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Tooth loss, dementia and neuropathology in the Nun Study
Pamela Sparks Stein, Mark Desrosiers, Sara Jean Donegan, SSND,
Juan F. Yepes, and Richard J. Kryscio
Background. Numerous studies have linked dementia to the subsequent deterioration of oral health. Few investigators, however, have examined oral disease as a potential risk factor in the development of dementia. The authors conducted a study to investigate a potential association between a history of oral disease and the development of dementia.
Methods. Longitudinal dental records supplemented data collected from 10 annual cognitive assessments of 144 Milwaukee participants in the Nun Study, a longitudinal study of aging and Alzheimer disease, who were 75 to 98 years old. Neuropathologic findings at autopsy were available for 118 participants who died.
Results. A low number of teeth increased the risk of higher prevalence and incidence of dementia.
Conclusion. Participants with the fewest teeth had the highest risk of prevalence and incidence of dementia.
Clinical Implications. Edentulism or very few (one to nine) teeth may be predictors of dementia late in life.
Journal of the American Dental Association 2007;138(10):1314-1322
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Healthy ageing in the Nun Study: Definition and neuropathologic correlates
Suzanne L. Tyas, David A. Snowdon, Mark F. Desrosiers, Kathryn P. Riley
and William R. Markesbery
Background: although the concept of healthy ageing has stimulated considerable interest, no generally accepted definition has been developed nor has its biological basis been determined.
Objective: to develop a definition of healthy ageing and investigate its association with longevity and neuropathology.
Methods: analyses were based on cognitive, physical, and post-mortem assessments from 1991 to 1998 in the Nun Study, a longitudinal study of ageing in participants 75+ years at baseline. We defined three mutually exclusive levels of healthy ageing (excellent, very good, and good) based on measures of global cognitive function, short-term memory, basic and instrumental activities of daily living, and self-rated function. Mortality analyses were based on 636 participants; neuropathologic analyses were restricted to 221 who had died and were autopsied.
Results: only 11% of those meeting criteria for the excellent level of healthy ageing at baseline subsequently died, compared with 24% for the very good, 39% for the good, and 60% for the remaining participants. Survival curves showed significantly greater longevity with higher levels of healthy ageing. The risk of not attaining healthy ageing, adjusted for age, increased two-fold in participants with brain infarcts alone, six-fold in those with Alzheimer neuropathology alone, and more than thirteen-fold in those with both brain infarcts and Alzheimer neuropathology.
Conclusions: the biological validity of our definition of healthy ageing is supported by its strong association with mortality and longevity. Avoiding Alzheimer and stroke neuropathology is critical to the maintenance of healthy ageing, and the presence of both pathologies dramatically decreases the likelihood of healthy ageing.
Age and Ageing, 2007; 36(6):650-655, 2007.
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Neuropathological findings processed by artificial neural networks (ANNs)
can perfectly distinguish Alzheimer’s patients from controls in the Nun Study
Enzo Grossi, Massimo P. Buscema, David Snowdon, Piero Antuono
Background: Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old.
The aim of this study is to discover the hidden and non-linear associations among AD pathognomonic brain lesions and the clinical diagnosis of AD in participants in the Nun Study through Artificial Neural Networks (ANNs) analysis
Methods:
The analyses were based on 26 clinically- and pathologically-confirmed AD cases and 36 controls who had normal cognitive function. The inputs used for the analyses were just NFT and neuritic plaques counts in neocortex and hippocampus, for which, despite substantial differences in mean lesions counts between AD cases and controls, there was a substantial overlap in the range of lesion counts.
Results: By taking into account the above four neuropathological features, the overall predictive capability of ANNs in sorting out AD cases from normal controls reached 100%. The corresponding accuracy obtained with Linear Discriminant Analysis was 92.30%. These results were consistently obtained in ten independent experiments. The same experiments were carried out with ANNs on a subgroup of 13 non severe AD patients and on the same 36 controls. The results obtained in terms of prediction accuracy with ANNs were exactly the same.
Input relevance analysis confirmed the relative dominance of NFT in neocortex in discriminating between AD patients and controls and indicated the lesser importance played by NP in the hippocampus.
Conclusion:
The results of this study suggest that: a) cortical NFT represent the key variable in AD neuropathology; b) the neuropathologic profile of AD subjects is complex, however, c) ANNs can analyze neuropathologic features and differentiate AD cases from controls.
BMC Neurology, 2007;7:15;doi:10.1186/1471-2377-7-15
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Transitions
to Mild Cognitive Impairments, Dementia, and Death:
Findings from the Nun Study
Suzanne
L. Tyas, Juan Carlos Salazar, David A. Snowdon, Mark F. Desrosiers,
Kathryn P. Riley, Marta S. Mendiondo, and Richard J. Kryscio
The
potential of early interventions for dementia has increased interest in
cognitive impairments less severe than dementia. However, predictors of
the trajectory from intact cognition to dementia have not yet been
clearly identified. The purpose of this study was to determine whether
known risk factors for dementia increased the risk of mild cognitive
impairments or progression from mild cognitive impairments to dementia.
A polytomous logistic regression model was used, with parameters
governing transitions within transient states (intact cognition, mild
cognitive impairments, global impairment) estimated separately from
parameters governing the transition from transient toabsorbing state
(dementia or death). Analyses were based on seven annual examinations
(1991–2002) of 470 NunStudy participants aged 75 years at baseline and
living in the United States. Odds of developing dementia increased
with age primarily for those with low educational levels. In these
women, presence of an apolipoproteinE gene *E4 allele increased the odds
more than fourfold by age 95 years. Age, education, and the
apolipoprotein Egene were all significantly associated with mild
cognitive impairments. Only age, however, was associated with
progression to dementia. Thus, risk factors for dementia may operate
primarily by predisposing individuals todevelop mild cognitive
impairments; subsequent progression to dementia then depends on only
time and competingmortality.
American Journal of Epidemiology
2007; 165(11):1231-1238.
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Very
early detection of Alzheimer neuropathology
and the role of brain reserve in modifying its clinical expression
James A.
Mortimer, Amy R. Borenstein, Karen M.Gosche,
and David A. Snowdon
Numerous
studies show that the pathology of Alzheimer’s disease is present decades
before a clinical diagnosis of dementia can be made. Given the likelihood
that agents will become available that reliably delay onset and/or slow
progression of Alzheimer's disease, it will be important to detect
preclinical Alzheimer's disease as early as possible for maximal treatment
effect. Detection of individuals by sensitive cognitive measures provides
one way to identify people who are at high risk of developing clinical
Alzheimer's disease. However, it is likely that those with considerable
brain or cognitive reserve will be able to mask cognitive deficits until
very close to the onset of the dementia, rendering such cognitive measures
insensitive. Optimum biomarkers for Alzheimer's disease therefore need to
target the severity of underlying brain pathology independently of brain
reserve. Findings are presented showing the importance of higher
education and larger brain size in masking the underlying disease
pathology.
