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Midlife Blood Pressure and the Risk of Hippocampal Atrophy

The Honolulu Asia Aging Study
Originally published 2004;44:29–34


Hippocampal atrophy (HA) is usually attributed to the neurofibrillary tangles and neuritic plaques of Alzheimer disease. However, the hippocampus is vulnerable to global ischemia, which may lead to atrophy. We investigated the association of midlife blood pressure (BP) and late-life HA in a sample of Japanese-American men born between 1900 and 1919. BP was measured on 3 occasions between 1965 and 1971. In 1994 to 1996 a subsample underwent magnetic resonance imaging (MRI) of the brain. Hippocampal volume was estimated by manually drawing regions of interest on relevant scan slices; HA was defined as the lowest quartile of hippocampal volume. Also assessed on the MRI were cortical and subcortical infarcts, lacunes, and white matter hyperintensities. The risk (OR, 95% CI) was estimated for HA associated with systolic (<140 versus ≥140 mm Hg) and diastolic (<90 versus ≥90 mm Hg) BP and with antihypertensive treatment. Analyses were adjusted for sociodemographic factors, other cardiovascular risk factors, apolipoprotein E allele, and correlated brain pathology. Those never treated with antihypertensive medication had a significantly increased risk for HA (OR 1.7; CI=1.12; 2.65). The nontreated subjects with high systolic BP had an increased risk (OR=1.98; CI=0.89; 4.39) for HA. Results were similar for untreated men with high diastolic BP (OR=3.51; CI=1.26; 9.74). In conclusion, treatment with antihypertensive treatment modifies the association of BP and HA, such that high levels of BP adversely affect the hippocampus in persons never treated with antihypertensives.

Damage to the hippocampus may cause anterograde and retrograde memory impairment.1 The hippocampus and surrounding areas within the medial temporal lobe are typically involved in Alzheimer disease (AD),2–6 but are also affected in other dementias, such as vascular dementia (VaD).7–10 In AD, hippocampal atrophy (HA) is usually attributed to the deposition of neurofibrillary tangles and neuritic plaques.11,12 However, the hippocampus, particularly the CA1 area, is vulnerable to global ischemia. This vascular damage, leading to selective capillary abnormalities, neuronal necrosis, and microglial and macrophage formation13–16 may contribute to HA in both AD and VaD.

For these reasons, we investigated the association of high blood pressure (BP) and HA in a subsample of Japanese-American men participating in the longitudinal community—based Honolulu Aging Asia Study (HAAS). Previously in this cohort, we found that hypertension in midlife increased the risk for late-life cognitive impairment, AD and VaD, and neuropathological markers of AD.17–20 Results, particularly for the clinical end points of AD, were strongest in those never treated for hypertension.


The design of the HAAS has been described elsewhere.22 The original cohort included Japanese-American men born between 1900 and 1919 who underwent 5 exams (examination 1: 1965 to 1968; examination 2: 1968 to 1970; examination 3: 1971 to 1974; examination 4: 1991 to 1993; examination 5: 1994 to 1996). At each examination, clinical measures were made and sociodemographic and medical conditions assessed.

Dementia, Blood Pressure, and Treatment

At exams 4 and 5, cognitive status was tested with the Cognitive Abilities Screening Instrument (CASI)23 and prevalent (examination 4) and incident (examination 5) dementia was ascertained.22,24 Diagnostic and Statistics Manual of Mental Disorders (DSM-IIIR) criteria25 were applied for dementia, National Institute of Neurologic Diseases and Stroke—Alzheimer’s Disease and Related Disorders26 for AD, and the State of California Alzheimer’s Disease Diagnostic and Treatment Centers for VaD.27 Stroke was identified through the ongoing hospital surveillance system. Apolipoprotein E (apoE) genotyping was performed at examination 4.28

