Delayed recall, hippocampal volume and Alzheimer neuropathology: findings from the Nun Study.

OBJECTIVE: To examine the associations of hippocampal volume and the severity of neurofibrillary lesions determined at autopsy with delayed verbal recall performance evaluated an average of 1 year prior to death. METHODS: Hippocampal volumes were computed using postmortem brain MRI from the first 56 scanned participants of the Nun Study. Quantitative neuropathologic studies included lesion counts, Braak staging, and determination of whether neuropathologic criteria for Alzheimer disease (AD) were met. Multiple regression was used to assess the association of hippocampal volume and neuropathologic lesions with the number of words (out of 10) recalled on the Consortium to Establish a Registry for Alzheimer's Disease Delayed Word Recall Test administered an average of 1 year prior to death. RESULTS: When entered separately, hippocampal volume, Braak stage, and the mean neurofibrillary tangle counts in the CA-1 region of the hippocampus and the subiculum were strongly associated with the number of words recalled after a delay, adjusting for age and education. When hippocampal volume was entered together with each neuropathologic index, only hippocampal volume retained a significant association with the delayed recall measure. The association between hippocampal volume and the number of words recalled was present in both demented and nondemented individuals as well as in those with and without substantial AD neurofibrillary pathology. CONCLUSIONS: The association of neurofibrillary tangles with delayed verbal recall may reflect associated hippocampal atrophy.

Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study.

OBJECTIVE: To determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. METHODS: Postmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. RESULTS: Hippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). CONCLUSION: Volumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.

An automated technique for measuring hippocampal volumes from MR imaging studies.

We describe an automated volumetric measure of the hippocampus obtained with software called the Knowledge-Guided MRI Analysis Program (KGMAP). Postmortem MR images from 56 participants in the Nun Study were used to validate the measure. KGMAP-determined volumes strongly correlated with those obtained with manual tracings and neurofibrillary pathologic findings of Alzheimer disease in the hippocampus. KGMAP provides a rapid and accurate estimate of hippocampal volume that is suitable for use in clinical practice.

Positive emotions in early life and longevity: findings from the nun study.

Handwritten autobiographies from 180 Catholic nuns, composed when participants were a mean age of 22 years, were scored for emotional content and related to survival during ages 75 to 95. A strong inverse association was found between positive emotional content in these writings and risk of mortality in late life (p < .001). As the quartile ranking of positive emotion in early life increased, there was a stepwise decrease in risk of mortality resulting in a 2.5-fold difference between the lowest and highest quartiles. Positive emotional content in early-life autobiographies was strongly associated with longevity 6 decades later. Underlying mechanisms of balanced emotional states are discussed.

Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease. Findings from the Nun Study.

Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In the present study, we investigated the relationship of linguistic ability in early life to the neuropathology of Alzheimer's disease and cerebrovascular disease. The analyses were done on a subset of 74 participants in the Nun Study for whom we had handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years). An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they died and their brains were removed for our neuropathologic studies. Linguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimer's disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were -0.59 for the frontal lobe, -0.48 for the temporal lobe, and -0.49 for the parietal lobe (all p values < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts. Low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimer's disease pathology in late life.

Cognitive function and apolipoprotein E in very old adults: findings from the Nun Study.

OBJECTIVES: The epsilon4 allele of apolipoprotein E (APOE) has been associated with Alzheimer' s disease and with milder forms of cognitive impairment. We investigated the possibility that the absence of the epsilon4 allele may predict the maintenance of high cognitive function among very old individuals. METHODS: Our data are from the Nun Study, a longitudinal study of aging and Alzheimer's disease in 678 Catholic sisters. All sisters participate in annual functional exams that include the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests. High cognitive function was defined as intact scores on five of the CERAD tests. A total of 241 participants aged 75 to 98 met this criterion at the first exam. RESULTS: Findings showed that 62% of the 241 participants maintained intact scores on the five CERAD tests throughout their participation in the study. Life table analyses indicated that those without the APOE epsilon4 allele spent more time with intact cognitive function than those with the epsilon4 allele (p = .007). Cox regression analyses indicated that those without the epsilon4 allele had half the risk of losing their intact status during the study when compared with those with the epsilon4 allele (p < .01). DISCUSSION: Our findings suggest that the APOE epsilon4 allele may be included among the variables that predict high cognitive function in cognitively intact, very old adults. Although the presence or absence of the epsilon4 allele is known to be related to the risk of dementia, it also appears to be related to maintaining high levels of cognitive function in old age.

Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study.

BACKGROUND: Previous studies suggested that low concentrations of folate in the blood are related to poor cognitive function, dementia, and Alzheimer disease-related neurodegeneration of the brain. OBJECTIVE: Our aim was to determine whether serum folate is inversely associated with the severity of atrophy of the neocortex. DESIGN: Nutrients, lipoproteins, and nutritional markers were measured in the blood of 30 participants in the Nun Study from one convent who later died when they were 78-101 y old (mean: 91 y). At autopsy, several neuropathologic indicators of Alzheimer disease were determined, including the degree of atrophy of 3 lobes of the neocortex (frontal, temporal, and parietal) and the number of neocortical Alzheimer disease lesions (ie, senile plaques and neurofibrillary tangles) as assessed by a neuropathologist. RESULTS: The correlation between serum folate and the severity of atrophy of the neocortex was -0.40 (P = 0.03). Among a subset of 15 participants with significant numbers of Alzheimer disease lesions in the neocortex, the correlation between folate and atrophy was -0.80 (P = 0.0006). Atrophy may be specific to low folate because none of the 18 other nutrients, lipoproteins, or nutritional markers measured in the blood had significant negative correlations with atrophy. CONCLUSIONS: Among elderly Catholic sisters who lived in one convent, ate from the same kitchen, and were highly comparable for a wide range of environmental and lifestyle factors, low serum folate was strongly associated with atrophy of the cerebral cortex. Definitive evidence for this relation and its temporal sequence awaits the findings of other studies.

White matter volumes and periventricular white matter hyperintensities in aging and dementia.

OBJECTIVE: To determine the relationship between MRI periventricular white matter hyperintensities, cerebral white matter volumes, neuropathologic findings, and cognitive status in aged individuals. BACKGROUND: The significance of periventricular white matter hyperintensities seen on MR images in aged individuals remains controversial. The Nun Study is a longitudinal cohort aging study in which all 678 initially enrolled participants agreed to autopsy neuropathologic examination. METHODS: We used MRI to measure white matter volumes of the cerebral hemispheres in 52 formaldehyde-fixed brains for correlation with white matter and neocortical pathology, postmortem MRI observations, and cognitive measures. RESULTS: Reduced white matter volume is associated with dementia, but periventricular white matter hyperintensities were not related to white matter volume, stroke, or dementia. CONCLUSIONS: Our results do not support the hypothesis that periventricular hyperintensities seen on MR images have deleterious consequences in these aged individuals.

Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study.

Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Alzheimer's disease, dental amalgam and mercury.

BACKGROUND: Mercury, or Hg, is a neurotoxin that has been speculated to play a role in the pathogenesis of Alzheimer's disease, or AD. Dental amalgam releases low levels of Hg vapor and is a potential source of Hg for a large segment of the adult population. METHODS: The authors studied 68 subjects with AD and 33 control subjects without AD to determine Hg levels in multiple brain regions at autopsy and to ascertain the subjects' dental amalgam status and history. The subjects were from central Kentucky and Elm Grove, Wis. The authors conducted dental amalgam assessments during the lives of the majority of subjects and in some subjects at the time of autopsy only. The authors also determined three dental amalgam index scores--Event (placement, repair or removal of amalgam), Location and Time In Mouth--in addition to the numbers of and surface area of occlusal amalgam restorations. The authors determined Hg levels in multiple brain regions and performed full neuropathologic evaluations to confirm the normal status of the brain or the presence of AD. RESULTS: The authors found no significant association of AD with the number, surface area or history of having dental amalgam restorations. They also found no statistically significant differences in brain Hg level between subjects with AD and control subjects. CONCLUSIONS: Hg in dental amalgam restorations does not appear to be a neurotoxic factor in the pathogenesis of AD. The authors found that brain Hg levels are not associated with dental amalgam, either from existing amalgam restorations or according to subjects' dental amalgam restoration history. CLINICAL IMPLICATIONS: Dental amalgam restorations, regardless of number, occlusal surface area or time, do not relate to brain Hg levels.

