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1.  Association of Plasma Leptin Levels with Incident Alzheimer’s Disease and MRI Measures Of Brain Aging: The Framingham Study 
Context
The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes β-amyloid clearance and improves memory function in animal models of aging and Alzheimer’s disease (AD).
Objective
To relate baseline circulating leptin concentrations in a dementia-free community-based sample prospectively to 1) incident dementia and AD during follow-up and 2) to MRI (magnetic resonance imaging) measures of brain aging in survivors.
Design, Setting and Participants
Plasma leptin concentrations were measured in 785 dementia-free persons (mean age 79 [SD, 5 yrs], 62% women) from the Framingham Original cohort at the 22nd examination cycle (1990–1994). A sub-sample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, the total cerebral brain volume (TCBV) and temporal horn volume (THV; inversely related to hippocampal volume) were assessed.
Main outcome measure
Incidence of dementia and AD during follow-up till December 31st, 2007.
Results
During a median follow-up of 8.3 (range 0 to 15.5) years, 111 participants developed incident dementia, 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratios [HR] per one-SD increment in log-leptin were 0.68 [0.54–0.87] for all-cause dementia and 0.60 [0.46–0.79] for AD). This corresponds to an absolute AD risk over a 12 year follow-up of 25% for persons in the lowest quartile (Q1) versus 6% for persons in Q4 of sex-specific leptin levels. In addition, a one SD elevation in plasma leptin was associated with higher TCBV and lower THV, although the association of leptin with THV did not reach statistical significance.
Conclusions
Circulating leptin is directly related to indices of brain health in asymptomatic adults and inversely related to risk of incident dementia and AD. Our findings require confirmation in independent samples.
doi:10.1001/jama.2009.1836
PMCID: PMC2838501  PMID: 20009056
leptin; adipokines; dementia; Alzheimer’s disease
2.  Evaluation of the combined use of adiponectin and C-reactive protein levels as biomarkers for predicting the deterioration in glycaemia after a median of 5.4 years 
Diabetologia  2011;54(10):2552-2560.
Aims/hypothesis
Hypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years.
Methods
In total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not.
Results
Baseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status.
Conclusions/interpretation
Adiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2227-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2227-0
PMCID: PMC3168746  PMID: 21727999
Adiponectin; Biomarker; C-reactive protein; Glycaemia
3.  Hearing Loss and Incident Dementia 
Archives of Neurology  2011;68(2):214-220.
Context
Earlier studies have suggested that hearing loss, which is prevalent in more than 30% of adults >60 years, may be a risk factor for dementia, but this hypothesis has never been investigated prospectively.
Objective
To determine if hearing loss is associated with incident all-cause dementia and Alzheimer’s disease (AD).
Design, Setting, and Participants
Prospective study of 639 participants (age 36 – 90 y) of the Baltimore Longitudinal Study of Aging who had audiometric testing and who were dementia-free in 1990-1994. Hearing loss was defined by a pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear (normal <25 dB [n = 455], mild loss 25-40 dB [n = 125], moderate loss 41-70 dB [n = 53], severe loss >70 dB [n = 6]). Diagnosis of incident dementia was made by consensus diagnostic conference. Cox proportional hazard models were used to model time to incident dementia according to severity of hearing loss and were adjusted for age, sex, race, education, diabetes, smoking, and hypertension.
Main Outcome Measure
Incidence of all-cause dementia and AD until May 31, 2008.
Results
During a median follow-up of 11.9 years, 58 cases of incident all-cause dementia were diagnosed of which 37 cases were AD. The risk of incident all-cause dementia increased log-linearly with the severity of baseline hearing loss (1.27 per 10 db loss, 95% CI: 1.06 – 1.50). Compared to normal hearing, the hazard ratio for incident all-cause dementia was 1.89 for mild hearing loss (95% CI: 1.00 – 3.58), 3.00 for moderate hearing loss (95% CI: 1.43 – 6.30), and 4.94 for severe hearing loss (95% CI: 1.09 – 22.4). The risk of incident AD also increased with baseline hearing loss but with a wider confidence interval (1.20 per 10 dB of hearing loss, 95% CI: 0.94 – 1.53).
Conclusions
Hearing loss is independently associated with incident all-cause dementia. Whether hearing loss is a marker for early stage dementia or is actually a modifiable risk factor for dementia deserves further study.
doi:10.1001/archneurol.2010.362
PMCID: PMC3277836  PMID: 21320988
4.  Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia 
JAMA neurology  2014;71(1):55-61.