We categorized BP, measured at the 3 midlife exams, as follows17: systolic BP (SBP) low (<110 mm Hg), normal (110 to 139 mm Hg), and borderline/high (≥140 mm Hg); diastolic BP (DBP) low (<80 mm Hg), normal (80 to 89 mm Hg), and borderline/high (≥90 mm Hg). Subjects were further classified as (n)ever treated with antihypertensive medication or report of treatment at any of the first 4 examinations. A new variable was created that combined treatment and midlife BP. The BP categories were collapsed into 2 categories: SBP ≥140 mm Hg versus <140 mm Hg; DBP ≥90 mm Hg versus <90 mm Hg. These BP categories were combined with treatment status (yes/no) to form 4 groups: never-treated–normal, treated-normal, never-treated–high, treated-high. For the analyses, the never treated–normal BP served as the reference group. Isolated high SBP was defined as SBP ≥140 mm Hg with a DBP <90 mm Hg. Isolated high DBP was defined as DBP ≥90 mm Hg with an SBP <140 mm Hg. These categories were also combined with treatment status in the same way as described above.

Magnetic Resonance Imaging Substudy

At examination 5, a magnetic resonance imaging (MRI) study was conducted on a subsample,29 including an ≈10% random sample and a randomly selected oversample of those with prevalent dementia, those who scored poorly on the CASI but did not meet criteria for dementia, those with apoE ε4 genotype, and those with clinical stroke.

Scans were acquired with a GE Signa Advantage 1.5 Tesla machine. The acquisition protocol included a T1 weighted sagital sequence, a three-dimensional coronal spoiled gradient echo sequence, and axial T2 and proton density weighted fast-spin echo sequences.

The coronal spoiled gradient echo sequence sequence was reformatted to oblique coronal, perpendicular to the long axis of the left hippocampus. The left and right hippocampal formations were measured according to published criteria30 and corrected for the total intracranial volume. One reader performed all measurements. The intraclass correlation coefficient for the intrareader agreement of the hippocampal volume (HV) was 0.97. Number of lacunes, cortical and subcortical infarcts,31 and white matter lesions (WMLs), graded on a scale of 0 to 9,32 were determined.

Measures of Confounding Variables

In addition to the variables used in sample selection, other possible confounders of the association between HA and BP were considered: education (<7 years, 7 to 9 years, >9 years [reference]), smoking (never [reference], current, and past) and daily alcohol use (none [reference], <1 drink, 1 or 2 drinks, >2 drinks per day).

Analytical Sample

Of 621 MRI scans collected, 543 MRI scans could be processed successfully for all relevant variables. The MRI sample subjects are somewhat older (81.6 versus 79.6 years; P<0.001) and had fewer years of education (10.3 versus 10.9 years; P=0.01) compared with the total sample at examination 5, but did not differ with respect to BP.

Statistical Analyses

We examined the relationship between BP and HV. We also created 2 groups by dichotomizing HV at the 25th percentile; ≤25 percentile was defined as HA. ANOVA was used to test age-adjusted differences in HV by subject characteristics; Mantel-Hansel test was used to test for differences in HA. We used a linear regression approach for HV and logistic regression approach for HA. Separate adjusted models were run for SBP and DBP, treatment status, and the combined BP/treatment variables. Three models were estimated: model 1 adjusted for age and education; model 2 also included apoE genotype, dementia status, smoking, and alcohol use; model 3 added other pathologies related to BP and HA, including lacunes, WMLs, and cortical and subcortical infarcts. The interaction between high and normal levels of BP and treatment was tested by entering into model 1 the cross product between the 2 variables. Because the conclusions were similar, we present the logistic regression association (OR and 95% confidence interval [CI]) of BP with HA.


The mean age of the MRI sample was 81.6 years (SD 5.0). In this sample, the left hippocampal volumes were smaller than the right hippocampal volumes (mean difference 138 mm3; SD 270; P<0.001). The results of the analyses for the left, right, and total HV did not differ, so we only present the analyses with the total HV. HVs were significantly higher in nondemented men compared with those with AD, AD with cardiovascular disease, and VaD (Table 1). HV was also significantly related to the CASI score (P<0.001; Table 2).

