY PARTICIPANTS

The Framingham Offspring Cohort, recruited in 1971, has undergone 7 periodic physical and medical examinations to identify risk factors for cardiovascular and cerebrovascular diseases.21 The initial Offspring cohort consisted of 5124 men and women; 88% of survivors (3539 of 4031) participated in Examination 7 in 1998 to 2001.

From 1999 to 2001, surviving members of the Offspring cohort were asked to take a neuropsychological (NP) test battery and to undergo brain MR imaging. The institutional review board at Boston University, Boston, Mass, approved the study protocol, and all participants provided informed consent. Of the 2187 participants who agreed to undergo NP testing, 1889 also had MR imaging. We eliminated 47 participants who had a clinical stroke (n = 28) or diagnoses of probable dementia (n = 2), multiple sclerosis (n = 6), or other neurologic illnesses (n = 11). A consensus review process determined whether a clinical stroke22 or probable dementia23 was present. An additional 22 participants had missing data. After all exclusions, total study size was 1820 (966 women, 854 men; age range, 34-88 years; mean ± SD age, 61.1 ± 9.40 years). We did not exclude potential cases of mild cognitive impairment because the intent of this study was to document the naturally occurring relationship between WMH and cognition within a nondemented sample. The MR imaging and NP testing were performed on the same day for 97.3% of participants and within 6 months for 99.5% of participants.

We compared the demographic characteristics of members of the Offspring cohort who participated fully in the MR imaging study with those of (1) participants who underwent the NP portion but refused the MR imaging and (2) participants who declined the NP and MR imaging study altogether for any reason: illness, claustrophobia, contraindications, or refusal. Our analysis confirmed the well-documented sample bias that occurs with population-based MR imaging studies12,24,25; MR imaging study participants were younger and healthier than nonparticipants. Although vascular risk factors were more common in nonparticipants, the direction of these findings suggests that any significant negative correlations between these risk factors and cognition are conservative estimates of the general population.

WMH MEASURE

DeCarli et al26 provided a detailed description of the quantification of WMH volume. We considered WMH volume as a continuous variable, but previous research from the Framingham Heart Study indicated that only large WMH volume (WMH-L) was linked to higher vascular risk,27 suggesting that only extensive changes in WMH have clinical significance among those with no neurologic disease. Thus, for these analyses, we used the same binary WMH variable used in the previous Framingham Heart Study,28 eg, no or little WMH volume (WMH-N) vs WMH-L (group definitions are presented in the “Results” section).

NP TEST BATTERY

The NP battery consisted of tests sufficient to provide a comprehensive cognitive profile, all administered according to standard protocols (Table 1).

Table Graphic Jump LocationTable 1. Neuropsychological Test Battery
STATISTICAL ANALYSIS

Age is a strong predictor of WMH volume.26 Hence, to remove the strong age effect from our analyses, we first grouped participants according to age group (35-44 years [n = 52], 45-54 years [n = 449], 55-64 years [n = 632], 65-74 years [n = 531], 75-84 years [n = 153], and ≥85 years [n = 2]); 1 participant younger than 35 years was excluded, bringing the analysis sample size to 1819. Second, participants were categorized as having large (WMH-L) or no or nonlarge (WMH-N) WMHs within each age group (adjusted for head size by dividing WMH by total cranial volume [TCV] before the categorization) as follows. The natural log of the WMH/TCV ratio was linearly regressed vs age. A participant was categorized as having WMH-L when the residual (predicted WMH/TCV minus actual WMH/TCV) was greater than 1 SD of the mean residual for the participant's age group. We based this grouping on the natural log of WMH/TCV as opposed to untransformed WMH/TCV because of the highly skewed distribution of the WMH/TCV ratio.29

Previous factor analyses described elsewhere30 identified 3 cognitive domains: (1) verbal memory, (2) visuospatial memory and organization, and (3) visual scanning and motor speed (see Table 1 for tests composing each factor). We used the natural log of scores for Trails A and B, immediate recall, delayed recall, and delayed recognition to correct for skewed distribution. Additional cognitive measures of new learning, abstract reasoning, and naming were composed of scores from individual NP tests. Although the primary measure for new learning is immediate recall after the learning trials, we also included scores of delayed recall to assess retention of newly learned verbal stimuli. Also analyzed were the scores from the individual tests that composed the 3 cognitive factors.