IMPORTANCE
In animal studies, brain-derived neurotrophic factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset.
OBJECTIVE
To examine whether higher serum BDNF levels in cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
DESIGN, SETTING, AND PARTICIPANTS
Framingham Study original and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as related BDNF genetic variants to AD risk. This community-based, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72 [7] years; 56% women).
MAIN OUTCOMES AND MEASURES
Ten-year incidence of dementia and AD.
RESULTS
During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95%CI, 0.28–0.85; P = .01; and hazard ratio, 0.46; 95%CI, 0.24–0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95%CI, 0.50–0.85], P = .001; 0.63 [95%CI, 0.47–0.85], P = .002; and 0.27 [95%CI, 0.11–0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
CONCLUSIONS AND RELEVANCE
Higher serum BDNF levels may protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons.
doi:10.1001/jamaneurol.2013.4781
PMCID: PMC4056186  PMID: 24276217
5.  The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia 
Annals of internal medicine  2013;158(3):162-168.
Background
Primary prevention of Alzheimer disease and other types of dementia (all-cause dementia) is an important public health goal. Evidence to date is insufficient to recommend any lifestyle change to prevent or delay the onset of dementia.
Objective
To assess the association between objectively measured midlife cardiorespiratory fitness (“fitness”) levels and development of all-cause dementia in advanced age.
Design
Prospective, observational cohort study.
Setting
Preventive medicine clinic.
Patients
19 458 community-dwelling, nonelderly adults who had a baseline fitness examination.
Measurements
Fitness levels, assessed using the modified Balke treadmill protocol between 1971 and 2009, and incident all-cause dementia using Medicare Parts A and B claims data from 1999 to 2009.
Results
1659 cases of incident all-cause dementia occurred during 125 700 person-years of Medicare follow-up (median follow-up, 25 years [interquartile range, 19 to 30 years]). After multivariable adjustment, participants in the highest quintile of fitness level had lower hazard of all-cause dementia than those in the lowest quintile (hazard ratio, 0.64 [95% CI, 0.54 to 0.77]). Higher fitness levels were associated with lower hazard of all-cause dementia with previous stroke (hazard ratio, 0.74 [CI, 0.53 to 1.04]) or without previous stroke (hazard ratio, 0.74 [CI, 0.61 to 0.90]).
Limitations
Dementia diagnoses were based on Medicare claims, and participants generally were non-Hispanic white, healthy, and well-educated and had access to preventive health care. This study evaluated fitness levels, so a specific exercise prescription cannot be generated from results and the findings may not be causal.
Conclusion
Higher midlife fitness levels seem to be associated with lower hazards of developing all-cause dementia later in life. The magnitude and direction of the association were similar with or without previous stroke, suggesting that higher fitness levels earlier in life may lower risk for dementia later in life, independent of cerebrovascular disease.
doi:10.7326/0003-4819-158-3-201302050-00005
PMCID: PMC3926646  PMID: 23381040
6.  Carotid Atherosclerosis and Prospective Risk of Dementia 
Background and Purpose
Though vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer’s disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia.
Methods
Participants from the Baltimore Longitudinal Study of Aging (n=364, aged 60–95, median age=73, 60% male, 82% white) underwent initial carotid atherosclerosis assessment and were subsequently assessed for dementia and AD annually for up to 14 years (median=7.0). Cox proportional hazards models predicting (a) all-cause dementia and (b) AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes, and smoking.
Results
Sixty participants developed dementia, with 53 diagnosed as Alzheimer’s disease. Raw rates of future dementia and AD among individuals initially (a) in the upper quintile of carotid intimal medial thickness (IMT) or (b) with bilateral carotid plaque were generally double the rates of individuals with IMT in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed a >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid IMT, and a nearly 2.0-fold increased risk of dementia among individuals with bilateral plaque.
Conclusions
Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid IMT or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.
doi:10.1161/STROKEAHA.112.672527
PMCID: PMC3508298  PMID: 23103489
atherosclerosis; intimal medial thickness; dementia; Alzheimer’s disease
7.  Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study 
PLoS Medicine  2012;9(2):e1001170.
A set of cross-sectional surveys carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India reveal the prevalence and between-country variation in mild cognitive impairment at a population level.
Background
Rapid demographic ageing is a growing public health issue in many low- and middle-income countries (LAMICs). Mild cognitive impairment (MCI) is a construct frequently used to define groups of people who may be at risk of developing dementia, crucial for targeting preventative interventions. However, little is known about the prevalence or impact of MCI in LAMIC settings.
