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1.  Amyloid imaging and cognitive decline in non-demented oldest-old: The 90+ Study 
Background
The goal of this study was to examine cross-sectional and longitudinal associations between cognitive performance and beta amyloid (Aβ) load determined by florbetapir F18 positron emission tomography (PET) in non-demented oldest-old.
Methods
Thirteen non-demented (normal or cognitively impaired non-demented) participants (median age=94.2 years) from The 90+ Study underwent florbetapir-PET scanning within 3 months of baseline neuropsychological testing. Amyloid load was measured with a semiautomated quantitative analysis of average cortical to cerebellar standard uptake values (SUVr) ratio and a visual interpretation (Aβ- or Aβ+). Neuropsychological testing was repeated every 6 months.
Results
At baseline, SUVr correlated significantly with tests of global cognition and memory. During follow-up (median=1.5 years), the Aβ+ group had steeper declines on most cognitive tests, particularly global cognitive measures.
Conclusion
This preliminary study suggests that greater amyloid load is associated with poorer cognition and faster cognitive decline in non-demented oldest-old. Amyloid load may identify individuals at increased risk of developing Alzheimer's disease.
doi:10.1016/j.jalz.2012.06.005
PMCID: PMC3604036  PMID: 23164550
2.  Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old 
Objective
Apolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia.
Methods
The study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody.
Results
Both APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer's Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes.
Conclusions
Lower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers' decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.
doi:10.1016/j.jalz.2012.11.011
PMCID: PMC3971646  PMID: 23474043
Alzheimer; Apolipoprotein E; Beta-amyloid; Dementia; Oldest-old
3.  Medications and Diet Protective Factors for AD? 
Alzheimer Disease and Associated Disorders  2006;20(3 Suppl 2):S89-S96.
In the past decade, studies of Alzheimer disease risk and medication exposures, supplement intake, and dietary factors have grown in number. Typically identified in case-control and cross-sectional studies, many of these exposures have also been replicated in prospective studies. These observational studies have provided the foundation for the development of several prevention trials. This brief review focuses on exposures that have been identified in multiple studies. Observational studies of medications suggesting protection for Alzheimer disease include estrogen hormonal therapy, nonsteroidal anti-inflammatory drugs, and cholesterol-lowering statins. Evidence regarding dietary and supplemental intake of vitamins E, C, and folate, and studies of alcohol and wine intake are also reviewed. At present, there is insufficient evidence to make public health recommendations, but these studies can provide potentially important clues and new avenues for clinical and laboratory research.
PMCID: PMC3373253  PMID: 16917203
risk factor; medications; diet; Alzheimer disease
4.  High Levels of Serum C-Reactive Protein (CRP) are Associated with Increased Risk of All-Cause Mortality, but not Dementia, in the Oldest-Old: Results from The 90+ Study 
OBJECTIVES
To evaluate whether high levels of C-reactive protein (CRP) in serum are associated with increased risk of all-cause dementia or mortality in the oldest-old.
DESIGN
Prospective.
SETTING
Research clinic and in-home visits.
PARTICIPANTS
Population-based sample of adults (n = 227; age, 93.9 ± 2.8 years) from The 90+ Study, a longitudinal cohort study of people aged 90 and older.
MEASUREMENTS
CRP levels were divided into three groups according to the assay detection limit: Undetectable (< 0.5 mg/dL), detectable (0.5-0.7 mg/dL) and elevated (≥ 0.8 mg/dL). Neurological examination was used to determine dementia diagnosis (DSM-IV criteria). Adjusted hazards ratios (HR) and 95% confidence intervals (CI) were computed using Cox regression and results were stratified by gender and apolipoprotein E4 (APOE4) genotype.