Journal
of Geriatric Psychiatry and Neurology
2005; 18(4):218-223
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Artificial Neural Networks and Artificial
Organisms Can Predict
Alzheimer Pathology in Individual Patients Only on The Basis
of Cognitive and Functional Status
Massimo
Buscema, Enzo Grossi, David Snowdon, Piero Antuono,
Marco Intraligi, Guido Maurelli, Rita Savarč
Data from
several studies have pointed out the existence of a strong correlation
between Alzheimer's disease (AD) neuropathology and cognitive state.
However, because of their highly complex and nonlinear relationship, it
has been difficult to develop a predictive model for individual patient
classification through traditional statistical approaches. When exposed to
complex data sets, artificial neural networks (ANNs) can recognize
patterns, learn the relationship of different variables, and address
classification tasks. To predict the results of postmortem brain
examinations, we applied ANNs to the Nun Study data set, a longitudinal
epidemiological study, which includes annual cognitive and functional
evaluation. One hundred seventeen subjects from the study participated in
this analysis. We determined how demographic data and the cognitive and
functional variables of each subject during the last year of her life
could predict the presence of brain pathology expressed as Braak stages,
neurofibrillary tangles (NFTs) and neuritic plaques (NPs) count in the
neocortex and hippocampus, and brain atrophy. The result of this analysis
was then compared with traditional statistical models. ANNs proved to be
better predictors than Linear Discriminant Analysis in all
experimentations (+ ~10% in overall accuracy), especially when assembled
in Artificial Organisms (+ ~20% in overall accuracy). Demographic,
cognitive, and clinical variables were better predictors of tangles count
in the neocortex and in the hippocampus when compared to NPs count. These
findings strengthen the hypothesis that neurofibrillary pathology may
represent the major anatomic substrate of the cognitive impairment found
in AD.
Neuroinformatics Winter 2004; 2(4):399-416
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Early life linguistic ability, late life cognitive
function, and neuropathology: Findings from the Nun Study
Kathryn
P. Riley, David A. Snowdon, Mark F. Desrosiers,
and William R. Markesbery
The
relationships between early life variables, cognitive function, and
neuropathology were examined in participants in the Nun Study who were
between the ages of 75 and 95. Our early life variable was idea density,
which is a measure of linguistic ability, derived from autobiographies
written at a mean age of 22 years. Six discrete categories of cognitive
function, including mild cognitive impairments, were evaluated, using the
CERAD battery of cognitive tests. Neuropathologic data included Braak
staging, neurofibrillary tangle and senile plaque counts, brain weight,
degree of cerebral atrophy, severity of atherosclerosis, and the presence
of brain infarcts. Early-life idea density was significantly related to
the categories of late-life cognitive function, including mild cognitive
impairments: low idea density was associated with greater impairment. Low
idea density also was significantly associated with lower brain weight,
higher degree of cerebral atrophy, more severe neurofibrillary pathology,
and the likelihood of meeting neuropathologic criteria for Alzheimer’s
disease.
Neurobiology of Aging 2005; 26(3):341-347
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The Use of Convent Archival Records in Medical
Research:
The School Sisters of Notre Dame Archives and the Nun Study
Gari-Anne
Patzwald and Sister Carol Marie Wildt
The School
Sisters of Notre Dame (SSND) archives program is a cooperative system for
the arrangement and preservation of the records of the SSND provinces in
North America, including records of individual sisters. Archival records
include autobiographies, school and college transcripts, employment
histories, and family socioeconomic data. The Nun Study, a longitudinal
study of Alzheimer’s disease and aging in 678 SSND sisters, compares data
extracted from these records with data on late-life cognitive and physical
function and postmortem brain neuropathology to explore early life factors
that may affect late-life cognitive function and longevity.
American
Archivist 2004; 67(1):86-106
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Delayed recall, hippocampal volume and
Alzheimer neuropathology:
Findings from the Nun Study
James A.
Mortimer, Karen M. Gosche, Kathryn P. Riley,
William R. Markesbery, and David A. Snowdon
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 MRIs
from the first 56 scanned participants of the Nun Study. Quantitative
neuropathological studies included lesion counts, Braak staging and
determination of whether neuropathological criteria for 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 CERAD 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 non-demented
individuals as well as in those with and without substantial AD
neurofibrillary pathology.
Conclusions: The findings suggest that hippocampal volume is strongly
correlated with delayed recall performance and that the association of
neurofibrillary tangles with delayed verbal recall may reflect associated
hippocampal atrophy.
Neurology 2004; 62:428-432
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Estimating intensity functions on multi-state
Markov models
with application to the Nun Study
Juan
Carlos Salazar, Suzanne L Tyas, Mark F Desrosiers, David A Snowdon,
Kathryn Perez Riley, Marta S Mendiondo, Richard J Kryscio
We consider a multi-state
Markov process with two competing absorbing states (dementia and death)
and several transitory non-demented states. Transitions among states are
determined by intensity functions which account for the effect of
covariates. The likelihood function is derived and inference for
estimating the effects of the covariates on transitions is determined when
the process can be view as a Markov chain and when the likelihood function
can be factored as the product of several functions: one for the
transitions among non-absorbing states and the others for transitions from
transient to absorbing states. Inference for more general cases such as
when the progression of the disease is assumed to follow a Markov-process
will be discussed. These approaches are illustrated using a longitudinal
study on aging and Alzheimer’s disease conducted in a population of 678
catholic sisters (NUN Study ) aged 75 to 102 when the study began in 1991.
Proceedings of the
Joint Statistical Meeting, San Francisco 2003. Biometrics section,
3616-3623
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Oral and written language in late adulthood:
Findings from the Nun Study
Tracy L.
Mitzner and Susan Kemper
As a part of the Nun Study,
a longitudinal investigation of aging and Alzheimer's disease, oral and
written autobiographies from 118 older women were analyzed to examine the
relationship between spoken and written language. The written language
samples were more complex than the oral samples, both conceptually and
grammatically. The relationship between the linguistic measures and
participant characteristics was also examined. The results suggest that
the grammatical and conceptual characteristics of oral and written
language are affected by participant differences in education, cognitive
status, and physical function and that written language samples have
greater power than oral language samples to differentiate between high-
and low-ability older adults.