TABLE 1. Demographic Data of MRI Participants in the HAAS

Characteristic% of Subjects (n=543)HV, mm3 (mean [SD])% in Lower Quartile of HV
Age-adjusted P values compared to the normal reference group:
Age, years
    <8049.45583 (786)*16.4*
    >8050.65202 (842)32
Education, years
    <79.65120 (905)34.6
    7–938.35369 (830)24.5
    >952.15455 (820)22.3
ApoE ε genotype
    3356.25344 (842)25.7
    24, 34, 4436.15484 (821)21.4
    22, 237.75314 (843)26.2
    Not demented78.85560 (752)*16.8*
    AD9.24631 (820)62.0
    AD+4.24697 (888)56.5
    VaD4.14868 (810)40.9
    Other dementias3.75029 (822)*35*
    Never40.15313 (868)25.2
    Past31.95473 (773)22.0
    Current23.25426 (840)23.8
Alcohol (drinks per day)
    None27.85394 (891)21.9
    <147.35434 (801)23.0
    1–28.35229 (886)31.1
    >312.35373 (763)25.4
WMLs grade
    1–253.05470 (815)20.8
    319.95328 (868)26.9
    >427.15280 (844)29.3
    056.45358 (856)25.8
    1–232.25428 (803)22.3
    3–511.45443 (834)22.6
Subcortical infarcts
    096.35388 (831)24.1
    1–23.75454 (992)30.0
Cortical infarcts
    091.05395 (828)23.7
    1–49.05341 (926)30.6

TABLE 2. Mean CASI Score per Quartile of the HVs in the HAAS

Quartile of HVCASI Score (mean [SD])
The age-adjusted test of trend is P<0.001.
164.1 (20.6)
272.9 (13.7)
377.1 (11.5)
479.6 (11.8)

The prevalence of lacunes and infarcts was high. There was 3.7% with 1 or more subcortical infarcts, 9.0% with 1 or more cortical infarcts, and 47% with 1 or more lacunes. There was 27.3% with a WML score of 4 or higher. There were no significant differences in HV between the subjects with and without subcortical infarcts, cortical infarcts, lacunes, or white matter hyperintensities. However, the percentage of subjects with HV in the lowest quartile was higher in the subjects with cortical infarcts compared with the subjects without cortical infarcts (Table 3).

TABLE 3. Late-Age HV and HA by Midlife Blood Pressure and Treatment Group in the HAAS

GroupSubjects, %Mean HV, mm3 (mean [SD])% in Lower Quartile of HV
Treatment refers to high blood pressure treatment.
Normal SBP is <140 mm Hg; high SBP is ≥140 mm Hg; normal DBP is <90 mm Hg; high DBP is ≥90 mm Hg.
SBP, mm Hg
    <14074.25402 (840)23.3
    >14025.85358 (826)27.1
DBP, mm Hg
    <9083.15392 (860)25.1
    >9016.95384 (712)20.7
Treated with antihypertensives
    No52.35343 (898)28.6
    Yes47.75448 (757)19.3
    Not-treated–normal SBP46.05369 (903)26.8
    Treated-normal SBP28.05466 (717)17.1
    Not-treated–high SBP6.35147 (845)42.4
    Treated-high SBP19.75423 (813)22.4
    Not-treated–normal DBP48.85363 (902)27.5
    Treated-normal DBP34.15441 (790)21.1
    Not-treated–high DBP3.55045 (792)44.4
    Treated-high DBP13.65466 (671)14.9

In the total sample, DBP and SBP were not significantly associated with HA. Those not treated with antihypertensive medication, however, had a significantly increased risk for HA (OR=1.7: CI=1.12; 2.65), adjusting for age, education, ApoE genotype, smoking, alcohol use, and dementia. Treatment history modified the association between BP and HA. Compared with the never-treated–normal group, the treated men with normal or high SBP had a reduced risk (OR=0.56: CI=0.33; 0.97 and OR=0.74: CI=0.42; 1.32, respectively) for HA; the nontreated high SBP group had an increased risk (OR=1.98: CI=0.89; 4.39) for HA.