RESULTS
Subjects with detectable CRP levels had significantly increased risk of mortality (HR 1.7, 95% CI 1.0-2.9), but not dementia (HR 1.2, 95% CI 0.6-2.1), 0.4-4.5 years later relative to subjects with undetectable CRP. The highest relative risk for both dementia and mortality was in APOE4 carriers with detectable CRP (dementia HR: 4.5, 95% CI 0.9-23.3; mortality HR: 5.6, 95% CI 1.0-30.7).
CONCLUSION
High levels of CRP are associated with increased risk of mortality in those aged 90 and older, particularly in APOE4 carriers. There was a trend towards an increased risk of dementia in APOE4 carriers with high CRP levels, although this relationship did not reach significance. High levels of CRP in the oldest-old represent a risk factor for negative outcomes.
doi:10.1111/j.1532-5415.2009.02169.x
PMCID: PMC2913621  PMID: 19245412
c-reactive protein; dementia; mortality; nonagenarian; serum
5.  APOE genotype, dementia and mortality in the oldest-old: The 90+ Study 
Background
Although the ApolipoproteinE (APOE) ε4 allele is a major genetic risk factor for Alzheimer’s disease (AD), it is not clear if this relationship persists among the oldest-old. Several European studies suggest that the effect of the APOEε4 allele on dementia and mortality disappears in very old age. We describe the APOE allele and genotype frequencies and examine whether the presence of the APOEε4 or APOEε2 alleles are related to prevalent dementia, incident dementia, and mortality in a population-based cohort of oldest-old participants in the United States.
Methods
We studied 904 participants aged 90 and older from The 90+ Study. 802 (89%) participants were genotyped and included in the prevalent dementia and mortality analyses. The 520 initially non-demented participants were included in the incident dementia analyses and were evaluated for dementia every six months.
Results
The APOEε4 allele was significantly associated with prevalent dementia (odds ratio [OR]=2.06) and AD (OR=2.37) in women, but not in men. The APOEε2 allele was not related to prevalent dementia in either sex. After an average followup of 2.4 years, 188 incident dementia cases were identified. Neither the APOEε4 nor the APOEε2 allele was related to incident dementia or AD. 510 (64%) participants died after an average followup of 2.3 years and their mortality was not related to the presence of either the APOEε2 or APOEε4 alleles.
Conclusions
Our findings suggest that the associations between APOEε4, dementia and mortality are age dependent and that APOEε4 no longer plays a role in dementia and mortality at very old ages.
doi:10.1016/j.jalz.2011.12.004
PMCID: PMC3543489  PMID: 23123227
Apolipoprotein E; Dementia; Alzheimer’s disease; Mortality; Oldest-old
6.  Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia 
Neurology  2012;79(9):915-921.
Objective:
It has been hypothesized that individuals without dementia with Alzheimer disease (AD) neuropathology may be in the preclinical stages of dementia and could be experiencing subtle cognitive decline. The purpose of this study was to compare longitudinal cognitive performance in oldest-old individuals without dementia with and without AD neuropathology.
Methods:
The study included 58 individuals without dementia from The 90+ Autopsy Study, a population-based study of aging and dementia in individuals aged 90 and older. Participants had neurologic and neuropsychological testing every 6 months with an average of 3 years of follow-up. We compared the trajectory of cognitive performance on the Modified Mini-Mental State Examination (3MS) and the California Verbal Learning Test II (CVLT) by level of AD neuropathology. Based on Consortium to Establish a Registry for Alzheimer's Disease plaque staging, individuals were categorized as having low (none or sparse) or high (moderate or frequent) plaques. Based on Braak and Braak staging, participants were classified as having low (stages I–III) or high (IV–VI) tangles.
Results:
No significant differences were found in 3MS or CVLT cognitive performance over time based on plaque or tangle staging. Both high and low pathology groups showed modest improvements on the 3MS and CVLT consistent with learning effects.