Experimental Aging
Research 2003; 29(4):457-474
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Healthy aging and
dementia:
Findings from the Nun Study
David A. Snowdon
The Nun Study is a longitudinal study of
678 Catholic sisters 75 to 107 years of age who are members of the
School Sisters of Notre Dame congregation. Data collected for this study
include early and middle-life risk factors from the convent archives,
annual cognitive and physical function evaluations during old age, and
postmortem neuropathologic evaluations of the participants’ brains. The
case histories presented include a centenarian who was a model of
healthy aging, a 92-year-old with dementia and clinically significant
Alzheimer disease neuropathology and vascular lesions, a cognitively and
physically intact centenarian with almost no neuropathology, and an
85-year-old with well-preserved cognitive and physical function despite
a genetic predisposition to Alzheimer disease and an abundance of
Alzheimer disease lesions. These case histories provide examples of how
healthy aging and dementia relate to the degree of pathology present in
the brain and the level of resistance to the clinical expression of the
neuropathology.
Annals of Internal
Medicine 2003;
139 (5 Part 2):450-454
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Head Circumference, Education and Risk of
Dementia:
Findings from the Nun Study
James A. Mortimer, David A. Snowdon, and William R.
Markesbery
To examine the prevalence of dementia associated with having a smaller
brain, lower education or both of these characteristics, 294 Catholic
sisters were assessed annually for dementia. Sixty participants died and
their brains were evaluated to determine fulfillment of neuropathological
criteria for Alzheimer’s disease (AD). Lower education attainment and the
interaction of smaller head circumference with lower education were
associated with the presence of dementia, controlling for age and the
presence of one or more apolipoprotein E-4 alleles. By contrast, neither
low educational attainment nor head circumference was significantly
associated with fulfillment of neuropathological criteria for AD.
Individuals having both low education and small head circumference were 4
times as likely to be demented as the rest of the sample. The findings
suggest that higher education and larger head size, alone or in
combination, may reduce the risk of expressing dementia in late life.
Journal of Clinical and Experimental
Neuropsychology 2002; 25(5):671-679
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Hippocampal volume as an
index of Alzheimer neuropathology:
Findings from the Nun Study
Karen M. Gosche, James A. Mortimer, Charles D.
Smith, William R. Markesbery,
and David A. Snowdon
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,
positive and negative predictive values were used to assess the
diagnostic accuracy of hippocampal volume in predicting fulfillment of
Alzheimer’s neuropathological criteria and differences in Braak
staging.
Results: Hippocampal volume predicted fulfillment of neuropathological
criteria for AD for all 56 participants (p<0.001); 24 sisters who
were demented (p=0.036); 32 sisters who remained non-demented
(p<0.001); eight sisters who remained non-demented, 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 non-demented, hippocampal volume was a
better indicator of AD neuropathology than a delayed memory measure.
Among non-demented 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).
Conclusions: Volumetric measures of the hippocampus may be useful in
identifying non-demented individuals who satisfy neuropathological
criteria for AD as well as pathological stages of AD that may be present
decades before initial clinical expression.
Neurology 2002;
58:1476-1482
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Alzheimer’s
Neurofibrillary Pathology and the Spectrum of Cognitive Function:
Findings from the Nun Study
Kathryn
P. Riley, David A. Snowdon, and William R. Markesbery
The
development of interventions designed to delay the onset of dementia
highlights the need to determine the neuropathologic characteristics of
individuals whose cognitive function ranges from intact to demented,
including those with mild cognitive impairments. We used the Braak
method of staging Alzheimer’s disease pathology in 130 women aged
76-102 who were participants in the Nun Study, a longitudinal study of
aging and Alzheimer’s disease. All participants had complete autopsy
data and were free from neuropathologic conditions other than
Alzheimer’s disease lesions that could affect cognitive function.
Findings showed a strong relationship between Braak stage and cognitive
state. The presence of a memory impairment was associated with more
severe Alzheimer’s disease pathology and higher incidence of
conversion to dementia in the groups classified as having mild or global
cognitive impairments. In addition to Braak stage, atrophy of the
neocortex was significantly related to the presence of dementia. Our
data indicate that Alzheimer’s neurofibrillary pathology is one
of the neuropathologic substrates of mild cognitive impairments.
Additional studies are needed to help explain the variability in
neuropathologic findings seen in individuals whose cognitive performance
falls between intact function and dementia.
Annals of Neurology 2002;
51:567-577
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An automated technique
for measuring hippocampal
volumes from MR imaging studies
Karen M. Gosche, James A. Mortimer, Charles D.
Smith, William R. Markesbery,
and David A. Snowdon
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.
American Journal of
Neuroradiology 2001; 22:1686-1689
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Language decline
across the life span: Findings from the Nun Study
Susan Kemper, Lydia H. Greiner, Janet
G. Marquis,
Katherine Prenovost, Tracy L. Mitzner
The
present study examines language samples from the Nun Study. Measures of
grammatical complexity and idea density were obtained from autobiographies
written over a 60-year span. Participants who had met criteria for dementia were
contrasted with those who did not. Grammatical complexity initially averaged
4.78 (on a 0-to-7 point scale) for participants who did not meet criteria for
dementia and declined .04 units per year; grammatical complexity for
participants who met criteria for dementia initially averaged 3.86 and declined
.03 units per year. Idea density averaged 5.35 propositions per 10 words
initially for participants who did not meet criteria for dementia and declined
an average of .03 units per year, whereas idea density averaged 4.34
propositions per 10 words initially for participants who met criteria for
dementia and declined .02 units per year. Adult experiences, in general, did not
moderate these declines.
Psychology and Aging 2001;16(2):227-239
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Positive
Emotions in Early Life and Longevity: Findings from the Nun Study
Deborah
D. Danner, David A. Snowdon, Wallace V. Friesen
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.
Journal of Personality and Social Psychology
2001;80(5):804-813
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Linguistic
ability in early life and the neuropathology of Alzheimer’s disease
and cerebrovascular disease: Findings from the Nun Study
David
A. Snowdon, Lydia H. Greiner, William R. Markesbery
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). 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.
Vascular factors in Alzheimer's
disease
2000;903:34-38
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Cognitive
function and apolipoprotein-E in the very old:
Findings from the Nun Study
Kathryn
P. Riley, David A. Snowdon, Ann M. Saunders, Allen
D. Roses,
James A. Mortimer and Nuwan Nanayakkara
Objectives:
The ε4 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 ε4 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 which include the 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 ε4
allele spent more time with intact cognitive function than those with the ε4 allele (p =
.007).