This same trend is seen in the DBP groups: the treated subjects with normal or with high DBP had a reduced risk (OR=0.69: CI=0.43; 1.12 and OR=0.50: CI=0.24; 1.04 respectively) and the untreated subjects with high DBP had an increased risk (OR=3.51: CI=1.26; 9.74) for HA compared with the nontreated subjects with normal DBP. The interaction between DBP and treatment was significant (P=0.03) as was the interaction between SBP and treatment (P=0.02). Adjusting for lacunes, subcortical infarcts, cortical infarcts, or WMLs did not change these associations (Table 4). Regression analyses with only the nondemented subjects resulted in essentially the same associations; the OR of untreated high DBP was somewhat higher (OR=4.76: CI=1.56; 14.5).

TABLE 4. Risk (OR [95% CI]) for Late-Age HA by Midlife Blood Pressure and Treatment With Antihypertensives in the HAAS

GroupModel 1Model 2Model 2+lacunesModel 2+ subcortical infarctsModel 2+ cortical infarctsModel 2+WML
Treatment refers to high blood pressure treatment.
Normal SBP is <140 mm Hg; high SBP is ≥140 mm Hg; normal DBP is<90 mm Hg; high DBP is ≥90 mm Hg.
Model 1: adjusted for age and education.
Model 2: adjusted for age, education, apoE genotype, smoking, alcohol, and dementia.
Not-treated–normal SBP111111
Treated-normal SBP0.580.560.600.560.550.56
Not-treated–high SBP1.741.982.141.902.051.89
Treated-high SBP0.790.740.770.730.730.73
Not-treated–normal DBP111111
Treated-normal DBP0.730.690.710.690.680.70
Not-treated–high DBP2.813.513.593.283.583.51
Treated-high DBP0.530.500.520.490.490.48

Isolated high SBP and isolated high DBP were not significantly associated with HA. Compared with those with untreated normal blood pressure, there were no significant differences in HA in men with isolated SBP who were treated (OR=0.9: CI=0.45;1.81) or not treated (OR=1.21: CI=0.49;3.02). Similarly, the risk for isolated DBP in treated (OR=0.17: CI=0.02;1.30) and untreated (OR=0.02: CI=0.44;8.42) men did not differ from those with untreated normal blood pressure.


In this longitudinal, prospective, population-based study we found that men never treated for high midlife BP had an increased risk for HA compared with never-treated men with normal midlife BP. Treatment with antihypertensive medication reduced the risk associated with high BP. Several studies show that more hippocampal atrophy is associated with poorer cognitive function, AD, as well as other causes of dementia.3–6,9,10,33–46

This study has several strengths. One is the community-based sample, which has a wide range of BP and includes persons who have never been treated with antihypertensive medication despite high levels of SBP or DBP in midlife. Second, BP was measured in midlife, years before the onset of dementia. This is crucial, because dementia, as well as other factors more prevalent in old age, may lead to a lowering of BP. This decline may begin many years before the clinical detection of dementia. Third, BP was measured at 3 different time points, 3 times at each examination, so a reasonable estimation of average BP was obtained. Furthermore, in the analyses, we controlled for WMLs and infarcts, which may mediate or confound any associations of HA to BP. Another important advantage of this study is that 1 rater performed the quantitative measure of HV, with a high intrarater reliability.

However, we might have missed subjects who were treated and than stopped treatment between exams 3 and 4. Further, the men were very old at the time the MRI was made. As subjects with longstanding hypertension are likely to die at a younger age because of the adverse effects of hypertension on other organs, the effects of high BP on the hippocampus may be underestimated. In addition, within subgroups that were oversampled, those in the MRI sample may have been slightly healthier compared with subgroup members randomly selected but who did not participate.

High BP was a significant risk factor for dementia in longitudinal studies.21,47 In the studies based on HAAS data we have found that higher levels of blood pressure increased the risk for cognitive impairment,17,19 clinical AD and VaD,18 and neuropathological markers of AD.20 In the clinical data these associations were modified by treatment status, whereby the greatest risk for adverse brain events was in those never treated with antihypertensives. The findings of a blood pressure and treatment interaction on the risk for HA is consistent with these previously published analyses based on different measures of brain pathology.