Methods and Findings
Data were analysed from cross-sectional surveys established by the 10/66 Dementia Research Group and carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India on 15,376 individuals aged 65+ without dementia. Standardised assessments of mental and physical health, and cognitive function were carried out including informant interviews. An algorithm was developed to define Mayo Clinic amnestic MCI (aMCI). Disability (12-item World Health Organization disability assessment schedule [WHODAS]) and informant-reported neuropsychiatric symptoms (neuropsychiatric inventory [NPI-Q]) were measured. After adjustment, aMCI was associated with disability, anxiety, apathy, and irritability (but not depression); between-country heterogeneity in these associations was only significant for disability. The crude prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Country differences changed little (range 0.6%–4.6%) after standardization for age, gender, and education level. In pooled estimates, aMCI was modestly associated with male gender and fewer assets but was not associated with age or education. There was no significant between-country variation in these demographic associations.
Conclusions
An algorithm-derived diagnosis of aMCI showed few sociodemographic associations but was consistently associated with higher disability and neuropsychiatric symptoms in addition to showing substantial variation in prevalence across LAMIC populations. Longitudinal data are needed to confirm findings—in particular, to investigate the predictive validity of aMCI in these settings and risk/protective factors for progression to dementia; however, the large number affected has important implications in these rapidly ageing settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, more than 35 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. Dementia, the commonest form of which is Alzheimer's disease, mainly affects older people and, because more people than ever are living to a ripe old age, experts estimate that, by 2050, more than 115 million people will have dementia. At present, there is no cure for dementia although drugs can be used to manage some of the symptoms. Risk factors for dementia include physical inactivity, infrequent participation in mentally or socially stimulating activities, and common vascular risk factors such as high blood pressure, diabetes, and smoking. In addition, some studies have reported that mild cognitive impairment (MCI) is associated with an increased risk of dementia. MCI can be seen as an intermediate state between normal cognitive aging (becoming increasingly forgetful) and dementia although many people with MCI never develop dementia, and some types of MCI can be static or self-limiting. Individuals with MCI have cognitive problems that are more severe than those normally seen in people of a similar age but they have no other symptoms of dementia and are able to look after themselves. The best studied form of MCI—amnestic MCI (aMCI)—is characterized by memory problems such as misplacing things and forgetting appointments.
Why Was This Study Done?
Much of the expected increase in dementia will occur in low and middle income countries (LAMICs) because these countries have rapidly aging populations. Given that aMCI is frequently used to define groups of people who may be at risk of developing dementia, it would be useful to know what proportion of community-dwelling older adults in LAMICs have aMCI (the prevalence of aMCI). Such information might help governments plan their future health care and social support needs. In this cross-sectional, population-based study, the researchers estimate the prevalence of aMCI in eight LAMICs using data collected by the 10/66 Dementia Research Group. They also investigate the association of aMCI with sociodemographic factors (for example, age, gender, and education), disability, and neuropsychiatric symptoms such as anxiety, apathy, irritability, and depression. A cross-sectional study collects data on a population at a single time point; the 10/66 Dementia Research Group is building an evidence base to inform the development and implementation of policies for improving the health and social welfare of older people in LAMICs, particularly people with dementia.
What Did the Researchers Do and Find?
In cross-sectional surveys carried out in six Latin American LAMICS, China, and India, more than 15,000 elderly individuals without dementia completed standardized assessments of their mental and physical health and their cognitive function. Interviews with relatives and carers provided further details about the participant's cognitive decline and about neuropsychiatric symptoms. The researchers developed an algorithm (set of formulae) that used the data collected in these surveys to diagnose aMCI in the study participants. Finally, they used statistical methods to analyze the prevalence, distribution, and impact of aMCI in the eight LAMICs. The researchers report that aMCI was associated with disability, anxiety, apathy, and irritability but not with depression and that the prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Other analyses show that, considered across all eight countries, aMCI was modestly associated with being male (men had a slightly higher prevalence of aMCI than women) and with having fewer assets but was not associated with age or education.
What Do These Findings Mean?