Cox regression analyses indicated those without the ε4
allele had half the risk of losing their intact status during the study when
compared to those with the ε4
allele (p< .01).
Discussion: Our findings suggest that the APOE ε4
allele may be included among the variables that predict high cognitive function
in the cognitively intact very old. While the presence or absence of the ε4 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.
Journals of Gerontology: Social
Sciences 2000;55B(2):S69-S75
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Serum folate
and the severity of atrophy of the neocortex in Alzheimer disease:
Findings from the Nun Study
David
A. Snowdon, Christine L. Tully, Charles D. Smith, Kathryn Perez Riley,
and William R. Markesbery
Background:
Previous studies suggest that low levels of folate in the blood are related to
poor cognitive function, dementia, and Alzheimer’s disease-related
neurodegeneration of the brain.
Objective: 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 to 101 years old (mean=91). At autopsy, several neuropathologic
indicators of Alzheimer’s disease were determined, including an assessment by
a neuropathologist of the degree of atrophy of three lobes of the neocortex
(i.e., frontal, temporal, and parietal), and the number of neocortical
Alzheimer’s disease lesions (i.e., senile plaques and neurofibrillary
tangles).
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’s disease lesions in the neocortex, the correlation between folate
and atrophy was -0.80 (P
= 0.0006). Atrophy may be specific to low folate, since none of the 18 other
nutrients, lipoproteins, or nutritional markers measured in the blood had
statistically significant negative correlations with atrophy.
Conclusions: Among
elderly Catholic sisters who lived in one convent, ate out of the same kitchen,
and were highly comparable on a wide range of environmental and lifestyle
factors, low serum folate was strongly associated with atrophy of the cerebral
cortex. Definitive evidence for this relationship awaits the findings of
other studies.
American Journal of Clinical
Nutrition 2000;71(4):993-998
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White matter volumes
and periventricular white matter hyperintensities in aging and dementia
Charles
D. Smith, David Snowdon , Hao Wang and William R. Markesbery
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 magnetic resonance imaging to measure white matter volumes of
the cerebral hemispheres in 52 formalin-fixed brains for correlation with white
matter and neocortical pathology, post
mortem magnetic resonance imaging 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 magnetic resonance images have deleterious consequences
in these aged individuals.
Neurology 2000;54(3):838-842
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Periventricular white matter hyperintensities on
MRI: Correlation with neuropathologic findings
Charles
D. Smith, David Snowdon and William R. Markesbery
Periventricular
white matter hyperintensities on postmortem
magnetic resonance imaging (MRI) and myelin-stained frontal and parietal
histologic sections were evaluated independently in 12 cases. There was a strong
relationship between the extent of white matter hyperintensities on MRI and the
extent of gross and microscopic changes seen in the white matter of
myelin-stained sections, particularly in the frontal lobe. In this material, the
extent of myelin rarefaction correlated with an 0-8 point white matter
hyperintensity scale rating on MRI in the same brains.
Journal of Neuroimaging 2000;13-16
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Progression of regional neuropathology in Alzheimer
disease and normal elderly:
Findings from the Nun Study
David S. Wolf, Marla Gearing,
David A. Snowdon, Hiroshi Mori,
William R. Markesbery, Suzanne S. Mirra
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 Disease and Associated Disorders 1999;13(4):226-231
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The
prevalence of neuropathologically confirmed vascular dementia:
Findings from the Nun Study
David
A. Snowdon and William R. Markesbery
The Nun Study is a longitudinal study
of aging and Alzheimer’s disease in 678 Catholic sisters who agreed to annual
examinations and brain donation at death. By the end of 1997, 262 participants
had died and brains were collected and neuropathologic examinations completed on
241 (92 %). These 241 women were 76 to 103 years of age at death (mean=89).
Prior to death, 118 (49 %) of the 241 women fulfilled our clinical criteria for
dementia and only 3 of them had neuropathologic confirmation of vascular
dementia. That is, the 3 cases had vascular pathology that was judged by a
neuropathologist to be sufficient to produce dementia and they had no other
significant pathology that could have produced the dementia, such as
Alzheimer’s disease. Overall, vascular dementia appears to be an uncommon
cause of dementia in this population.
1st International Congress on
Vascular Dementia 1999;10:19-24
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Self-rated
Function, Self-rated Health and Postmortem Evidence of Brain Infarcts: Findings
from the Nun Study
Philip A. Greiner, David A.
Snowdon, and Lydia H. Greiner
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 five-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 to ratings of very good and excellent. Self-rated
function ratings of fair or poor were associated with a three-fold 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.
Journals of Gerontology: Social Sciences 1999;54B(4):S219-S222
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Linguistic ability in early life and
longevity: Findings from the Nun Study
David A. Snowdon PhD, Lydia H. Greiner BSN, Susan J. Kemper
PhD,
Nuwan Nanayakkara PhD and James A. Mortimer
Findings from the Nun
Study indicate that low linguistic ability in early life has a strong
relationship to poor cognitive function and dementia in late life, and the
number of Alzheimer's disease lesions in the brain. In the present analyses,
we investigated the relationship between linguistic ability in early life and
all cause mortality in late life in a subset of 180 participants in the Nun
Study. Two measures of linguistic ability in early life, idea (proposition)
density and grammatical complexity, were derived from autobiographies written
by the participants when they were 18 to 32 years old. An average of 58 years
later, when these participants were 75 to 93 years old, all cause mortality
rates were determined. Of the two linguistic measures, idea density in early
life had the strongest and most consistent relationship to the rate of all
cause mortality in late life: A one-unit decrease in idea density in early
life (i.e., one idea expressed per ten words in a sentence) was associated
with a 49 percent increase in the mortality rate (95% CI=17-89;
p-value=0.001). This finding did not appear to be due to confounding by birth
year, education attained at the time when the autobiography was written, or
age during the mortality surveillance period. Standard life table analyses
indicated that the median age at death for 75-year-olds was 81.7 years for
those with low idea density in early life and 88.5 years for those with high
idea density in early life. Low linguistic ability in early life may reflect
suboptimal cognitive and neurological development which may increase
susceptibility to aging-related declines and disease processes, resulting in a
higher mortality rate late in life. Overall, low linguistic ability and its
correlates in early life may place potent limits on the longevity of
individuals.