Conclusions:
AD neuropathology at autopsy is not associated with the trajectory of cognitive performance in the 3 years before death in oldest-old without dementia. Despite the presence of AD neuropathology at death, oldest-old without dementia display learning effects on cognitive tests. Further research is necessary to understand factors other than AD neuropathology that may affect cognition in the oldest-old.
doi:10.1212/WNL.0b013e318266fc77
PMCID: PMC3425842  PMID: 22895581
7.  Cognitive impairment in non-1 demented oldest-old: Prevalence and relationship to cardiovascular risk factors 
Objective
To determine the prevalence and types of cognitive impairment in a sample of non-demented aged 90 and older (the oldest-old) and to examine the relationships between cognitive impairment and cardiovascular risk factors.
Participants
420 non-demented participants from The 90+ Study, a study of aging and dementia in the oldest-old. Participants were categorized into four non-overlapping groups: normal cognition, amnestic mild cognitive impairment (aMCI), non-amnestic MCI (naMCI), and other cognitive impairment (OCI). History of cardiovascular risk factors was assessed through self-report.
Results
The overall prevalence of cognitive impairment in non-demented was 34.0% (95%CI: 29.5–38.5). The prevalence of OCI was highest (17.4%; 95%CI: 13.9–21.4) followed by aMCI (8.3%; 95%CI: 5.9–11.4) and naMCI (8.3%; 95%CI: 5.9–11.4). Normal cognition was present in 66.0% (95%CI: 61.2–70.5) of participants. History of hypertension and stroke were the only risk factors that varied between the groups, occurring more frequently in participants with naMCI (χ2=3.82; p<0.05) and OCI (χ2=5.51; p<0.05).
Conclusions
This study found a high prevalence of cognitive impairment in a sample of non-demented oldest-old. We did not find a strong relationship between cardiovascular risk factors and the cognitive impairment groups other than between hypertension and naMCI and stroke and OCI. Future studies comparing the incidence of dementia in these groups will ultimately determine their predictive utility in the oldest-old.
doi:10.1016/j.jalz.2011.02.008
PMCID: PMC3276712  PMID: 22055654
mild cognitive impairment; oldest-old; cardiovascular risk factors
8.  Disability in the Oldest-old: Incidence and Risk Factors in The 90+ Study 
Objectives
To measure the incidence of disability in individuals aged 90 and older and examine factors that may increase risk of disability.
Design and Setting
The 90+ Study, a longitudinal study of aging initiated in January 2003 with follow-up through May 2009.
Participants
216 non-disabled, prospectively followed participants who were aged 90 or older at baseline.
Measurements
The incidence of disability, measured as needing help on one or more Activities of Daily Living, and calculated using person-years. Risk factors were examined using a Cox proportional hazards analysis.
Results
The overall incidence of disability was 16.4%per year (95% confidence interval, 13.3–20.0), and did not differ by gender. Disability incidence increased with age from 8.3%in the 90–94 age group to 25.7%in the 95 and older age group. Several factors were associated with increased risk of disability including history of congestive heart failure, history of depression poor self-rated quality of life and cognitive impairment.
Conclusion
Disability incidence is high and increases rapidly with age in the oldest-old, with rates essentially tripling between ages 90–94 and 95+. Some factors associated with increased risk of disability in younger elderly continue to be risk factors in the oldest-old. Because of the tremendous social and financial impact of disability and the rapid growth of the oldest-old, the development of strategies to delay disability in the elderly should be a priority for health care research.
doi:10.1097/JGP.0b013e31820d9295
PMCID: PMC3266513  PMID: 22273736
9.  Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old 
Brain  2011;134(12):3705-3712.
The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-β pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-β plaques, more abundant neocortical amyloid-β deposition and hippocampal sclerosis with its attendant TDP-43 pathology.
doi:10.1093/brain/awr308
PMCID: PMC3235569  PMID: 22120149
Alzheimer's; tau; amyloid; dementia; oldest-old
10.  Incidence of dementia in oldest-old with amnestic MCI and other cognitive impairments 
Neurology  2011;77(21):1906-1912.
