Cerebral amyloid angiopathy and cognitive function
The HAAS autopsy study
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Abstract
Objective: To investigate the relationship between cerebral amyloid angiopathy (CAA), dementia, and cognitive function in an autopsy sample of 211 Japanese-American men from the population-based Honolulu–Asia Aging Study.
Methods: Starting in 1991, participants were assessed with the Cognitive Abilities Screening Instrument (CASI) and diagnosed with dementia (including subtype) based on published criteria. At autopsy, neuropathologists blinded to clinical data examined brains for neurofibrillary tangles (NFT), neuritic plaques (NP), and a number of vascular pathologies, including CAA. CAA was detected by immunostaining for βA4 amyloid in parenchymal vessels in the neocortex and semiquantitatively rated. Linear regression models were used to examine the association of CASI score, dementia subtype, and CAA controlling for age at death, time between CASI administration and death, education, NP and NFT counts, infarcts, hemorrhage, and APOE genotype.
Results: A total of 44.1% of subjects had CAA in at least one neocortical area. The presence of CAA was associated with higher mean NFT and NP counts and having at least one APOE-ε4 allele. The interaction between CAA and AD on the adjusted mean CASI score was significant; compared with nondemented men without CAA, the CASI score was 16.6% lower in men with AD and no CAA and 45.9% lower in men with AD plus CAA.
Conclusions: CAA may contribute to the clinical presentation of dementia by interacting with other neuronal pathologies, leading to more severe cognitive impairment in men with both CAA and AD compared with men with only AD or CAA.
Sporadic cerebral amyloid angiopathy (CAA) is a microangiopathy that frequently co-occurs with AD1 and appears to increase with age.2 This pathology is characterized by the accumulation of amyloid β-protein (Aβ) in the media and adventitia of parenchymal and leptomeningeal vessels and also has been seen in association with several other neurologic conditions such as Down’s syndrome and dementia pugilistica. Other forms of CAA include the heritable CAA types and CAA due to transthyretin variants or prion disease.3 With severe CAA, affected vessels often assume a characteristic “double-barreled” appearance as smooth muscle cells separate and degenerate. Eventually, amyloid fibrils replace the smooth muscle cells, resulting in brittle vessel walls that are vulnerable to microaneurysm and hemorrhage.4 Except in instances in which hemorrhages suggestive of CAA have occurred,5 the majority of cases of CAA are diagnosed at autopsy.
We hypothesized that CAA itself may affect cognitive function and modify the clinical presentation of dementia, including the major subtypes AD and vascular dementia (VaD). To address this question, we examined clinical and neuropathologic data from the Honolulu–Asia Aging Study (HAAS), a prospective cohort study of dementia that includes an autopsy substudy.
Methods.
Study population.
The HAAS is a follow-up to the Honolulu Heart Program (HHP), a longitudinal study of heart disease and stroke. The HHP cohort was comprised of 8006 Japanese-American men born between 1900 and 1919 and living on Oahu at the time of enrollment (1965 to 1968).6 In 1991, surviving HHP cohort members were invited to join the HAAS7: 80% (n = 3734) of the surviving participants were examined. In 1994 through 1996, 2,704 participants returned for a follow-up examination. During the HAAS visits, information on medical history and psychosocial factors was obtained and clinical and neuropsychologic evaluations were performed. Blood collected in 1991 through 1993 was used for APOE genotyping.8 The study was approved by the Institutional Review Boards of the Kuakini Medical Center and the Honolulu Department of Veterans Affairs. All participants gave written informed consent.
In 1991 through 1993, the autopsy study was established. Nondemented participants were asked to sign an autopsy consent form and to share copies with their family. An appropriate family member was asked to sign in the case of demented participants. The entire cohort was eligible for the autopsy study, but participants with a diagnosis of dementia were targeted to ensure an adequate sample size for comparisons of cases to controls. To date, 259 individuals have come to autopsy: 71.0% died in the hospital, 13.1% died at home, 11.2% died in a nursing home, and 4.6% died in a hospice or other place. Consent for the autopsy was obtained from a family representative at the time of death.
Assessment of cognitive function and dementia.