The Paradoxes of
Longevity
1999; 103-113
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The
challenges and successes of aging: Findings from the Nun Study
Kathryn Perez Riley and David A. Snowdon
The Nun Study is a
longitudinal study of aging and Alzheimer's disease conducted in a population
of Catholic sisters (nuns) aged 75 to 102 when the study began in 1991. All
participants agreed to annual medical examinations and functional assessments,
as well as to brain donation at death. A major purpose of the Nun Study is to
identify predictors and correlates of the clinical symptoms and
neuropathologic signs of Alzheimer's disease and other dementias. Other key
themes include change and stability in functional abilities, factors related
to mortality and survival, and successful aging as defined by cognitive,
functional, and neuropathologic indicators. The multidisciplinary team working
with the Nun Study includes researchers from a diverse set of scientific and
academic fields of study. These researchers bring a variety of perspectives to
bear upon their examinations of the data collected in the study. This chapter
will present a brief overview of the Nun Study, focusing on a synthesis of its
major findings.
Advances in
Medical Psychotherapy 1999-2000,
Volume 10; 1-12
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Alzheimer's
disease, dental amalgam and mercury
Stanley R. Saxe DMD, Merle W. Wekstein MPA, Richard J. Kryscio PhD,
Robert G. Henry DMD, Charles R. Cornett PhD, David A. Snowdon PhD,
Ford T. Grant DMD, Frederick A. Schmitt PhD, Sara Jean Donegan SSND DMD, David
R. Wekstein PhD, William D. Ehmann PhD, William R. Markesbery MD
Background: Mercury is a
neurotoxin and it has been speculated that it may play a role in the
pathogenesis of Alzheimer's disease. Dental amalgams (silver fillings) release
low-levels of mercury vapor and are a potential source of mercury for a large
segment of the adult population.
Methods: Mercury levels in multiple brain areas at autopsy and dental amalgam
status and history were determined in Alzheimer's disease subjects and
prospectively evaluated normal control subjects. Participants were from
central Kentucky and from the Nun Study at a covent in Elm Grove, Wisconsin.
Dental amalgam assessments were carried out during life in the majority of
subjects and in some subjects at the time of autopsy. Three dental indices of
amalgam were determined, Event (placement, repair or removal of amalgam),
Location and Time In Mouth in addition to the number and surface area of
occlusal amalgams. Mercury levels were determined in multiple brain regions.
Full neuropathological evaluation was performed to confirm the normal status
or the presence of Alzheimer's disease. Sixty-eight AD patients and 33 control
subjects were autopsied.
Results: No significant association of Alzheimer's disease with the number,
surface area or past history of dental amalgams was found. No statistically
significant differences in brain mercury level between Alzheimer's disease and
control subjects were found.
Conclusions: Mercury in dental amalgam restorations does not appear to be a
neurotoxic factor in the pathogenesis of Alzheimer's disease. Brain mercury
levels are not associated with dental amalgam, either existing amalgams or
past dental amalgam experience..
Journal of the
American Dental Association
1999;130:191-199
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Brain
infarction and the clinical expression of Alzheimer disease:
The Nun Study
David A. Snowdon PhD, Lydia H. Greiner BSN, James A.
Mortimer PhD,<>
Kathryn P. Riley PhD, Philip A. Greiner DNSc and William R. Markesbery
MD
Objective: To
determine the relationship of brain infarction to the clinical expression of
Alzheimer's 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 to those without infarcts
(the odds ratio [OR] for dementia was 20.7, 95% confidence internal
[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.
Journal of the
American Medical Association (JAMA)1997;277(10):813-817
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Brain
infarction and the clinical expression of Alzheimer disease
David A. Snowdon PhD, Lydia H. Greiner BSN, Kathryn P. Riley PhD,
William R. Markesbery MD, Philip A. Greiner DNSc and James A. Mortimer
PhD
In Reply to
Editor:
The analyses of Drs. Mirra and Gearing indicate that brain infarcts
are not associated with NFTs in the neocortex. Our analyses also indicated
that brain infarcts were not associated with the number of NFTs, senile
plaques, or neuritic plaques in the neocortex, suggesting that AD lesions and
brain infarcts were likely to have occurred independently of each other.
While AD and brain infarction may represent separate disease
processes, their combination may nonetheless increase the likelihood that
dementia will occur. Among the participants in our study who met our
neuropathologic criteria for AD (i.e., abundant senile plaques and some NFTs
in the neocortex), those with 1 or 2 lacunar infarcts in the basal ganglia,
thalamus, or deep white matter had an especially high prevalence of dementia,
compared with those without brain infarcts. The prevalence of dementia was 93%
for those with such subcortical lacunar infarcts and 57% in those without
infarcts. Because of the vital connections between the neocortex and the basal
ganglia, thalamus, and deep white matter, infarcts in these subcortical
regions may be particularly disabling if the neocortex has already been
damaged by AD. Mirra and Gearing did not specify the size or location of the
infarcts in their study, making it difficult to compare our findings with
theirs.
As Mirra and Gearing noted, our findings also indicated that fewer AD
lesions may be required to produce dementia if subcortical lacunar infarcts
are present. As shown in Figure 2, at a mean of 1.9 or more NFTs in the
neocortex, 100% of participants with subcortical lacunar infarcts were
demented, compared with 64% (95% confidence interval, 45%-83%) of those
without infarcts. In contrast, it took a mean of 15.7 or more NFTs in the
neocortex to produce dementia in 100% of those without infarcts.
These findings reflect the traditional way of testing dose responses
-- i.e., examining the percentage of individuals affected at any given dose.
In this case, dose is represented by the number of Alzheimer lesions, and
response is represented by the percentage of individuals who are demented.
Because Mirra and Gearing used data from an autopsy series of demented
individuals, they could not look at the percentage demented at any given
lesion count.
We agree with Dr. Roman that lacunar infarcts may only be part of the
story. While we have not yet investigated the extent of periventricular white
matter lesions, atherosclerosis of the major blood vessels of the brain was
associated with lacunar brain infarcts in our study. Thus, small-vessel
disease and ischemic damage to the brain (short of an infarct) also may be
involved in the clinical expression of AD.
Overall, our findings and those cited by Roman suggest that
cerebrovascular disease may play an important role in determining the presence
and severity of the symptoms of AD.