Self-rated function, self-rated health, and postmortem evidence of brain infarcts: findings from the Nun Study.

OBJECTIVES: Self-rated function is a new global measure. Previous findings suggest that self-rated function predicts future functional decline and is strongly associated with all-cause mortality. We hypothesized that the strength of the relationship of self-rated function to all-cause mortality was in part due to functional decline, such as would occur with brain infarcts. METHODS: Self-ratings of function and health (on a 5-point scale, ranging from excellent to poor) were assessed annually on 630 participants in the Nun Study. Mortality surveillance extended from October 31, 1991 to March 1, 1998, and, among those who died, neuropathological examination determined postmortem evidence of brain infarcts. Cox regression modeling with self-rated function and health as time-dependent covariates and stratification by assessment period were used in these analyses. RESULTS: Self-rated function and health ratings of good, fair, and poor were significantly associated with doubling of the risk of mortality, compared with ratings of very good and excellent. Self-rated function ratings of fair or poor were associated with a threefold increase in the risk of mortality with brain infarcts, but self-rated function and health ratings of fair and poor were comparable in their association with all-cause mortality and mortality without brain infarcts. DISCUSSION: Self-rated function was significantly associated with mortality with brain infarcts, suggesting that brain infarcts may be experienced as functional loss but not recognized or labeled as disease. Our results suggest that self-rated function and health should be explored simultaneously in future research.

Height as a marker of childhood development and late-life cognitive function: the Honolulu-Asia Aging Study.

OBJECTIVE: Growing evidence suggests that structural and functional brain reserves, thought to develop in childhood and adolescence, may be crucial in determining when cognitive impairment begins. The purpose of this report is to examine the relationship of height, as a marker of childhood development, to late-life cognitive function in a sample of elderly Japanese-American men. METHOD: Cognitive performance was assessed from 1991 to 1993 in the Honolulu-Asia Aging Study in 3733 men aged 71 to 93 years and related to height that was measured 25 years earlier. RESULTS: Among the study sample, shorter men were older, leaner, and less educated than taller men. Shorter men also spent more years of their childhood living in Japan and were more likely to have had fathers in unskilled professions. After adjustment for age, the prevalence of poor cognitive performance declined consistently with increasing height from 25% in men shorter than 154 cm (61 in) to 9% in those taller than 174 cm (69 in). Excluding men with stroke or dementia did not alter the association between height and cognitive performance. Apolipoprotein E4 was unrelated to height and did not effect the association between height and cognitive function. The prevalence of Alzheimer's disease was higher in men who were 154 cm (61 in) or shorter as compared with men who were taller (4.7% vs 2.9%, respectively). There was no association between height and vascular dementia. CONCLUSION: Efforts to improve prenatal and early life conditions to maximize growth in childhood and adolescence could diminish or delay the expression of cognitive impairments that occur later in life. Prevention of some late-life cognitive impairments may have pediatric origins.

Aging and Alzheimer's disease: lessons from the Nun Study.

Sister Mary, the gold standard for the Nun Study, was a remarkable woman who had high cognitive test scores before her death at 101 years of age. What is more remarkable is that she maintained this high status despite having abundant neurofibrillary tangles and senile plaques, the classic lesions of Alzheimer's disease. Findings from Sister Mary and all 678 participants in the Nun Study may provide unique clues about the etiology of aging and Alzheimer's disease, exemplify what is possible in old age, and show how the clinical expression of some diseases may be averted.

Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.