At both the HAAS baseline (1991 through 1993) and follow-up visit (1994 through 1996), participants were evaluated with the Cognitive Abilities Screening Instrument (CASI). The CASI is a cross-culturally validated test of global cognitive function designed for use in comparative studies of dementia in the United States and Japan.9 It is a composite of the Hasegawa Dementia Screening Scale,10 the Mini-Mental State Examination,11 and the Modified Mini-Mental State Test.12 The CASI consists of seven sections that assess attention, concentration, orientation, short- and long-term memory, language ability, visual construction, word list generation, abstraction, and judgment. Scores may range from 0 to 100, with higher scores indicating better overall cognitive function. The CASI score obtained closest to time of death was used in the analyses.
The dementia workup has been described in detail elsewhere.7 Briefly, after the CASI an additional workup was performed on a subsample of individuals that included the following: a repeat CASI, neurologic examination, hearing and vision testing, proxy interview including the Informant Questionnaire on Cognitive Decline in the Elderly,13 neuroimaging, blood tests, and the Consortium to Establish a Registry for AD (CERAD) neuropsychologic battery.14 A panel composed of the study neurologist and at least two other physicians with expertise in geriatrics and dementia reviewed subjects’ information and assigned a clinical diagnosis. The panel used the criteria from the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed.—rev. to diagnose dementia.15 AD was diagnosed using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke/AD and Related Disorders Association16 and VaD was diagnosed using the California AD and Treatment Centers criteria.17
Neuropathologic assessment.
The HAAS autopsy study aims to identify pathology related to neurodegenerative and cerebrovascular pathologies. In this study, we focused on the pathologies of CAA and AD and a subset of other cerebrovascular pathology. Brains were removed from the skull, weighed, and immersed in 10% buffered formalin for 2 to 6 weeks. After fixation, brains were reweighed and the dural membranes and external brain surfaces (including blood vessels and leptomeninges) were removed. A neuropathologist examined 1-cm-thick coronal sections of cerebral cortex and 3-mm-thick transverse sections of brainstem and cerebellum for macroscopic lesions. Microscopic assessments were performed by one of three neuropathologists blinded to clinical information. The analyses of CAA, neurofibrillary tangles (NFT), and neuritic plaques (NP) were performed in a microscopic examination of four neocortical areas—middle frontal gyrus, superior–middle temporal gyri, inferior parietal lobule, and occipital association cortex along the calcarine sulcus. The analysis of microscopic cerebrovascular lesions was performed in evaluations of 32 brain regions, which included the four neocortical areas.
Assessment of CAA.
Eight-micron blocks of paraffin embedded tissue were prepared using standard histologic methods and stained with hematoxylin and eosin. To detect CAA, sections were immunostained for βA4 amyloid (clone 10D5, Athena Neurosciences, San Francisco, CA).18 Blood vessels in each neocortical section were examined under 250× magnification and separate grades were given to meningeal and parenchymal vessels. The measure of CAA obtained from parenchymal vessels (mainly arteries and arterioles) was used in these analyses. CAA assessments were standardized among the three raters according to published guidelines.19 The raters discussed specific problems related to field selection and grading during training sessions. A grade of “mild” CAA was given to sections containing one or two βA4-positive vessels. Sections with three to five positive vessels were designated as “moderate,” and sections with greater than five positive vessels were designated as “severe.” If all vessels within an area were nonreactive the section was designated “CAA absent.” For this study, CAA grades from the four neocortical areas were combined to yield an overall CAA grade. Men free of CAA in all four areas received an overall grade of CAA absent. An overall grade of mild was given to men with only mild CAA in one or more areas. Men with moderate CAA in at least one area received an overall grade of moderate, and men with severe CAA in at least one area received an overall grade of severe.
Assessment of AD neuropathology.
The assessment for AD pathology has been described elsewhere.20 Briefly, senile plaques and NFT were visualized with modified Bielschowsky21 and Gallyas silver stains and examined under magnifications of 100× and 200×. Plaques containing silver-positive neurites (NP) were differentiated from neurite-free (diffuse) plaques and separate counts were made. To obtain maximum NP and NFT counts, five fields standardized to 1 mm2 in diameter were examined for each neocortical area. In each region, the field with the highest count was taken to represent the area.22 NP counts were truncated at 17/mm2 but there was no upper limit for NFT counts.