Journal of the
American Medical Association (JAMA)1997;277(10):813-817
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Underrecognition
of dementia by caregivers cuts across cultures
Lydia H. Greiner and David A. Snowdon
We investigated
unrecognized dementia in 383 participants in the Nun Study, aged 75 to 102
years old (mean=88), who were under nursing supervision in assisted-living or
skilled-nursing facilities. Participants have annual assessments of cognitive
and physical function and neuropathological evaluations of their brains at
death. Clinical criteria were used to identify those with dementia, and
neuropathologic criteria were used to identify those with lesions sufficient
to produce dementia. As part of the annual assessment, nurses were asked:
"Based on your observations, do you think this sister has
dementia?". Of the 179 participants who met the clinical criteria for
dementia, nursing staff did not recognize dementia in 22% (95% confidence
interval [95% CI],16-29). Results were similar in the 52 who later died and
who met both clinical and neuropathologic criteria for dementia. Of the 204
participants who did not meet the clinical criteria for dementia, nursing
staff labeled 16% (95% CI, 11-22) as having dementia. Results were similar in
the 20 who later died and who did not meet either the clinical or
neuropathologic criteria for dementia. Failure to accurately recognize
dementia may present a substantial barrier to receiving appropriate health
care.
Journal of the
American Medical Association (JAMA)1997;277(22):1757
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Aging
and Alzheimer's disease: Lessons from the Nun Study
David A. Snowdon PhD
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.
The Gerontologist
1997;37(2):150-156
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Linguistic
ability in early life and cognitive function and Alzheimer's disease
in late life: Findings from the Nun Study
David A. Snowdon PhD, Susan J. Kemper PhD, James A.
Mortimer PhD,
Lydia H. Greiner BSN, David R. Wekstein PhD, and William R. Markesbery
MD
Objective: To
determine if linguistic ability in early life is associated with cognitive
function and Alzheimer's disease in late life.
Design: Two measures of linguistic ability in early life, idea density
and grammatical complexity, were derived from autobiographies written at a
mean age of 22 years. Approximately 58 years later, the women who wrote these
autobiographies participated in an assessment of cognitive function, and those
who subsequently died were evaluated neuropathologically.
Setting: Convents in the United States participating in the Nun Study;
primarily convents in the Milwaukee, Wis, area.
Participants: Cognitive function was investigated in 93 participants
who were aged 75 to 95 years at the time of their assessments, and Alzheimer's
disease was investigated in the 14 participants who died at 79 to 96 years of
age.
Main Outcome Measures: Seven neuropsychological tests and
neuropathologically confirmed Alzheimer's disease.
Results: Low idea density and low grammatical complexity in
autobiographies written in early life were associated with low cognitive test
scores in late life. Low idea density in early life had stronger and more
consistent associations with poor cognitive function than did low grammatical
complexity. Among the 14 sisters who died, neuropathologically confirmed
Alzheimer's disease was present in all of those with low idea density in early
life and in none of those with high idea density.
Conclusions: Low linguistic ability in early life was a strong
predictor of poor cognitive function and Alzheimer's disease in late life.
Journal of the
American Medical Association (JAMA)1996;275:528-532
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Linguistic
ability in early life and Alzheimer's disease in late life
David A. Snowdon PhD, Lydia H. Greiner BSN, David R.
Wekstein PhD, Deborah Danner PhD,
William R. Markesbery MD, Susan J. Kemper PhD
and James A. Mortimer
PhD
In Reply to
Editor:
Massey and Miranda raise issues that we considered when investigating
the relationship between writing style demonstrated in autobiographies written
at an average age of 22 years, and cognitive function and Alzheimer's disease
assessed an average of 58 years later. We found a strong relationship between
low idea (proposition) density in autobiographies written in early life and
poor cognitive function and Alzheimer's disease in late life.
In agreement with Massie, the correlation with idea density was 0.26
(P=0.01) for the density of positive-emotion words, and 0.19 (P=0.07) for the
density of negative- emotion words. However, the correlation with cognitive
function, as measured by the Mini-Mental State Exam score in late life, was
0.66 (P=0.0001) for idea density; 0.19 (P=0.07) for the density of
positive-emotion words; 0.19 (P=0.07) of negative-emotion words. While emotion
may play an important role in the generation of ideas expressed, these
correlations indicate that emotional content does not explain the relationship
between idea density and cognitive function.
Before involving a linguist in our research, we (D.A.S. and L.H.G.)
believed that those with poor cognitive function in late life wrote
autobiographies that were less emotional or sensuous. We have often described
sisters with low late life cognitive function as "listers" i.e.,
they had a high concentration of dates, numbers, and proper nouns in their
autobiographies from early life. We also have described their writing style as
monotone, and the writing style of other sisters with high cognitive function
in late life as high fidelity.
In agreement with Miranda, sentences that were low in idea density
were in general less complex and easier to understand. However, it should not
be inferred that sisters with low idea density had poor linguistic ability.
There was nothing wrong with their sentences, they just lacked a complexity of
interrelated ideas. Overall, a reading of the autobiographies of sisters who
did and did not develop Alzheimer's disease reveals stark contrasts in their
abilities to express ideas in early life. This difference in written
expression may be more a reflection of fundamental differences in their
cognitive abilities during early life, than their linguistic proficiency.
Journal of the
American Medical Association (JAMA) 1996;275(24):1879
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Plasma
antioxidant concentrations in a population of elderly women:
Findings from the Nun Study
Myron D. Gross PhD and David A. Snowdon PhD
Low plasma alpha-tocopherol and beta-carotene concentrations have been associated with an
increased risk of numerous degenerative diseases, including cancer. Several
characteristics that accompany aging, including changes in dietary habits and
physiologic capacity, may place elderly populations at a high risk of low
plasma antioxidant concentrations. Thus, the present study was undertaken to
characterize plasma concentrations of alpha-tocopherol, beta-carotene and
several other carotenoids in elderly subjects, to describe the relationship
between age and plasma antioxidant concentrations in this population and to
compare the concentrations of plasma antioxidants in middle-aged and elderly
individuals. The study recruited 94 participants from the Nun Study, a
longitudinal study of aging and Alzheimer disease. Women in this population
were unique for their advanced age, 77-99 years old, and their comparability
across age groups due to the absence of several potential confounders of
plasma antioxidant concentrations. The population mean and standard deviation
of several plasma carotenoids and alpha-tocopherol concentrations (g/dl) were
as follows: lycopene, 15.0 +/- 10.0; beta-carotene, 30.0 +/- 19.7;
alpha-carotene, 15.0 +/- 9.6; zeaxanthin plus lutein, 22.0 +/- 7.4; beta-cryptoxanthin,
14.0 +/- 8.6 and alpha-tocopherol, 980 +/- 310. Concentrations of all analytes,
except lycopene, were similar to or higher than those reported for several
middle-aged American populations. Lycopene concentrations were significantly
lower in the population of sisters as compared with the middle-aged
populations and tended to decrease across age groups within the population of
sisters. Age appeared to be a relatively minor determinant of plasma alpha-tocopherol
and the concentrations of carotenoids, other than lycopene, in this
population. Importantly, the plasma concentrations of most carotenoids and
alpha-tocopherol in this population of independent elderly women were
apparently adequate on the basis of population comparisons. Further studies of
this population may define determinants essential for the maintenance of
antioxidant status in elderly populations.