OBJECTIVE: To determine the relationship of brain infarction to the clinical expression of Alzheimer disease (AD). DESIGN: Cognitive function and the prevalence of dementia were determined for participants in the Nun Study who later died. At autopsy, lacunar and larger brain infarcts were identified, and senile plaques and neurofibrillary tangles in the neocortex were quantitated. Participants with abundant senile plaques and some neurofibrillary tangles in the neocortex were classified as having met the neuropathologic criteria for AD. SETTING: Convents in the Midwestern, Eastern, and Southern United States. PARTICIPANTS: A total of 102 college-educated women aged 76 to 100 years. MAIN OUTCOME MEASURES: Cognitive function assessed by standard tests and dementia and AD assessed by clinical and neuropathologic criteria. RESULTS: Among 61 participants who met the neuropathologic criteria for AD, those with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. Participants with lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without infarcts (the odds ratio [OR] for dementia was 20.7, 95% confidence interval [95% CI], 1.5-288.0). Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter than in those without infarcts. In contrast, among 41 participants who did not meet the neuropathologic criteria for AD, brain infarcts were only weakly associated with poor cognitive function and dementia. Among all 102 participants, atherosclerosis of the circle of Willis was strongly associated with lacunar and large brain infarcts. CONCLUSION: These findings suggest that cerebrovascular disease may play an important role in determining the presence and severity of the clinical symptoms of AD.

The relationship of self-rated function and self-rated health to concurrent functional ability, functional decline, and mortality: findings from the Nun Study.

We investigated the relationship of self-rated function (i.e., the ability to take care of oneself) and self-rated health to concurrent functional ability, functional decline, and mortality in participants in the Nun Study, a longitudinal study of aging and Alzheimer's disease. A total of 629 of the 678 study participants self-rated their function and health and completed an initial functional assessment in 1991-93. Survivors completed a second assessment in 1993-94. Overall, self-rated function had a stronger relationship to functional ability at the first assessment and to functional decline between the first and second assessments than did self-rated health. Self-rated function also had a stronger relationship to mortality than did self-rated health. Self-rated function may be a better marker of global function than is self-rated health and may be a useful addition to clinical assessment and scientific investigation of the relationships among function, health, and disease.

Trends in mortality in older women: findings from the Nun Study.

During this century, Catholic sisters have remained constant in many life-style characteristics such as smoking and reproduction (Catholic sisters are nonsmoking and nulliparous). It is therefore of interest to compare trends in the health of elderly Catholic sisters to those in the general population. In this study, mortality rates at ages 50 to 84 years in a population of 2,573 Catholic sisters were compared to those in the general population during the years 1965 to 1989. The Catholic sisters had a mortality advantage that increased dramatically over calendar time, and from early to more recent birth cohorts. This coincided with increases in smoking by U.S. women, while during the same time period the Catholic sisters had very low rates of mortality from smoking-related diseases. The Catholic sisters had high rates of mortality from cancers of the breast and reproductive organs, suggesting an effect of nulliparity manifested in older women.

Acute phase response and plasma carotenoid concentrations in older women: findings from the nun study.

This cross-sectional study investigated whether the acute phase response was associated with suppressed circulating levels of antioxidants in a population of 85 Catholic sisters (nuns) ages 77-99 y. Fasting blood was drawn to determine the presence of an acute phase response, as defined by an elevation in the serum concentration of C-reactive protein. Serum concentrations of albumin, thyroxine-binding prealbumin, zinc, copper, and fibrinogen were determined as were plasma concentrations of carotenoids and alpha tocopherol. Results showed that the presence of an acute phase response was associated with (1) an expected significant decrease in the serum concentrations of albumin (p < 0.001) and thyroxine-binding prealbumin (p < 0.001); (2) an expected significant increase in copper (p < 0.001) and fibrinogen (p = 0.003); and (3) a significant decrease in the plasma concentrations of lycopene (p = 0.03), alpha carotene (p = 0.02), beta carotene (p = 0.02), and total carotenoids (p = 0.01). The acute phase response was associated with decreased plasma levels of the antioxidants lycopene, alpha carotene, and beta carotene. This decrease in circulating antioxidants may further compromise antioxidant status and increase oxidative stress and damage in elders.