The studies of Amenta et al and Sabbatini et al are of interest in the light of our findings.48,49 In both studies, a group of normal rats and a group of genetically manipulated hypertensive rats were investigated. In the study of Amenta et al, hypertensive rats had reduced BP and tunica media thickness of intracerebral arteries after treatment with nicardipine, a calcium-channel blocker. In the hippocampus of the hypertensive rats, the number and size of neurons in the CA1 field were reduced compared with the normal rats, and the number of neurons in the CA1 field was increased after treatment with nicardipine. The study of Sabbatini et al also showed that the volume of hippocampi in hypertensive rates was smaller, and the volume increased when the rats were treated with antihypertensives. This volume decrease and increase was mostly explained by volume changes in the CA1 field. The treatment effects found in these animal studies are consistent with our finding that treatment was associated with a protective effect on HV. In the HAAS we do not have information on the type of antihypertensive medication that was taken nor is it known whether the treatment effect in the animals studies was specific for the nicardipine. Further research in this area is warranted.

Also of interest in light of our findings is the study of de Jong et al,16 in which chronic brain hypoperfusion was found to cause selective capillary abnormalities in the CA1 region in rats, and the severity of capillary abnormalities was significantly related to cognitive performance. It is possible that the capillary changes precede neuronal changes and atrophy, and hypotension (ie, caused by long-standing hypertensive vascular changes) plays a role in the atrophy of the hippocampus.

We took vascular damage in the brain into account, because it may confound or mediate the association between the HV and BP. Lacunes, subcortical and cortical infarcts, and WMLs did not change the associations of interest. Earlier reports suggest that small vessel disease may be closely associated with hippocampal volume loss39 or hippocampal hypoperfusion.50 In this study, correction for WMLs and lacunes did not alter the relation we found between BP/treatment and HV. This is in contrast to the hypothesis that hypertension influences the white matter changes and hippocampus through similar mechanisms. That the mechanism of BP on HV is probably different from the hypertensive effect on WMLs is supported by the findings of Fein et al,51 who found that WMLs correlated with cortical atrophy, but not specifically with HA.

In conclusion, high levels of untreated BP was associated with HA. Treatment with antihypertensive treatment may modify this association.


HA is usually classified as a pure neurodegenerative process. This study shows that a risk factor for vascular damage, hypertension, may also be associated with HA. The precise mechanism is unknown. Our findings should stimulate more studies to explore the effect on hippocampal atrophy of elevated levels of BP and of antihypertensive treatments. Also, other clinical and experimental studies are needed to delineate the pathophysiology of how elevated blood pressure modifies brain structure and risk for neurodegeneration. Such studies may help us to understand the etiology of the prevalent types of late-life cognitive disorders.

The Honolulu Asia Aging Study is supported by the National Institutes of Health, National Institute on Aging (NO1-AG-4–2149), and the National Heart, Lung and Blood Institute (NO1-HC-05102). Additional funds were received from the Stichting Alzheimer &amp; Neuropsychiatrie Foundation, Amsterdam (ESC Korf).


Correspondence to L.J. Launer, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Ave, Suite 3C-309, Bethesda, MD 20892. E-mail