These findings suggest that aMCI, as diagnosed using the algorithm developed by the researchers, is consistently associated with higher disability and with neuropsychiatric symptoms in the LAMICs studied but not with most sociodemographic factors. Because prevalidated and standardized measurements were applied consistently in all the countries and a common algorithm was used to define aMCI, these findings also suggest that the prevalence of aMCI varies markedly among LAMIC populations and is similar to or slightly lower than the prevalence most often reported for European and North American populations. Although longitudinal studies are now needed to investigate the extent to which aMCI can be used as risk marker for further cognitive decline and dementia in these settings, the large absolute numbers of older people with aMCI in LAMICs revealed here potentially has important implications for health care and social service planning in these rapidly aging and populous regions of the world.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001170.
Alzheimer's Disease International is the international federation of Alzheimer associations around the world; it provides links to individual associations, information about dementia, and links to three World Alzheimer Reports; information about the 10/66 Dementia Research Group is also available on this web site
The Alzheimer's Society provides information for patients and carers about dementia, including information on MCI and personal stories about living with dementia
The Alzheimer's Association also provides information for patients and carers about dementia and about MCI, and personal stories about dementia
A BBC radio program that includes an interview with a man with MCI is available
MedlinePlus provides links to further resources about MCI and dementia (in English and Spanish)
doi:10.1371/journal.pmed.1001170
PMCID: PMC3274506  PMID: 22346736
8.  First Diagnosis and Management of Incontinence in Older People with and without Dementia in Primary Care: A Cohort Study Using The Health Improvement Network Primary Care Database 
PLoS Medicine  2013;10(8):e1001505.
Robert Grant and colleagues used the British THIN primary care database to determine rates of first diagnosis of urinary and faecal incontinence among people aged 60–89 with dementia compared with those without dementia, and the use of medication or indwelling catheters for urinary incontinence in those with and without dementia.
Please see later in the article for the Editors' Summary
Background
Dementia is one of the most disabling and burdensome diseases. Incontinence in people with dementia is distressing, adds to carer burden, and influences decisions to relocate people to care homes. Successful and safe management of incontinence in people with dementia presents additional challenges. The aim of this study was to investigate the rates of first diagnosis in primary care of urinary and faecal incontinence among people aged 60–89 with dementia, and the use of medication or indwelling catheters for urinary incontinence.
Methods and Findings
We extracted data on 54,816 people aged 60–89 with dementia and an age-gender stratified sample of 205,795 people without dementia from 2001 to 2010 from The Health Improvement Network (THIN), a United Kingdom primary care database. THIN includes data on patients and primary care consultations but does not identify care home residents. Rate ratios were adjusted for age, sex, and co-morbidity using multilevel Poisson regression.
The rates of first diagnosis per 1,000 person-years at risk (95% confidence interval) for urinary incontinence in the dementia cohort, among men and women, respectively, were 42.3 (40.9–43.8) and 33.5 (32.6–34.5). In the non-dementia cohort, the rates were 19.8 (19.4–20.3) and 18.6 (18.2–18.9). The rates of first diagnosis for faecal incontinence in the dementia cohort were 11.1 (10.4–11.9) and 10.1 (9.6–10.6). In the non-dementia cohort, the rates were 3.1 (2.9–3.3) and 3.6 (3.5–3.8).
The adjusted rate ratio for first diagnosis of urinary incontinence was 3.2 (2.7–3.7) in men and 2.7 (2.3–3.2) in women, and for faecal incontinence was 6.0 (5.1–7.0) in men and 4.5 (3.8–5.2) in women. The adjusted rate ratio for pharmacological treatment of urinary incontinence was 2.2 (1.4–3.7) for both genders, and for indwelling urinary catheters was 1.6 (1.3–1.9) in men and 2.3 (1.9–2.8) in women.
Conclusions
Compared with those without a dementia diagnosis, those with a dementia diagnosis have approximately three times the rate of diagnosis of urinary incontinence, and more than four times the rate of faecal incontinence, in UK primary care. The clinical management of urinary incontinence in people with dementia with medication and particularly the increased use of catheters is concerning and requires further investigation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 35 million people have dementia, brain disorders that are characterized by an irreversible decline in cognitive functions such as language and memory. Alzheimer's disease and other forms of dementia mainly affect older people and, because people are living longer than ever, experts estimate that by 2050 more than 115 million people will have dementia. The earliest sign of dementia is usually increasing forgetfulness but, as the disease progresses, people gradually lose their ability to deal with normal daily activities such as dressing, they may become anxious or aggressive, and they may lose control of their bladder (urinary incontinence), bowels (bowel or fecal incontinence), and other physical functions. As a result, people with dementia require increasing amounts of care as the disease progresses. Relatives and other unpaid carers provide much of this care—two-thirds of people with dementia are cared for at home. However, many people with dementia end their days in a care or nursing home.