We assessed the significance of the difference in NP measures (both cognitive factors and individual tests) between the WMH groups by means of analysis of covariance adjusting for sex, age, years of education, height, and the Framingham Stroke Risk Profile. This profile is a composite score of individual risk factors summarizing the 10-year probability of stroke.31,32

There were no significant differences in the WMH groups for any demographic measure, risk factor score, or total brain volume (Table 2).

Table Graphic Jump LocationTable 2. Background and Risk Factor Characteristics

For the cognitive factor visuospatial memory and organization, participants with WMH-L volumes performed significantly worse than participants with WMH-N volumes (P = .04) (Table 3). Similarly, for the visual scanning and motor speed factor, WMH-L volumes were associated with poorer performance than WMH-N volumes (P = .01). For the verbal memory factor, performance did not differ between the 2 groups (P = .52). For individual tests of abstract reasoning and naming, no differences between the 2 groups were found (P = .47 and .33, respectively), whereas for new learning (immediate recall score), participants with WMH-L volumes did worse than participants with WMH-N volumes (P = .04).

Table Graphic Jump LocationTable 3. Results From Individual Test Measures

For the significant visuospatial memory and organization factor, an analysis of the components showed that the Hooper Visual Organization total score was the only test result significantly different between WMH groups (P = .02). Approaching significance was Visual Reproductions–immediate recall (P = .10). For the significant visual scanning and motor speed factor, Trails B was significantly different between groups (P = .004), while Trails A was of borderline significance (P = .07); the WMH-L group performed more slowly than the WMH-N group (see Table 3 for complete list of results).

To test for a potential age × WMH interaction, participants were stratified into 2 age groups (<65 years vs ≥65 years); results indicated that the WMH effect was larger among older participants than younger ones only for the visual scanning and motor speed factor (P = .01 vs P = .23).

We also examined qualitative measures of new learning, which included separate analysis of the easy and hard learning conditions in the acquisition stage. There were marginally significant differences, where the WMH-L group did significantly worse for both easy test items (P = .05) and hard test items (P = .09). Further analyses of the retention condition of paired associates indicated significant forgetting among the WMH-L group compared with the WMH-N group (P = .04). These results were largely driven by decreased retention of hard test items by the WMH-L group (easy items, P = .72; hard items, P = .02).

Our principal finding was that, within a large, relatively young, nondemented community-based population, individuals with large WMH volumes performed significantly worse on measures of visual organization, attention, planning and initiation of complex activity, and new learning, particularly for more difficult verbal material as compared with those with WMH-N volumes. Although we found that the WMH-L group's performance on the Visual Reproductions–immediate recall task only was of borderline significance (P = .10), it is one of the components of the visuospatial memory and organization factor and suggests possible deficits in perception, attention, and concentration, executive functions necessary to perform this test. Marginally significant findings for Trails A (P = .07) also lend support to the potential deficits in attention. Our pattern of results supports other studies that have indicated that cognitive deficits associated with WMH are suggestive of subcortical frontal system involvement.1517,33,34

Our analyses were limited to global measures of WMH volumes. There is conflicting evidence suggesting regional WMH and specific cognitive domains. Several studies15,16,18 suggest that increased WMH volume in the frontal region is linked to processing speed and cognitive flexibility, tasks associated with executive functioning. Gunning-Dixon and Raz,16 however, did not find a similar association between frontal WMH volumes and working memory. In contrast, Tulberg et al17 reported that all regional measures of WMH were associated with poorer performance on executive function tests. These discrepancies likely reflect methodologic differences, as recent evidence finds that WMH formation is a generalized process and WMH volumes in one brain region are highly correlated with total WMH volume and WMH in other brain regions.35

These results support the notion that the cognitive deficits of WMH are likely the manifestation of asymptomatic cerebrovascular vascular disease. Jeerakathil et al28 reported that the Framingham Stroke Risk Profile and the individual measure of systolic blood pressure were significant predictors of WMH-L for participants drawn from this same Framingham Offspring Cohort. Similarly, DeCarli et al26 found larger WMH volume in participants who also had an infarction on MR imaging than in participants without such infarctions. In another study, similar patterns of cognitive impairments were linked to brain atrophy significantly associated with increased Framingham Stroke Risk Profile scores.36

Although the availability of cognitive performance measures taken at the time of MR imaging in this relatively younger cohort is a key strength of this study, several limitations restrict the generalizability of these data. The Framingham Offspring Cohort lacks ethnic diversity because their parents, the original cohort, were predominantly Anglo-American, which was representative of the population of Framingham, Mass, at the inception of the study. The exclusion of participants who refused MR imaging or were claustrophobic also decreases the representativeness of this cohort. In addition, the bias introduced by the inability to include participants with pacemakers may serve to underestimate the cases of WMH-L if the relationship between cardiovascular risk factors and WMH is true, as we contend.