  • 1 Rempel-Clower NL, Zola SM, Squire LR, Amaral DG. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J Neurosci. 1996; 16: 5233–5255.CrossrefMedlineGoogle Scholar
  • 2 Convit A, de Asis J, de Leon MJ, Tarshish CY, De Santi S, Rusinek H. Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer’s disease. Neurobiol Aging. 2000; 21: 19–26.MedlineGoogle Scholar
  • 3 Dickerson BC, Goncharova I, Sullivan MP, Forchetti C, Wilson RS, Bennett DA, Beckett LA, DeToledo-Morrell L. MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease. Neurobiol Aging. 2001; 22: 747–754.CrossrefMedlineGoogle Scholar
  • 4 Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA. Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology. 2002; 58: 1476–1482.CrossrefMedlineGoogle Scholar
  • 5 Jack CR, Jr., Dickson DW, Parisi JE, Xu YC, Cha RH, O’Brien PC, Edland SD, Smith GE, Boeve BF, Tangalos EG, Kokmen E, Petersen RC. Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology. 2002; 58: 750–757.CrossrefMedlineGoogle Scholar
  • 6 Killiany RJ, Hyman BT, Gomez-Isla T, Moss MB, Kikinis R, Jolesz F, Tanzi R, Jones K, Albert MS. MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology. 2002; 58: 1188–1196.CrossrefMedlineGoogle Scholar
  • 7 Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, Morris CM, O’Brien JT. Apolipoprotein E epsilon4 allele, temporal lobe atrophy, and white matter lesions in late-life dementias. Arch Neurol. 1999; 56: 961–965.CrossrefMedlineGoogle Scholar
  • 8 Pantel J, Schroder J, Essig M, Jauss M, Schneider G, Eysenbach K, von Kummer R, Baudendistel K, Schad LR, Knopp MV. In vivo quantification of brain volumes in subcortical vascular dementia and Alzheimer’s disease. An MRI-based study. Demen Geriatr Cogn Disord. 1998; 9: 309–316.CrossrefMedlineGoogle Scholar
  • 9 Golomb J, Kluger A, de Leon MJ, Ferris SH, Convit A, Mittelman MS, Cohen J, Rusinek H, De Santi S, George AE. Hippocampal formation size in normal human aging: a correlate of delayed secondary memory performance. Learn Mem. 1994; 1: 45–54.CrossrefMedlineGoogle Scholar
  • 10 Toledo-Morrell L, Dickerson B, Sullivan MP, Spanovic C, Wilson R, Bennett DA. Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer’s disease. Hippocampus. 2000; 10: 136–142.CrossrefMedlineGoogle Scholar
  • 11 Kazee AM, Eskin TA, Lapham LW, Gabriel KR, McDaniel KD, Hamill RW. Clinicopathologic correlates in Alzheimer disease: assessment of clinical and pathologic diagnostic criteria. Alzheimer Dis Assoc Disord. 1993; 7: 152–164.CrossrefMedlineGoogle Scholar
  • 12 Van Hoesen GW, Hyman BT. Hippocampal formation: anatomy and the patterns of pathology in Alzheimer’s disease. Prog Brain Res. 1990; 83: 445–457.CrossrefMedlineGoogle Scholar
  • 13 Gadian DG, Aicardi J, Watkins KE, Porter DA, Mishkin M, Vargha-Khadem F. Developmental amnesia associated with early hypoxic-ischaemic injury. Brain. 2000; 123 Pt 3: 499–507.MedlineGoogle Scholar
  • 14 Horsburgh K, Graham DI, Stewart J, Nicoll JA. Influence of apolipoprotein E genotype on neuronal damage and apoE immunoreactivity in human hippocampus following global ischemia. J Neuropathol Exp Neurol. 1999; 58: 227–234.CrossrefMedlineGoogle Scholar
  • 15 Smith ML, Auer RN, Siesjo BK. The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol(Berl). 1984; 64: 319–332.CrossrefMedlineGoogle Scholar
  • 16 De Jong GI, Farkas E, Stienstra CM, Plass JR, Keijser JN, de la Torre JC, Luiten PG. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience. 1999; 91: 203–210.CrossrefMedlineGoogle Scholar
  • 17 Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995; 274: 1846–1851.CrossrefMedlineGoogle Scholar