Objective:
To examine the incidence of dementia among the oldest-old people with normal cognition and different types of cognitive impairment.
Methods:
This study included 395 participants without dementia (mean age 93.3 years) from The 90+ Study, a prospective, population-based study of aging and dementia in people aged 90 years and older. The participants had evaluations for dementia every 6 months, and their average follow-up was 2.5 years. We examined the incidence of all-cause dementia in participants stratified into 4 cognitive groups: normal, amnestic mild cognitive impairment (aMCI), nonamnestic mild cognitive impairment (naMCI), and other cognitive impairment (OCI).
Results:
Dementia incidence was highest for participants with aMCI (31.4% per year) and OCI (39.9% per year). Participants with naMCI had an incidence of 14.1% per year, and participants with normal cognition had an incidence of 8.4% per year. Dementia incidence was associated with increasing age in both normal and cognitively impaired participants; however, an APOE4 allele was associated with a higher dementia incidence only in participants with baseline cognitive impairment.
Conclusions:
The risk of developing dementia in the oldest-old is high and increases to higher rates when cognitive impairment is present. Similar to results of studies in younger elderly individuals, cognitive impairment and increasing age were related to increased dementia incidence. High dementia incidence rates in the oldest-old individuals, particularly when cognitively impaired, emphasize the need to further study cognitive impairment and dementia in this rapidly expanding age group.
doi:10.1212/WNL.0b013e318238ee89
PMCID: PMC3233189  PMID: 22076544
11.  Diagnosing Dementia in the Oldest-Old 
Maturitas  2011;70(2):164-168.
The “oldest-old” comprise the fastest growing segment of the population in much of the world. Rates of dementia are extremely high in this age group and will present a major public health burden as the numbers of these individuals quadruple by the middle of the century. Studies in this age group are rare and frequently have small numbers of participants. In research studies and the clinic, the diagnosis of dementia and determination of the etiology of the disorder are challenging. In this review, we include some of our experiences in a population-based longitudinal investigation, The 90+ Study. Oldest-old individuals are more likely to suffer from medical comorbidities and have high rates of sensory loss, psychoactive medication usage, frailty and fatigue. Moreover, social and cultural expectations affect the reporting and interpretation of behavioral changes. These and other factors make it difficult to determine the relative contributions of cognitive losses and non-cognitive losses in the development of functional disability. Contributing further to the complexities of diagnosis, current research suggests that dementia in the oldest-old, compared to younger people, is more likely to be related to mixed disease pathologies. Frequent cerebral neuropathologies include Alzheimer’s disease neurodegeneration, small and large vessel vascular disease, and hippocampal sclerosis. More research is necessary in the oldest-old to better understand the etiologies of dementia in this age group, and factors that may affect the expression of disease as we age.
doi:10.1016/j.maturitas.2011.07.008
PMCID: PMC3171568  PMID: 21831546
Dementia; Oldest-Old; Diagnosis; Alzheimer’s Disease
12.  A Population-Based Clinicopathological Study in the Oldest-Old: The 90+ Study 
Current Alzheimer research  2012;9(6):709-717.
Population-based longitudinal clinicopathological studies provide an ideal opportunity to study a variety of risk and protective factors in relation to pathology associated with dementia in individuals who are representative of the general population. The 90+ Study is a population-based study designed specifically to study aging and dementia as well as its neuropathological correlates in participants 90 years of age and older. We present demographic and pathological data on the first 104 participants to come to autopsy from the brain donation component of the study, The 90+ Autopsy Study. Cognitive diagnosis was assigned according to Diagnostic and Statistical Manual 4th edition criteria for dementia and neuropathological diagnoses were made according to the Consortium to Establish a Registry for Alzheimer’s Disease protocol. Dementia was present in 61% of autopsied participants, the majority of whom were diagnosed with Alzheimer’s disease (85%). Many different types of pathology typically associated with dementia were common in the oldest-old, and included neurofibrillary tangles, neuritic plaques, diffuse plaques, Lewy bodies, hippocampal sclerosis, and cerebral infarctions. Most types of pathology were more frequently found in participants suffering from dementia but there was extensive overlap in pathology among those with and without dementia. In addition, 22% of demented participants did not have sufficient pathology to account for their cognitive loss. Our results highlight the poor associations between these common pathological lesions and dementia in the oldest-old and the importance of considering many different types of pathology, possibly including some yet to be identified, in order to account for all dementias in the oldest-old.