Our findings, however, support the growing literature focused on the clinical consequences of age cohort differences in brain morphologic characteristics. We argued that risk factors for vascular disease are tied to the presence of WMH, and that these same risk factors are associated with subtle cognitive impairments that are likely to increase lifetime risk of Alzheimer disease or vascular dementia. Recent studies suggest that WMH-L volumes are associated with increased prevalence of mild cognitive impairment.3739 Ongoing prospective studies will clarify whether WMH-L volume and the associated cognitive impairment indicate future risk of developing vascular dementia, Alzheimer disease, or other types of dementia. Given the potential for the treatment of cerebrovascular disease risk factors, the presence of WMH-L volumes may serve as a good measure of the need for more aggressive treatment.

Correspondence: Rhoda Au, PhD, Neurological Epidemiology and Genetics Division, Department of Neurology, Boston University School of Medicine, 715 Albany St, Mail Code B-6, Boston, MA 02118-2526.

Accepted for Publication: September 29, 2005.

Author Contributions:Study concept and design: Au, Wolf, Young, Beiser, Seshadri, D’Agostino, and DeCarli. Acquisition of data: Au, Wolf, Young, D’Agostino, and DeCarli. Analysis and interpretation of data: Au, Massaro, Wolf, Beiser, Seshadri, D’Agostino, and DeCarli. Drafting of the manuscript: Au, Young, and DeCarli. Critical revision of the manuscript for important intellectual content: Au, Massaro, Wolf, Beiser, Seshadri, and D’Agostino. Statistical analysis: Massaro, Beiser, D’Agostino, and DeCarli. Obtained funding: Wolf. Administrative, technical, and material support: Au, Wolf, Young, Seshadri, and DeCarli.

Financial Disclosure: None.

Funding/Support: This study was supported by contract N01-HC-25195 from the National Heart, Lung, and Blood Institute, Bethesda, Md; grants AG16495 and AG08122 from the National Institute on Aging, Bethesda; grant NS17950 from the National Institute of Neurological Disorders and Stroke, Bethesda; and grant AG13846 from the Boston University Alzheimer's Disease Center.