  • 18 Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobio Aging. 2000; 21: 49–55.CrossrefMedlineGoogle Scholar
  • 19 Peila R, White LR, Petrovich H, Masaki K, Ross GW, Havlik RJ, Launer LJ. Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment: the Honolulu-Asia aging study. Stroke. 2001; 32: 2882–2889.CrossrefMedlineGoogle Scholar
  • 20 Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, Nelson J, Davis DG, Hardman J, Foley DJ, Launer LJ. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000; 21: 57–62.MedlineGoogle Scholar
  • 21 Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, Ohmori S, Nomiyama K, Kawano H, Ueda K. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995; 45: 1161–1168.CrossrefMedlineGoogle Scholar
  • 22 White L, Petrovitch H, Ross GW, Masaki KH, Abbott RD, Teng EL, Rodriguez BL, Blanchette PL, Havlik RJ, Wergowske G, Chiu D, Foley DJ, Murdaugh C, Curb JD. Prevalence of dementia in older Japanese-Am men in Hawaii: The Honolulu-Asia Aging Study. JAMA. 1996; 276: 955–960.CrossrefMedlineGoogle Scholar
  • 23 Teng EL, Hasegawa K, Homma A, Imai Y, Larson E, Graves A, Sugimoto K, Yamaguchi T, Sasaki H, Chiu D. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr. 1994; 6: 45–58.CrossrefMedlineGoogle Scholar
  • 24 Havlik RJ, Izmirilian G, Petrovich H, Ross GW, Masaki K, Curb JD, Saunders AM, Foley D, Brock D, Launer LJ, White L. APOE-epsilon4 predicts incident AD in Japanese-Am men: the Honolulu Asia Aging Study. Neurology. 2000; 54: 1526–1529.CrossrefMedlineGoogle Scholar
  • 25 Am Psychiatric Association. Am Psychiatric Association Committee on Nomenclature and Statistics. Diagnostic and Statistical Manual of Mental Disorders (DSM-IIIR), Fourth Edition. Washington DC: 1987.Google Scholar
  • 26 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984; 34: 939–944.CrossrefMedlineGoogle Scholar
  • 27 Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology. 1992; 42: 473–480.CrossrefMedlineGoogle Scholar
  • 28 Hixson JE, Powers PK. Restriction isotyping of human apolipoprotein A-IV: rapid typing of known isoforms and detection of a new isoform that deletes a conserved repeat. J Lipid Res. 1991; 32: 1529–1535.CrossrefMedlineGoogle Scholar
  • 29 White LR, Petrovitch H, Ross GW, Masaki K, Hardman J, Nelson J, Davis D, Markesbery W. Brain aging and midlife tofu consumption. J Am Coll Nutr. 2000; 19: 242–255.CrossrefMedlineGoogle Scholar
  • 30 Jack CR, Jr. MRI-based hippocampal volume measurements in epilepsy. Epilepsia. 1994; 35 Suppl 6: S21–S29.Google Scholar
  • 31 Longstreth WT, Jr., Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol. 1998; 55: 1217–1225.CrossrefMedlineGoogle Scholar
  • 32 Bryan RN, Manolio TA, Schertz LD, Jungreis C, Poirier VC, Elster AD, Kronmal RA. A method for using MR to evaluate the effects of cardiovascular disease on the brain: the cardiovascular health study. AJNR Am J Neuroradiol. 1994; 15: 1625–1633.MedlineGoogle Scholar
  • 33 Du AT, Schuff N, Amend D, Laakso MP, Hsu YY, Jagust WJ, Yaffe K, Kramer JH, Reed B, Norman D, Chui HC, Weiner MW. Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2001; 71: 441–447.CrossrefMedlineGoogle Scholar
  • 34 Golebiowski M, Barcikowska M, Pfeffer A. Magnetic resonance imaging-based hippocampal volumetry in patients with dementia of the Alzheimer type. Dement Geriatr Cogn Disord. 1999; 10: 284–288.CrossrefMedlineGoogle Scholar
  • 35 Jack CR, Jr., Petersen RC, Xu YC, Waring SC, O’Brien PC, Tangalos EG, Smith GE, Ivnik RJ, Kokmen E. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology. 1997; 49: 786–794.CrossrefMedlineGoogle Scholar