PMCID: PMC3409303  PMID: 22471863
Dementia; Alzheimer’s disease; cohort study; longitudinal studies; neuropathology; oldest-old
13.  Dementia Incidence Continues to Increase with Age in the Oldest Old The 90+ Study 
Annals of Neurology  2010;67(1):114-121.
Objective
The oldest old are the fastest growing segment of the US population, and accurate estimates of dementia incidence in this group are crucial for healthcare planning. Although dementia incidence doubles every 5 years from ages 65 to 90 years, it is unknown if this exponential increase continues past age 90 years. Here, we estimate age- and sex-specific incidence rates of all-cause dementia in people aged 90 years and older, including estimates for centenarians.
Methods
Participants are from The 90+ Study, a population-based longitudinal study of aging and dementia. Three hundred thirty nondemented participants aged 90 years and older at baseline were followed between January 2003 and December 2007. Age- and sex-specific incidence rates of all-cause dementia were estimated by person-years analysis.
Results
The overall incidence rate of all-cause dementia was 18.2% (95% confidence interval [CI], 15.3-21.5) per year and was similar for men and women (risk ratio, 0.94; 95% CI, 0.65–1.37). Rates increased exponentially with age from 12.7% per year in the 90–94-year age group, to 21.2% per year in the 95–99-year age group, to 40.7% per year in the 100+-year age group. The doubling time based on a Poisson regression was 5.5 years.
Interpretation
Incidence of all-cause dementia is very high in people aged 90 years and older and continues to increase exponentially with age in both men and women. Projections of the number of people with dementia should incorporate this continuing increase of dementia incidence after age 90 years. Our results foretell the growing public health burden of dementia in an increasingly aging population.
doi:10.1002/ana.21915
PMCID: PMC3385995  PMID: 20186856
14.  Type of alcohol consumed, changes in intake over time and mortality: the Leisure World Cohort Study 
Age and Ageing  2007;36(2):203-209.
Background
modifiable behavioural risk factors including smoking and alcohol consumption are major contributing or actual causes of mortality.
Objective
to examine the effect of alcohol intake on all-cause mortality in older adults.
Design and Setting
prospective population-based cohort study of residents of a California, United States retirement community.
Subjects
8,877 women and 5,101 men (median age, 74 years) who in the early 1980s completed a postal health survey including details on alcohol consumption.
Methods
participants were followed for 23 years (1981–2004) including two follow-up questionnaires (in 1992 and 1998) asking about current alcohol intake. Age-adjusted and multivariate-adjusted risk ratios of death and 95% confidence intervals were calculated separately for men and women, using proportional hazard regression.
Results
of the 8,644 women and 4,980 men with complete information on the variables of interest and potential confounders, 6,930 women and 4,456 men had died (median age, 87 years). Both men and women who drank alcohol had decreased mortality compared with non-drinkers. Those who drank two or more drinks per day had a 15% reduced risk of death. The reduced risk was not limited to one type of alcohol. Stable drinkers (those who reported drinking both at baseline and follow-up) had a significantly decreased risk of death compared with stable non-drinkers. Those who started drinking at follow-up also had a significantly lower risk. Women who quit drinking were at increased risk of death.
Conclusion
in elderly men and women, moderate alcohol intake exhibits a beneficial effect on mortality. Those who quit may do so for health reasons that affect mortality.
doi:10.1093/ageing/afl184
PMCID: PMC3377489  PMID: 17350977
alcohol; beer; wine; spirits; mortality; elderly
15.  Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging 
Background
Study findings have suggested an association between Alzheimer’s disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B6, and B12) is associated with a reduced risk of AD.