de Leeuw  FEde Groot  JCBots  ML  et al.  Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study. J Neurol 2000;247291- 296
PubMed
Ylikoski  RYlikoski  AErkinjuntti  TSulkava  RRaininko  RTilvis  R  et al.  White matter changes in healthy elderly persons correlate with attention and speed of mental processing. Arch Neurol 1993;50818- 824
PubMed
Leys  DEnglund  EDel Ser  T White matter changes in stroke patients: relationship with stroke subtype and outcome. Eur Neurol 1999;4267- 75
PubMed
Wiszniewska  MDevuyst  GBogousslavsky  JGhika  Jvan Melle  MG What is the significance of leukoaraiosis in patients with acute ischemic stroke? Arch Neurol 2000;57967- 973
PubMed
Capizzano  AAAcion  LBekinschtein  T White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2004;75822- 827
PubMed
Gootjes  LTeipel  SJZebuhr  Y  et al.  Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging. Dement Geriatr Cogn Disord 2004;18180- 188
PubMed
Hirono  NKitagaki  HKazui  HHashimoto  MMori  E Impact of white matter changes on clinical manifestation of Alzheimer's disease: a quantitative study. Stroke 2000;312182- 2188
PubMed
Breteler  MMvan Amerongen  NMvan Swieten  JC  et al.  Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging: the Rotterdam Study. Stroke 1994;251109- 1115
PubMed
DeCarli  CMurphy  DGTranh  M  et al.  The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology 1995;452077- 2084
PubMed
DeCarli  CReed  TMiller  BLWolf  PASwan  GECarmelli  D Impact of apolipoprotein E ε4 and vascular disease on brain morphology in men from the NHLBI Twin Study. Stroke 1999;301548- 1553
PubMed
Pico  FDufouil  CLevy  C  et al.  Longitudinal study of carotid atherosclerosis and white matter hyperintensities: the EVA-MRI cohort. Cerebrovasc Dis 2002;14109- 115
PubMed
Swan  GEDeCarli  CMiller  BLReed  TWolf  PACarmelli  D Biobehavioral characteristics of nondemented older adults with subclinical brain atrophy. Neurology 2000;542108- 2114
PubMed
Merino  JGHachinski  V Leukoaraiosis: reifying rarefaction [comment]. Arch Neurol 2000;57925- 926
PubMed
Bigler  EDLowry  CMKerr  B  et al.  Role of white matter lesions, cerebral atrophy, and APOE on cognition in older persons with and without dementia: the Cache County, Utah, study of memory and aging. Neuropsychology 2003;17339- 352
PubMed
Burton  EJKenny  RAO’Brien  J White matter hyperintensities are associated with impairment of memory, attention, and global cognitive performance in older stroke patients. Stroke 2004;351270- 1275
PubMed
Gunning-Dixon  FMRaz  N Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study. Neuropsychologia 2003;411929- 1941
PubMed
Tullberg  MFletcher  EDeCarli  C White matter lesions impair frontal lobe function regardless of their location. Neurology 2004;63246- 253
PubMed
de Groot  JCde Leeuw  FEOudkerk  M  et al.  Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol 2000;47145- 151
PubMed
Liao  DCooper  LCai  J  et al.  Presence and severity of cerebral white matter lesions and hypertension, its treatment, and its control: the ARIC Study: Atherosclerosis Risk in Communities Study. Stroke 1996;272262- 2270
PubMed
Liao  DCooper  LCai  J  et al.  The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. Neuroepidemiology 1997;16149- 162
PubMed
Garrison  RJKannel  WBStokes  J  IIICastelli  WP Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med 1987;16235- 251
PubMed
Sacco  RLWolf  PAKannel  WBMcNamara  PM Survival and recurrence following stroke: the Framingham Study. Stroke 1982;13290- 295
PubMed
Bachman  DLWolf  PALinn  R  et al.  Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study. Neurology 1992;42115- 119
PubMed
Havlik  RJFoley  DJSayer  BMasaki  KWhite  LLauner  LJ Variability in midlife systolic blood pressure is related to late-life brain white matter lesions: the Honolulu-Asia Aging Study. Stroke 2002;3326- 30
PubMed
Mukamal  KJLongstreth  WT  JrMittleman  MACrum  RMSiscovick  DS Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the Cardiovascular Health Study. Stroke 2001;321939- 1946
PubMed
DeCarli  CMassaro  JHarvey  D  et al.  Measures of brain morphology and infarction in the Framingham Heart Study: establishing what is normal. Neurobiol Aging 2005;26491- 510
PubMed
Jeerakathil  TJWolf  PABeiser  A  et al Framingham coronary risk score predicts white matter hyperintensity and total cerebral brain volume: the Framingham Offspring Study [abstract]. Neurology200156(suppl 3)A107A108 Abstract P02.050
Jeerakathil  TWolf  PABeiser  A  et al.  Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke 2004;351857- 1861
PubMed
Massaro  JMD’Agostino  RB  SrSullivan  LM  et al.  Managing and analysing data from a large-scale study on Framingham Offspring relating brain structure to cognitive function. Stat Med 2004;23351- 367
PubMed
Elias  MFSullivan  LMD’Agostino  RB  et al.  Framingham stroke risk profile and lowered cognitive performance. Stroke 2004;35404- 409
PubMed
D’Agostino  RBWolf  PABelanger  AJKannel  WB Stroke risk profile: adjustment for antihypertensive medication: the Framingham Study. Stroke 1994;2540- 43
PubMed
Wolf  PAD’Agostino  RBBelanger  AJKannel  WB Probability of stroke: a risk profile from the Framingham Study. Stroke 1991;22312- 318
PubMed
Petkov  CIWu  CCEberling  JL  et al.  Correlates of memory function in community-dwelling elderly: the importance of white matter hyperintensities. J Int Neuropsychol Soc 2004;10371- 381
PubMed
Raz  NRodrigue  KMAcker  JD Hypertension and the brain: vulnerability of the prefrontal regions and executive functions. Behav Neurosci 2003;1171169- 1180
PubMed
DeCarli  CFletcher  ERamey  VHarvey  DJagust  WJ Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 2005;3650- 55
PubMed
Seshadri  SWolf  PABeiser  A  et al.  Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study. Neurology 2004;631591- 1599
PubMed
DeCarli  CMiller  BLSwan  GEReed  TWolf  PACarmelli  D Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch Neurol 2001;58643- 647
PubMed
Lopez  OLJagust  WJDulberg  C  et al.  Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 2003;601394- 1399
PubMed
Sachdev  PParslow  RSalonikas  C  et al.  Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men. Arch Neurol 2004;611369- 1376
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Neuropsychological Test Battery
Table Graphic Jump LocationTable 2. Background and Risk Factor Characteristics
Table Graphic Jump LocationTable 3. Results From Individual Test Measures