  • 36 Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein HC, Vermersch P, Kuiper M, Steinling M, Wolters EC, Valk J. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry. 1992; 55: 967–972.CrossrefMedlineGoogle Scholar
  • 37 Bigler ED, Lowry CM, Anderson CV, Johnson SC, Terry J, Steed M. Dementia, quantitative neuroimaging, and apolipoprotein E genotype. AJNR Am J Neuroradiol. 2000; 21: 1857–1868.MedlineGoogle Scholar
  • 38 Hashimoto M, Kitagaki H, Imamura G, Hirono H, Shimomura T, Kazui H, Tanimukai S, Hanihara T, Mori E. Medial temporal and whole-brain atrophy in dementia with Lewy-bodies: a volumetric MRI study. Neurology. 1998; 51: 357–362.CrossrefMedlineGoogle Scholar
  • 39 Kril JJ, Patel S, Harding AJ, Halliday GM. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J Neurol Neurosurg Psychiatry. 2002; 72: 747–751.CrossrefMedlineGoogle Scholar
  • 40 Jack CR, Jr., Petersen RC, Xu YC, O’Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999; 52: 1397–1403.CrossrefMedlineGoogle Scholar
  • 41 Visser PJ, Scheltens P, Verhey FR, Schmand B, Launer LJ, Jolles J, Jonker C. Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment. J Neurol. 1999; 246: 477–485.CrossrefMedlineGoogle Scholar
  • 42 Visser PJ, Verhey FR, Hofman PA, Scheltens P, Jolles J. Medial temporal lobe atrophy predicts Alzheimer’s disease in patients with minor cognitive impairment. J Neurol Neurosurg Psychiatry. 2002; 72: 491–497.MedlineGoogle Scholar
  • 43 Kohler S, Black SE, Sinden M, Szekely C, Kidron D, Parker JL, Foster JK, Moscovitch M, Winocour G, Szalai JP, Bronskill MJ, Wincour G. Memory impairments associated with hippocampal versus parahippocampal-gyrus atrophy: an MR volumetry study in Alzheimer’s disease. Neuropsychologia. 1998; 36: 901–914.CrossrefMedlineGoogle Scholar
  • 44 Launer LJ, Scheltens P, Lindeboom J, Barkhof F, Weinstein HC, Jonker C. Medial temporal lobe atrophy in an open population of very old persons: cognitive, brain atrophy, and sociomedical correlates. Neurology. 1995; 45: 747–752.CrossrefMedlineGoogle Scholar
  • 45 Mizuno K, Wakai M, Takeda A, Sobue G. Medial temporal atrophy and memory impairment in early stage of Alzheimer’s disease: an MRI volumetric and memory assessment study. J Neurol Sci. 2000; 173: 18–24.CrossrefMedlineGoogle Scholar
  • 46 Petersen RC, Jack CR, Jr., Xu YC, Waring SC, O’Brien PC, Smith GE, Ivnik RJ, Tangalos EG, Boeve BF, Kokmen E. Memory and MRI-based hippocampal volumes in aging and AD. Neurology. 2000; 54: 581–587.CrossrefMedlineGoogle Scholar
  • 47 Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, Persson G, Oden A, Svanborg A. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996; 347: 1141–1145.CrossrefMedlineGoogle Scholar
  • 48 Amenta F, Strocchi P, Sabbatini M. Vascular and neuronal hypertensive brain damage: protective effect of treatment with nicardipine. J Hypertens Suppl. 1996; 14: S29–S35.Google Scholar
  • 49 Sabbatini M, Tomassoni D, Amenta F. Hypertensive brain damage: comparative evaluation of protective effect of treatment with dihydropyridine derivatives in spontaneously hypertensive rats. Mech Ageing Dev. 2001; 122: 2085–2105.CrossrefMedlineGoogle Scholar
  • 50 Waldemar G, Christiansen P, Larsson HB, Hogh P, Laursen H, Lassen NA, Paulson OB. White matter magnetic resonance hyperintensities in dementia of the Alzheimer type: morphological and regional cerebral blood flow correlates. J Neurol Neurosurg Psychiatry. 1994; 57: 1458–1465.CrossrefMedlineGoogle Scholar
  • 51 Fein G, Di S, V, Tanabe J, Cardenas V, Weiner MW, Jagust WJ, Reed BR, Norman D, Schuff N, Kusdra L, Greenfield T, Chui H. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology. 2000; 55: 1626–1635.CrossrefMedlineGoogle Scholar


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