Nutrition
Research
1996;16(11-12):1881-1890
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The
relationship of self-rated function and self-rated health to concurrent
functionalability, functional decline,
and mortality:
Findings from the Nun Study
Philip A. Greiner, DNSc, David A. Snowdon PhD and
Lydia H. Greiner BSN
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.
Journal of
Gerontology: Social Sciences
1996;51B(5):S234-S241
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Acute
phase response
and plasma carotenoid concentrations in older women:
Findings from the Nun Study
Maria G. Boosalis PhD, David A. Snowdon PhD, Chrtine
L. Tully, MD
and Myron D. Gross PhD
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) who were 77 to 99 years old. 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] and (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], and beta
carotene [p=0.02], as well as 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.
Nutrition
1996;12:475-478
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The
loss of independence in activities of daily living:
The role of low normal cognitive function in elderly nuns
Philip A. Greiner DNSc, David A. Snowdon PhD, and
Frederick A. Schmitt PhD
Objectives: We
investigated the role of low normal cognitive function in the subsequent loss
of independence in activities of daily living.
Methods: Of the 678 participants in The Nun Study who completed
cognitive and physical function assessments in 1992-3, 575 were reassessed in
1993-4. Mini-Mental State Examination scores were divided into three
categories (i.e., 0-23 as impaired; 24-27 as low normal; 28-30 as high normal)
and related to the loss of independence in six activities of daily living.
Results: Participants with low normal cognitive function at first
assessment had twice the risk of losing independence in three activities of
daily living by second assessment as compared to those with high normal
cognitive function. This relationship was largely due to a progression from
low normal cognitive function at first assessment to impaired cognitive
function at second assessment, and was associated with an elevated risk of
losing independence in the six activities.
Conclusions: Progression from low normal to impaired cognitive
function was associated with loss of independence in activities of daily
living. Thus, low normal cognitive function could be viewed as an early
warning of impending cognitive impairment and loss of physical function.
American Journal
of Public Health
1996;86(1):62-66
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Trends
in mortality in older women: Findings from the Nun Study
Steven M. Butler PhD and David A. Snowdon PhD
During this
century, Catholic sisters have remained constant in many lifestyle
characteristics such as smoking and reproduction (Catholic sisters are
non-smoking 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 2573
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.
Journal of
Gerontology: Social Sciences
1996;51B(4):S201-S208
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Age,
education and changes in the Mini-Mental State Exam scores of elderly women:
Findings from the Nun Study
Steven M. Butler PhD, J. Wesson Ashford and David A. Snowdon PhD
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 elderly
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 score was feasible only in
sisters with time-one MMSE scores of 20 or above, due to the small numbers of
sisters with time-one scores below 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 due 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.
Journal of the
American Geriatrics Society
1996;44:675-681
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Antioxidants
and reduced functional capacity in the elderly:
Findings from the Nun Study
David A. Snowdon PhD, Myron D. Gross PhD, and Steven
M. Butler PhD
Background: This
study investigated the relationship of plasma antioxidants to reduced
functional capacity in the elderly. A hallmark of reduced functional capacity
in the elderly is dependence in self-care (i.e., requiring assistance with
bathing, walking, dressing, standing, toileting, and feeding).
Methods: This relationship was assessed in a cross-sectional study of
88 Catholic sisters (nuns). These 77 to 98 year old women lived in the same
building, ate food prepared in the same kitchen, and had all nursing services
provided by the same staff. In 1993, ability to perform self-care was assessed
and blood was drawn to determine plasma carotenoids (lycopene, beta carotene,
alpha carotene, zeaxanthin and lutein combined, and beta cryptoxanthin) and
alpha tocopherol.
Results: Dependence in self-care had a strong negative association
with lycopene, but was not clearly related to other carotenoids or alpha
tocopherol. Results from age-adjusted least squares regression indicated that
a 30 ug/dl decrease in lycopene was associated with 2.4 additional
dependencies in self-care (95% confidence interval = 1.5, 3.3; p<0.001).
Lycopene's relationship to dependence was modified by plasma LDL-cholesterol,
the predominant carrier of lycopene in the blood. Women with low lycopene and
low LDL-cholesterol had 3.6 dependencies (95% confidence interval = 3.1, 4.2;
p<0.001), compared to 1.0 dependency (95% confidence interval = 0.3,1.8) in
those with high lycopene and low LDL-cholesterol.
Conclusions: This is the first study to report an association between
lycopene and functional status. This finding needs to be replicated in other
human and animal studies before the association is accepted as real.
Journal of
Gerontology: Medical Sciences
1996;51A(1):M10-M16
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Serum
zinc and plasma lipoproteins in elderly women:
Findings from the Nun Study
Christine L. Tully MD, David A. Snowdon PhD, and John
D. Belcher PhD
Supplementation
with zinc has been associated with changes in lipoprotein levels in prior
studies. The purpose of this study was to define further the relationship
between serum zinc and plasma total cholesterol, low density lipoprotein (LDL)
cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides.
This study was conducted in a homogeneous population of elderly women who were
not taking zinc supplements. Fasting blood samples were drawn from 87 women
who were 77 to 99 years old. Serum zinc concentrations were significantly
positively correlated with total cholesterol (r=0.37, p=<0.01) and with LDL-cholesterol
(r=0.41. p=<0.001). In 77 to 84 year old women (N=47), a normal serum zinc
level ( 70 to 150 µg/dl) was associated with a 27 mg/dl higher mean LDL-cholesterol
(p=0.06) compared to low serum zinc (<70 µg/dl). In 85 to 99 year old
women (N=40), a normal serum zinc was associated with a 49 mg/dl higher mean
LDL-cholesterol (p=0.002) compared to low serum zinc. These associations were
not materially affected by the potential confounding effects of weight, weight
change over 8 years, triceps skinfold, or serum C-reactive protein. Overall,
serum zinc concentration had a strong positive association with plasma LDL-cholesterol
and, to a lesser extent, with total plasma cholesterol in this population of
elderly women. The association between serum zinc and plasma cholesterol may
be due to a third factor, such as red meat consumption which is a significant
source of zinc and saturated fat. Alternatively, zinc may play a role in
cholesterol metabolism.