References

de Leeuw  FEde Groot  JCBots  ML  et al.  Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study. J Neurol 2000;247291- 296
PubMed
Ylikoski  RYlikoski  AErkinjuntti  TSulkava  RRaininko  RTilvis  R  et al.  White matter changes in healthy elderly persons correlate with attention and speed of mental processing. Arch Neurol 1993;50818- 824
PubMed
Leys  DEnglund  EDel Ser  T White matter changes in stroke patients: relationship with stroke subtype and outcome. Eur Neurol 1999;4267- 75
PubMed
Wiszniewska  MDevuyst  GBogousslavsky  JGhika  Jvan Melle  MG What is the significance of leukoaraiosis in patients with acute ischemic stroke? Arch Neurol 2000;57967- 973
PubMed
Capizzano  AAAcion  LBekinschtein  T White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2004;75822- 827
PubMed
Gootjes  LTeipel  SJZebuhr  Y  et al.  Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging. Dement Geriatr Cogn Disord 2004;18180- 188
PubMed
Hirono  NKitagaki  HKazui  HHashimoto  MMori  E Impact of white matter changes on clinical manifestation of Alzheimer's disease: a quantitative study. Stroke 2000;312182- 2188
PubMed
Breteler  MMvan Amerongen  NMvan Swieten  JC  et al.  Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging: the Rotterdam Study. Stroke 1994;251109- 1115
PubMed
DeCarli  CMurphy  DGTranh  M  et al.  The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology 1995;452077- 2084
PubMed
DeCarli  CReed  TMiller  BLWolf  PASwan  GECarmelli  D Impact of apolipoprotein E ε4 and vascular disease on brain morphology in men from the NHLBI Twin Study. Stroke 1999;301548- 1553
PubMed
Pico  FDufouil  CLevy  C  et al.  Longitudinal study of carotid atherosclerosis and white matter hyperintensities: the EVA-MRI cohort. Cerebrovasc Dis 2002;14109- 115
PubMed
Swan  GEDeCarli  CMiller  BLReed  TWolf  PACarmelli  D Biobehavioral characteristics of nondemented older adults with subclinical brain atrophy. Neurology 2000;542108- 2114
PubMed
Merino  JGHachinski  V Leukoaraiosis: reifying rarefaction [comment]. Arch Neurol 2000;57925- 926
PubMed
Bigler  EDLowry  CMKerr  B  et al.  Role of white matter lesions, cerebral atrophy, and APOE on cognition in older persons with and without dementia: the Cache County, Utah, study of memory and aging. Neuropsychology 2003;17339- 352
PubMed
Burton  EJKenny  RAO’Brien  J White matter hyperintensities are associated with impairment of memory, attention, and global cognitive performance in older stroke patients. Stroke 2004;351270- 1275
PubMed
Gunning-Dixon  FMRaz  N Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study. Neuropsychologia 2003;411929- 1941
PubMed
Tullberg  MFletcher  EDeCarli  C White matter lesions impair frontal lobe function regardless of their location. Neurology 2004;63246- 253
PubMed
de Groot  JCde Leeuw  FEOudkerk  M  et al.  Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol 2000;47145- 151
PubMed
Liao  DCooper  LCai  J  et al.  Presence and severity of cerebral white matter lesions and hypertension, its treatment, and its control: the ARIC Study: Atherosclerosis Risk in Communities Study. Stroke 1996;272262- 2270
PubMed
Liao  DCooper  LCai  J  et al.  The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. Neuroepidemiology 1997;16149- 162
PubMed
Garrison  RJKannel  WBStokes  J  IIICastelli  WP Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med 1987;16235- 251
PubMed
Sacco  RLWolf  PAKannel  WBMcNamara  PM Survival and recurrence following stroke: the Framingham Study. Stroke 1982;13290- 295
PubMed
Bachman  DLWolf  PALinn  R  et al.  Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study. Neurology 1992;42115- 119
PubMed
Havlik  RJFoley  DJSayer  BMasaki  KWhite  LLauner  LJ Variability in midlife systolic blood pressure is related to late-life brain white matter lesions: the Honolulu-Asia Aging Study. Stroke 2002;3326- 30
PubMed
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