Assessment of cerebrovascular lesions.
Large and small infarcts were detected in the macroscopic examination and defined as circumscribed, cavitary lesions traversed by gliovascular trabeculae and distant from surface structures in the brain. Infarcts less than 1 mm in size were designated as lacunae. Lesions with a substantial collection of blood or hemosiderin and minimal evidence of ischemic infarction were designated large (>1 cm) or small (<1 cm) hemorrhages; these were detected on the macroscopic or microscopic examination.
Neuropathologic diagnosis of AD.
The CERAD neuropathology protocol23 was adapted to assign a postmortem diagnosis of neuropathologically confirmed AD (nAD). To meet the requirements for this diagnosis individuals were required to have a clinical history of dementia and a minimum number of NP—4 for probable AD and 17 for definite AD. Of the 22 men in our sample with a clinical diagnosis of AD, 12 had definite or probable nAD. Of the 14 men with a clinical diagnosis of AD with cerebrovascular disease (AD with CVD), four met the criteria for nAD. The cases that were neuropathologically confirmed did not differ from those who were not confirmed with regard to age, education, time between last CASI examination and autopsy, frequency of the APOE-ε4 allele, or presence of infarct. The confirmed cases had a slightly lower CASI score and more lacunae. Further neuropathologic descriptions of the clinical cases of AD and AD with CVD that did not meet CERAD criteria have been reported elsewhere.20
Analytical sample.
Our final sample consisted of 211 (81.5%) of the 259 completed autopsy cases; 41 individuals died before the CASI could be administered and seven individuals could not be tested. The mean length of time between the HAAS baseline examination and death was 3.9 years (range, <1 to 7.6 years) and the mean length of time between CASI administration and death was 2.4 ± 0.09 years. The mean age at death in our sample (84.7 ± 5.4 years) was similar to that for all nonautopsied decedents (85.3 ± 6.0 years). Years of education completed (9.8 ± 3.3 vs 10.0 ± 3.2 vs 10.7 ± 3.2 years) and late-life total cholesterol values (186.0 ± 34.5 vs 183.1 ± 35.4 vs 192.3 ± 31.8 mg/dL) were similar among our sample, nonautopsied decedents, and surviving HAAS cohort members. The percentage of individuals in our sample with at least one APOE-ε4 allele (12.8%) was slightly lower compared with the other groups (18%). By design, approximately 35% of autopsied decedents were demented (n = 73) compared with 18.4% of nonautopsied decedents. Participants still alive at the time of analysis were significantly younger and less often demented (4.3%).
Data analysis.
Sixty-seven subjects had severe CAA, 20 had moderate CAA and 10 had mild CAA. To increase statistical power we dichotomized the CAA variables as “CAA present” (overall CAA grade of mild, moderate, or severe CAA) and “CAA absent.” The CAA groups were compared with analysis of variance for continuous variables and with χ2 tests for categorical variables. Linear regression was used to examine the association of CASI score to CAA and clinical dementia diagnosis (all dementia, AD, AD with CVD, and VaD). We tested the joint effect of CAA and dementia on cognitive function by subdividing the subjects into four groups: nondemented/CAA absent (reference group), nondemented/CAA present, demented (subtype)/CAA absent, and demented (subtype)/CAA present. We also tested whether the interaction between CAA and dementia (subtype) was significant by putting the cross-product term (CAA × dementia diagnosis) into the models predicting CASI score. Possible confounding or mediating factors considered in the models included the following: APOE genotype (ε3,3 [n = 160], ε2,3 [n = 14], ε2,4/3,4/4,4 [n = 27], and missing [n = 10]), age at death, time between CASI administration and death, education level, and neuropathologic findings, including NP and NFT count and presence of infarcts and hemorrhages.