Methods
Participants were 579 nondemented elderly volunteers from the Baltimore Longitudinal Study of Aging who completed dietary diaries and recorded supplement intake for a 7-day period. Cox regression was used to estimate the relative risk (RR) of AD associated with total vitamin intake categorized into levels above or below the Recommended Dietary Allowance (RDA).
Results
After a mean follow-up of 9.3 years, AD developed in 57 participants. Higher intake of folate (RR, 0.41; 95% confidence interval [CI], 0.22 to 0.76), vitamin E (RR, 0.56; 95% CI, 0.30 to 1.06), and vitamin B6 (RR, 0.41; 95% CI, 0.20 to 0.84) were associated individually with a decreased risk of AD after adjusting for age, gender, education, and caloric intake. When these 3 vitamins were analyzed together, only total intake of folate at or above the RDA (RR, 0.45; 95% CI, 0.21 to 0.97) was associated with a significant decreased risk of AD. No association was found between total intake of vitamins C, carotenoids, or vitamin B12 and risk of AD.
Conclusions
These findings suggest that total intake of folate at or above the RDA is associated with a reduced risk of AD. Additional studies are necessary to further investigate whether folate or other(s) unmeasured factor(s) may be responsible for this reduction in risk.
doi:10.1016/j.jalz.2005.06.001
PMCID: PMC3375831  PMID: 19595811
Alzheimer’s disease; Antioxidants; B vitamins; Dementia; Folate; Prospective studies; Longitudinal studies
16.  Alzheimer’s and Dementia in the Oldest-Old: A Century of Challenges 
Current Alzheimer Research  2006;3(5):411-419.
Alzheimer’s disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century. Preventing or delaying the onset of AD could have a huge impact in the number of cases expected to develop. The oldest-old are the fastest growing segment of the population and are estimated to account for 12% of the population over 65. Establishing accurate estimates of dementia and AD rates in this group is crucial for public health planning. Prevalence and incidence estimates above age 85 are imprecise and inconsistent because of the lack of very old individuals in most studies. Moreover, risk and protective factors in our oldest citizens have been studied little, and clinical-pathological correlations appear to be poor. We introduce The 90+ Study, established to address some of the unanswered questions about AD and dementia in the oldest-old. Our preliminary results show that close to half of demented oldest-old do not have known cerebral pathology to account for their cognitive deficits. Furthermore, the APOE-e4 allele appears to be a risk factor for AD only in the women in our study. In addition to the challenge of preventing and treating AD, the oldest-old will require major investigative energy to better understand the concomitants of longevity, the causes of dementia, and the factors that promote successful aging in oldest citizens.
PMCID: PMC3373256  PMID: 17168640
Aging; Alzheimer’s disease; dementia; longevity; nonagenarians; oldest-old
17.  The oldest old and the 90+ Study 
Memories are the gifts from friends and family that stay with us forever, unless a person develops Alzheimer's disease. Leon J. Thal left many, many memories, along with his desire to create a world where people did not lose them to the ravages of dementing illnesses. Working from the bench to the clinic, he was an incomparable leader, scientist, and educator to whom many, including myself, owe much. The present description of a clinical, genetic, and pathologic study of the oldest old contains much of Leon's influence. With data from >950 subjects, a brain repository, and our collection of DNA, the investigators of the 90+ Study are receptive to collaborations. Through our collective efforts, we will continue the scientific work that Leon so strongly supported.
doi:10.1016/j.jalz.2007.11.007
PMCID: PMC3373258  PMID: 18632002
Oldest old; Dementia; Alzheimer's disease
18.  Diet and the Risk for Alzheimer’s Disease 
Annals of Neurology  2006;59(6):877-879.
doi:10.1002/ana.20898
PMCID: PMC3373259  PMID: 16718710
19.  Association of Body Mass Index and Weight Change with All-Cause Mortality in the Elderly 
American Journal of Epidemiology  2006;163(10):938-949.