Journal of Trace
Elements in Experimental Medicine1995-1996;8(4):201-209
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Dental
amalgam and cognitive function in older women:
Findings from the Nun Study
Stanley R. Saxe DMD MSD, David A. Snowdon PhD, Merle W. Wekstein MPA,
Robert G. Henry DMD, Sara Jean Donegan SSND, and David R. Wekstein PhD
The number and
surface area of occlusal dental amalgams were determined in a group of 129
Catholic sisters who were 75 to 102 years of age. Findings from this study of
women with relatively homogeneous adult lifestyles and environments suggest
that existing amalgams are not associated with lower performance on eight
different tests of cognitive function.
Journal of the
American Dental Association
1995;126:1495-1501
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Weight
change and physical function in elderly women:
Findings from the Nun Study
Christine L. Tully MD and David A. Snowdon PhD
Objective:
Investigate the association between change in weight and decline in physical
function in elderly women.
Design: Longitudinal study of a defined population of Catholic sisters
(nuns) whose weight and function were assessed twice, an average of 584 days
apart.
Setting: Unique life communities (convents) located throughout the
United States.
Participants: 475 Catholic sisters who were 75 to 99 years old (mean,
M=82.1; standard deviation, SD=4.8) and were independent in at least one
Activity of Daily Living at the first assessment of weight and function.
Interventions: None.
Measurements: At each assessment, weight, Activities of Daily Living,
and cognitive function were evaluated as part of the Nun Study, a longitudinal
study of aging and Alzheimer's disease. Annual percent weight change was
calculated using weights from the two assessments and the days that elapsed
between assessments.
Results: Mean weight at first assessment was 140 pounds (range 78 to
232, SD=27). The mean annual percent weight change was 0.1% (range 22% loss to
16% gain, SD=3.8). Age- and initial weight-adjusted findings indicated that
those with an annual percent weight loss of 3% or greater had 2.7 to 3.9 times
the risk of becoming dependent in each Activity of Daily Living, compared to
those with no weight change. The elevated risk persisted in those who were
mentally intact or independent in eating.
Conclusions: Monitoring of weight may be an easy and inexpensive
method of identifying older individuals at increased risk of disability.
Journal of the
American Geriatrics Society
1995;43:1394-1397
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Serum
zinc, senile plaques, and neurofibrillary tangles:
Findings from the Nun Study
Christine L. Tully MD, David A. Snowdon PhD, and
William R. Markesbery MD
Zinc appears to
have a role in binding amyloid precursor protein in vitro. It is not known
whether zinc plays a role in senile plaque formation in vivo in humans. Serum
zinc concentrations were available from 12 sisters who died in the Nun Study,
a longitudinal study of aging and Alzheimer's disease. Fasting serum zinc
concentrations, determined approximately one year before death, had moderate
to strong negative correlations with senile plaque counts in seven brain
regions. In all brain regions combined, the age-adjusted negative correlations
with serum zinc were statistically significant for total senile plaques and
diffuse plaques, and suggestive for neuritic plaques. Thus serum zinc in the
normal range may be associated with low senile plaque counts in elders.
NeuroReport
1995;6:2105-2108
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Temporomandibular
joint dysfunction and selected health parameters
in the elderly
Linda P. Harriman, David A. Snowdon, Louise B. Messer,
Del Marie Rysavy,
Sharon K. Ostwald, Char-Huei Lai and Annelle H. Soberay
Little research
has focused on temporomandibular joint dysfunction (TMJD) in the elderly. The
present study describes relationships between TMJD and selected health
parameters in a population of 75- to 94-year-old Roman catholic sisters
(nuns). Mental, physical, and oral assessments made on 117 sisters identified
26 with TMJD. Among all sisters, TMJD was not associated with age, education,
mental impairments, hand coordination, handgrip strength, mobility, or use of
walking aids. In 75- to 84-year-old sisters, TMJD was positively associated
with self-reported arthritis (p=0.12), edentulism (p=0.09), and the presence
of complete dentures (p=0.05), and negatively associated with the number of
teeth present (p=0.05), especially the posterior teeth. These associations
were weaker in 85- to 94-year-old sisters. This study suggests that TMJD is
associated with the presence of complete dentures and a low number of teeth,
especially the posterior teeth.
Oral Surgery,
Oral Medicine, and Oral Pathology
1990;70:406-413
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Videotape
dietary assessment: Validity, reliability, and comparison of results with
24-hour
dietary recalls from elderly women in a retirement home
Judith E. Brown PhD, Theresa M. Tharp MPH, Elizabeth
M. Dahlberg-Luby MS,
David A. Snowdon PhD, Sharon K. Ostwald PhD, I. Marilyn Buzzard PhD,
S. Del Marie Rysavy MS and S. Mary Aloysius Wieser MS
The validity and
reliability of a videotape method for quantifying food intake were tested, and
results of the method were compared with results obtained from 24-hour dietary
recalls. Participants were 37 elderly Catholic nuns (aged 81.8 ± 4.1 years)
who were ambulatory and living in a retirement home. The videotape method of
dietary assessment consisted of videotaping food trays of each participant for
three meals during 1 day and the subsequent identification of food types and
amounts from the videotapes. Estimates of food amounts obtained were used in
the calculation of energy and nutrient intake. Correlation coefficients
between values for energy and 14 nutrients obtained by direct measurement of
food and estimates from the videotape method were high (r=0.86 to 1.0).
Compared with measured food amounts, the videotape method underestimated food
quantities by an average of 6%. The reliability test indicated that mean
nutrient values obtained from the videotape method by two research assistants
differed by an average of 3.7% and were highly correlated (r=0.84 to 0.98).
Comparison of the videotape method with 24-hour dietary recalls revealed
differences between mean values that were greater than 10% for energy and 6 of
the 14 nutrients and correlations that ranged from 0.09 to 0.82. These results
suggest that use of 24-hour dietary recalls among the elderly may result in a
high percentage of error.
Journal of the
American Dietetic Association
1990:90;1675-1679
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Education,
survival, and independence in elderly Catholic sisters, 1936-1988
David A. Snowdon PhD, Sharon K. Ostwald PhD, Robert L.
Kane MD
Mortality among
306 Roman Catholic sisters (nuns) from Mankato, Minnesota, was assessed during
the period 1936-1988; daily use of nursing services by survivors was
determined in 1986; and the ability of survivors to eat, dress, and perform
other self-care activities was evaluated in 1987. The median age at death was
89.4 years for sisters with educational attainment of a bachelor's degree or
higher, 82.2 years for sisters with some hi | |