Two models are shown. The basic model (Model 1) is adjusted for age at death, time between CASI administration and death, and education level. The second model is fully adjusted for all confounders and includes the Model 1 variables as well as APOE genotype and neuropathologic measures. We also checked whether the separate addition of APOE genotype or any of the neuropathologic variables to Model 1 significantly altered the relationship between dementia (subtype), CAA, and CASI score. The AD/CAA present and AD/CAA absent groups were analyzed based on both clinical (n = 22) and neuropathologic (n = 16) diagnoses of AD. All analyses were conducted with SAS statistical software, release 6.12 (SAS Institute, Cary, NC).24
Results.
CAA was present in at least one neocortical area in 44.1% of subjects. Compared with the subset of individuals free of CAA, men with CAA were older at death and more likely to carry at least one APOE-ε4 allele (table 1). There was no difference in the age-adjusted mean CASI score between the groups. Individuals with CAA had significantly more NP and NFT but the presence of infarction or hemorrhage did not differ between the groups.
Description of study sample: The Honolulu–Asia Aging Study autopsy study
When all demented cases were combined, there was no significant difference in the prevalence of CAA in demented (54.8%) vs nondemented (38.4%) individuals. A significantly greater percentage of demented men had severe CAA (42.5%) compared with nondemented men (23.9%). The percentage with CAA varied among the dementia subtypes: 59.0% of AD cases and 63.0% of VaD cases had CAA, but only 42.9% of the AD with CVD cases had CAA. In multivariate analyses controlling for age, education, NFT and NP count, CVD, APOE allele, and time between the last CASI examination and autopsy, the presence of CAA did not significantly alter the risk for dementia or dementia subtypes. Of the 22 men with AD, 4.6% had mild, 9.1% had moderate, and 54.5% had severe CAA. Among the 27 VaD cases, 7.4% had mild, 11.1% had moderate, and 44.4% had severe CAA. Among the 14 AD with CVD cases, 42.9% had severe CAA and the rest were free of CAA.
CAA was detected in all four neocortical areas: 30.8% of the men had frontal, 28.2% had temporal, 29.0% had parietal, and 36.5% had occipital CAA. Severe CAA was most often found in the occipital lobe (28.0%). Demented men were more likely to have CAA in the occipital (age-adjusted p < 0.01) and temporal lobes (age-adjusted p < 0.06); CAA did not preferentially affect any particular neocortical area in nondemented men.
CAA was not associated with the adjusted mean CASI score in nondemented men (table 2). We also saw no association between CAA and CASI score when all demented men were grouped together. There was, however, a significant interaction between CAA and AD reflecting the difference in CASI score between the AD/CAA present and AD/CAA absent groups. The separate addition of the other neuropathologic variables, or of APOE genotype did not alter these associations. In the fully adjusted model (Model 2), compared with the nondemented/CAA absent group, CASI score was 16.6% lower in the AD/CAA absent group and 45.9% lower in the AD/CAA present group. The CASI score of the AD/CAA present group was significantly lower that than of the AD/CAA absent group. Owing to the small number of individuals in the AD/CAA present group with mild or moderate CAA (n = 3), we were unable to determine if this interaction depended on CAA severity.
CASI scores by clinical dementia diagnosis and CAA status: The Honolulu–Asia Aging Study autopsy study
In the analyses of AD with CVD cases, the significant difference in CASI score between cases with and without CAA (Model 1) was no longer significant after adjustment for NP and NFT. In the analyses based on the neuropathologic diagnosis of AD (which included both AD cases without CVD and AD with CVD cases), the difference in adjusted mean [95% CI] CASI score between the AD/CAA absent and AD/CAA present groups was not significant (43.1 [28.2 to 58.0]) vs 33.9 [22.3 to 45.5]). CAA was not associated with significantly lower CASI scores within the VaD groups.
Discussion.
We investigated the relationship between cognitive function, dementia (subtype), and CAA in an autopsy sample drawn from a population-based cohort of elderly Japanese-American men. CAA was not associated with cognitive function in nondemented men or men with AD with CVD or VaD. However, we did find a strong association between CASI score and presence of CAA in cases of AD: men with both AD and CAA performed significantly worse than men with AD alone, even after adjusting for potential confounders. This finding may be indicative of a synergistic relationship between the pathologies of CAA and AD, which leads to greater cognitive impairment in people with both conditions compared with those with no CAA, CAA only, or AD only.