The authors explored the relation of body mass index (BMI; weight (kg)/height (m)2) and weight change to all-cause mortality in the elderly, using data from a large, population-based California cohort study, the Leisure World Cohort Study. They estimated relative risks of mortality associated with self-reported BMI at study entry, BMI at age 21 years, and weight change between age 21 and study entry. Participants were categorized as underweight (BMI <18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9), or obese (BMI ≥30). Of 13,451 participants aged 73 years (on average) at study entry (1981–1985), 11,203 died during 23 years of follow-up (1981–2004). Relative to normal weight, being underweight (relative risk (RR) = 1.51, 95% confidence interval (CI): 1.38, 1.65) or obese (RR = 1.25, 95% CI: 1.13, 1.38) at study entry was associated with increased mortality. People who were either overweight or obese at age 21 also had increased mortality (RR = 1.17, 95% CI: 1.09, 1.25). Participants who lost weight between age 21 and study entry had increased mortality regardless of their BMI category at age 21. Obesity was significantly associated with increased mortality only among persons under age 75 years and among never or past smokers. This study highlights the influence on older-age mortality risk of being overweight or obese in young adulthood and underweight or obese in later life.
doi:10.1093/aje/kwj114
PMCID: PMC3373260  PMID: 16641311
aged; body mass index; body weight changes; longevity; mortality; risk factors
20.  Sensitivity and Specificity of the Mini-Mental State Examination for Identifying Dementia in the Oldest-Old: The 90+ Study 
OBJECTIVES
To evaluate the sensitivity and specificity of the Mini-Mental State Examination (MMSE) in identifying dementia in the oldest-old when stratified by age and education.
DESIGN
Cross-sectional.
SETTING
Research clinic and in-home visits.
PARTICIPANTS
Population-based sample of adults aged 90 and older (n = 435) who are enrolled in the 90+ Study, a longitudinal, population-based study.
MEASUREMENTS
Neurological examination to determine dementia diagnosis, MMSE, and demographic data.
RESULTS
Receiver operating characteristic (ROC) analyses indicated that the MMSE had high diagnostic accuracy for identifying dementia in subjects aged 90 and older across different age and education groups (area under the ROC curve values ranged from 0.82 to 0.98). A range of possible cutoff values and corresponding sensitivity and specificity are provided for the following age groups: 90–93, 94–96, and ≥97. Age groups were subdivided by educational attainment (≤high school, vocational school or some college, college degree or higher). In subjects aged 90 to 93 with a college degree or higher, the suggested MMSE cutoff score is ≥25 (sensitivity = 0.82, specificity = 0.80). In those aged 94 to 96 with a college degree or higher, the suggested cutoff is ≤24 (sensitivity = 0.85, specificity = 0.80). Those aged 97 and older with an education of high school or less had the lowest suggested cutoff ≤22 (sensitivity = 0.80, specificity = 0.76).
CONCLUSION
Overall, the MMSE had good sensitivity and specificity across all age and educational groups. Optimal cutoff points were lower in the older age groups and those with less education, primarily to preserve specificity. This screening instrument is appropriate for use with the oldest-old.
doi:10.1111/j.1532-5415.2007.01049.x
PMCID: PMC3373261  PMID: 17302668
dementia; MMSE; oldest-old; sensitivity; specificity
21.  Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study 
Menopause (New York, N.y.)  2006;13(1):12-18.
Objective
To examine the effect of postmenopausal estrogen therapy (ET), including duration and recency of use, on all-cause mortality in older women.
Design
As part of a prospective cohort study of residents of a California retirement community begun in the early 1980s, Leisure World Cohort women (median age, 73 y) completed a postal health survey including details on ETuse and were followed up for 22 years (1981–2003). Age- and multivariate-adjusted risk ratios (RR) and 95% CIs were calculated using proportional hazard regression.