Age, education, and changes in the Mini-Mental State Exam scores of older women: findings from the Nun Study.

OBJECTIVE: To describe the relationship of Mini-Mental State Exam (MMSE) scores and changes over time in MMSE scores to age and education in a population of older women. DESIGN: A prospective study of a defined population. SETTING: Various motherhouses and church-run health care facilities in the Eastern, Midwestern, and Southern regions of the United States. PARTICIPANTS: Catholic sisters (nuns) participating in the Nun Study, a study of aging and Alzheimer's Disease. The 678 participants were 75 to 102 years old (mean 83.3, standard deviation 5.5, median 82.3) at the time of the first functional assessment. Second assessments were obtained an average of 1.6 years later on 575 survivors. MEASUREMENTS: The outcome variables were MMSE scores at the first assessment (Time-one), and MMSE scores at the second assessment (Time-two). The independent variables were age at Time-one, and education (bachelor's degree or no bachelor's degree). RESULTS: Time-one MMSE scores decreased with age at Time-one. The decrease in MMSE scores with age was less in sisters with bachelor's degrees than in sisters without bachelor's degrees. The changes in MMSE scores had a "U-shaped" relationship with Time-one score, where the greatest declines occurred in sisters with intermediate Time-one scores. Stratified analysis by age, education, and Time-one MMSE scores of 20 or greater because of the small numbers of sisters with Time-one scores less than 20. In sisters with Time-one MMSE scores in the categories 20 to 23, 24 to 26, or 27 to 30, older ages at Time-one were associated with greater decline in those with bachelor's degrees, but not in those without bachelor's degrees. Also, lower education was associated with greater decline in sisters aged 75 to 84 years at Time-one, but this education effect disappeared or reversed in sisters who were 85 years of age or older at Time-one. CONCLUSIONS: Cognitive function as measured by the MMSE decreased with age at Time-one, most steeply as a function of age in those without bachelor's degrees. Cognitive function declined over 1.6 years within individuals, and the extent of decline increased with age in the sisters with bachelor's degrees. The extent of decline varied with age and education in an interactive manner, which may have been attributable to a hardy survivor effect in lower educated sisters. It may be necessary to consider such interactions whenever changes in function are studied, particularly when analyses are stratified by the initial level of function.

Carboxy terminal of beta-amyloid deposits in aged human, canine, and polar bear brains.

Immunocytochemistry, using antibodies specific for different carboxy termini of beta-amyloid. A beta 40 and A beta 42(43), was used to compare beta-amyloid deposits in aged animal models to nondemented and demented Alzheimer's disease human cases. Aged beagle dogs exhibit diffuse plaques in the absence of neurofibrillary pathology and the aged polar bear brains contain diffuse plaques and PHF-1-positive neurofibrillary tangles. The brains of nondemented human subjects displayed abundant diffuse plaques, whereas the AD cases had both diffuse and mature (cored) neuritic plaques. Diffuse plaques were positively immunostained with an antibody against A beta 42(43) in all examined species, whereas A beta 40 immunopositive mature plaques were observed only in the human brain. Anti-A beta 40 strongly immunolabeled cerebrovascular beta-amyloid deposits in each of the species examined, although some deposits in the polar bear brain were preferentially labeled with anti-A beta 42(43). beta-amyloid deposition was evident in the outer molecular layer of the dentate gyrus in the aged dog, polar bear, and human. Within this layer, A beta 42 was present as diffuse deposits, although these deposits were morphologically distinct in each of the examined animal models. In dogs, A beta 42 was cloud-like in nature; the polar bear demonstrated a more aggregated type of deposition, and the nondemented human displayed well-defined deposits. Alzheimer's disease cases were most frequently marked by neuritic plaques in this region. Taken together, the data indicate that beta-amyloid deposition in aged mammals is similar to the earliest stages observed in human brain. In each species, A beta 42(43) is the initially deposited isoform in diffuse plaques.