Although a number of other autopsy studies have examined CAA in elderly populations,1,2,25-31⇓⇓⇓⇓⇓⇓⇓⇓ only one other study has explored the functional consequences of CAA.1 This study of CERAD subjects with autopsy-confirmed AD found no association between cognitive function and CAA. However, in that study, outcome was measured with the Clinical Dementia Rating scale, while we used the CASI, a global test of cognitive function.
Other features of our study also distinguish it from other autopsy series that assessed CAA. The HAAS autopsy sample is larger than that of other studies27-29⇓⇓ and was drawn from a population-based cohort with participants exhibiting a range of clinical presentations, rather than from a more selected hospital or clinic-based population.1,19,25,26,29⇓⇓⇓⇓ In addition, we examined the relationship between CAA and cognitive function in all subjects, not just those with a history of dementia1,30⇓ or cerebral hemorrhage,26,31⇓ as others have done.
There are methodologic limitations of our study that should be addressed. Our cohort consists of Japanese-American men: differences in the prevalence of CAA, dementia subtypes, and CVD in women or in other ethnic groups may modify our observed relationship between CAA, AD, and cognitive function. Second, our CAA grades were assigned using a system based on the number of CAA-positive parenchymal vessels per area of neocortex.19 Several other CAA grading systems are in use, however, including systems based on measures of total amyloid burden,32 percentage of affected vessels,2 or extent of vessel damage.4 At present there is no consensus on the best criteria for grading CAA, but estimating involvement of the vessel wall may be preferred for studies of CAA and hemorrhage.3 Third, the results may be confounded by differences across groups in the intervals between diagnosis, CASI administration, and death, which could lead to misclassification of the CASI score. However, these intervals were not significantly different from one another across our analytical groups. Finally, our results may be biased by preferential inclusion of people with more severe AD who also had CAA into the sample. This is unlikely because CAA status before death was not known. Also, we saw no significant difference between the age-adjusted mean CASI score in autopsied and nonautopsied cases of AD.
Several biologically plausible pathways could account for our observed relationship between AD and CAA. Studies in humans and in a variety of animal models have demonstrated that CAA may lead to hemorrhage, necrosis, inflammation, release of neurotoxic substances, and increased oxidative stress.33 The presence of CAA in cerebral vessels may impair brain metabolism, homeostasis, nutrient delivery, and cerebral blood flow.34 It has also been demonstrated that CAA-laden vessels may be less able to respond to changes in blood pressure and to repair themselves or regenerate after injury.35 If the CAA- and AD-related pathologies act synergistically to prompt or promote these adverse consequences, it is possible that more neuronal death occurs than if only CAA or only AD pathology is present. Because we controlled for NP and NFT, other associated AD pathology36 leading to compromised neuronal function may be important in this interaction. It is also possible that the association reflects a greater amyloid burden32 or vascular burden34 not accounted for by our measures. Interestingly, the highest prevalence of CAA was in the occipital lobe, an area not traditionally thought to be involved in AD. This may be related to the fact that the occipital lobe is vascularized by the posterior circulatory system, which also feeds parts of the hippocampus.37 Reasons for a particular vulnerability of the occipital lobe to CAA warrants more investigation.
The presence of CAA did not modify the association of CASI score with a diagnosis of AD with CVD or VaD. CASI score in the AD with CVD/CAA absent group was lower than the mean in the corresponding AD group. Similarly, the CASI scores in the VaD group were very low. Perhaps the combination of other forms of vascular pathology and AD pathology overwhelmed any additional effect CAA may have had on pathways involved in cognition. It is also possible that subjects with a diagnoses of AD with CVD or VaD were so severely impaired, regardless of whether or not CAA was present, that there was a floor effect in CASI scores. Finally, CAA was not associated with CASI score in the nondemented group. This needs further investigation with larger samples to examine the effects of CAA location and severity on cognitive function.
Acknowledgments
Supported by the NIH National Institute on Aging contract NO1-AG-4-2149, and National Heart, Lung, and Blood Institute contract NO1-HC-O5102.
Footnotes
See also page 1587
- Received October 22, 2001.
- Accepted in final form March 12, 2002.
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