Results
Of the 8,801 women, 6,626 died during follow-up (median age, 88 y). ET users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91; 95% CI, 0.87–0.96). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P for trend <0.001). The risk was lowest among long-term (≥15 y) users (RR = 0.83; 95% CI, 0.74–0.93 for 15–19 y and RR = 0.87; 95% CI, 0.80–0.94 for 20+ y). For long-term users, the age-adjusted mortality rate was 50.4 per 1,000 person-years. Lower-dose users (≤0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84; 95% CI, 0.78–0.91 vs RR = 0.91; 95% CI, 0.83–0.97). Risk did not differ by route of administration (P = 0.56). Further adjustment for potential confounders had little effect on the observed RRs for ET.
Conclusion
Long-term ET is associated with lower all-cause mortality in older women.
doi:10.1097/01.gme.0000172880.40831.3b
PMCID: PMC3373269  PMID: 16607094
Mortality; Longevity; Estrogen therapy; Risk factors
22.  Activities and Mortality in the Elderly: The Leisure World Cohort Study 
Background.
Although physical activity has substantial health benefits and reduces mortality, few studies have examined its impact on survival beyond age 75.
Methods.
Using the population-based Leisure World Cohort Study, we explored the association of activity on all-cause mortality in older adults (median age at baseline = 74 years). We followed 8,371 women and 4,828 men for 28 years or until death (median = 13 years) and calculated relative risks for various measures of activity at baseline using Cox regression analysis for four age groups (<70, 70–74, 75–79, and 80+ years) in men and women separately.
Results.
Time spent in active activities, even ½ hour/day, resulted in significantly lower (15–35%) mortality risks compared with no time in active activities. This reduction was evident in all sex–age groups except the youngest men. Participants who reported spending 6 or more hours/day in other less physically demanding activities also had significantly reduced risks of death of 15–30%. The beneficial effect of activities was observed in both those who did and those who did not cut down their activities due to illness or injury. Neither adjustment for potential confounders, exclusion of the first 5 years of follow-up, nor exclusion of individuals with histories of chronic disease substantially changed the findings.
Conclusions.
Participation in leisure-time activities is an important health promoter in aging populations. The association of less physically demanding activities as well as traditional physical activities involving moderate exertion with reduced mortality suggests that the protective effect of engagement in activities is a robust one.
doi:10.1093/gerona/glq237
PMCID: PMC3074957  PMID: 21350247
Mortality; Physical activity; Elderly; Exercise; Longitudinal
23.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease 
The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer’s disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Bio-marker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
doi:10.1016/j.jalz.2011.03.005
PMCID: PMC3312024  PMID: 21514250
Alzheimer’s disease; Dementia; Diagnosis; Magnetic resonance brain imaging; Position emission tomography; Cerebrospinal fluid
24.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
Objective
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Design
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Setting
Academic medical centers
Patients
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Results
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Conclusions
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
doi:10.1001/archneurol.2010.295
PMCID: PMC3058918  PMID: 21059987
25.  Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment—Part 2* 
This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment/dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor regulating prevalence estimates of Alzheimer’s disease (AD) is the severity of cognitive impairment used for case ascertainment. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than studies aimed at identifying persons in the earliest stages of AD. There is limited autopsy data from the above-mentioned epidemiologic studies to address accuracy in the diagnosis of etiologic subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment (MCI) meet pathologic criteria for AD, and a large minority of persons without dementia or MCI also meets pathologic criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the highest published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiologic studies.
doi:10.1016/j.jalz.2010.12.002
PMCID: PMC3039838  PMID: 21255742
Alzheimer’s disease; Dementia; Mild cognitive impairment; Cognitive impairment not dementia; Diagnostic criteria; Population-based; Prevalence, Incidence

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