Why Was This Study Done?
Incontinence in people with dementia is distressing for the person with dementia and for their carers and often influences decisions to move individuals into care homes. However, little is known about the diagnosis and treatment of urinary and/or fecal incontinence among people with dementia living at home. This information is needed to help policymakers commission the services required for this section of society and insurers recognize the needs such patients have, as well as helping to raise clinicians' awareness of the issue. In this cohort study (an investigation that compares outcomes in groups of people with different characteristics), the researchers use data routinely collected from general practices (primary care) in the UK to determine the rate of first diagnosis of urinary and fecal incontinence in elderly patients with and without dementia and to find out whether a diagnosis of dementia affects the rate of use of drugs or of indwelling urinary catheters (tubes inserted into the bladder to drain urine from the body) for the treatment of urinary incontinence.
What Did the Researchers Do and Find?
The researchers extracted data collected between 2001 and 2010 on incontinence for nearly 55,000 people aged 60–89 with a diagnosis of dementia (the dementia cohort) and for more than 200,000 individuals without a diagnosis of dementia (the non-dementia cohort) from The Health Improvement Network (THIN) primary care database, which includes anonymized consultation records from nearly 500 UK general practices. In the dementia cohort, the rates of first diagnosis of urinary incontinence were 42.3 and 33.5 per 1,000 person-years at risk among men and women, respectively. In the non-dementia cohort, the corresponding rates were 19.8 and 18.6. The rates of first diagnosis of fecal incontinence were 11.1 and 10.1 in the dementia cohort, and 3.1 and 3.6 in the non-dementia cohort among men and women, respectively. After adjusting for age, sex and other diseases, the adjusted rate ratio for the first diagnosis of urinary incontinence in people with dementia compared to people without dementia was 3.2 in men and 2.7 in women; for fecal incontinence, it was 6.0 in men and 4.5 in women; the adjusted rate ratio was 2.2 for both men and women for drug treatment of urinary incontinence and 1.6 in men and 2.3 in women for use of indwelling urinary catheters.
What Do These Findings Mean?
These findings indicate that, in primary care in the UK, dementia is associated with a three-fold higher rate of diagnosis of urinary incontinence and a greater than four-fold higher rate of diagnosis of fecal incontinence. Moreover, the authors suggest that some aspects of clinical management of urinary continence vary between people with and without dementia. In particular, the use of indwelling urinary catheters appears to be more common among people with dementia than among people without dementia, increasing the risk of infection. Thus, health care practitioners providing care for people with dementia may be prioritizing ease of management over risk avoidance, a possibility that requires further investigation. Although the accuracy of these findings is limited by certain aspects of the study design (for example, the THIN database does not identify which patients are living in care homes), they nevertheless suggest that policymakers and insurers involved in planning and providing services for people with dementia living at home need to provide high levels of help with incontinence, including the provision of advice and support for carers.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001505.
The UK not-for-profit organization Alzheimers Society provides information for patients and carers about dementia, including information on coping with incontinence and personal stories about living with dementia
The US not-for-profit organization Alzheimers Association also provides information for patients and carers about dementia and about incontinence, and personal stories about dementia
The UK National Health Service Choices website provides information (including personal stories) about dementia, urinary incontinence, and bowel incontinence
MedlinePlus provides links to further resources about dementia, urinary incontinence and fecal incontinence (in English and Spanish)
The International Continence Society and the International Consultation on Urological Diseases provide independent advice on products to manage incontinence
More information about the THIN database is available
doi:10.1371/journal.pmed.1001505
PMCID: PMC3754889  PMID: 24015113
9.  Glucose Levels and Risk of Dementia 
The New England journal of medicine  2013;369(6):540-548.
BACKGROUND
Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes.
METHODS
We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension.
RESULTS
During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P = 0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P = 0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76).
CONCLUSIONS
Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1215740
PMCID: PMC3955123  PMID: 23924004
10.  Frailty and Incident Dementia 
Background.
We sought to examine whether frailty is associated with dementia, Alzheimer’s disease (AD), and non-AD dementia risk.
Methods.
This is a prospective population-based cohort derived from an integrated health maintenance organization. The sample consisted of 2,619 participants aged 65 and older without dementia at baseline followed from 1994 to 2010. Frailty was defined as having at least 3 of the following criteria: weakness (grip strength), slowness (walking speed), weight loss, low physical activity, and self-reported exhaustion. Follow-up occurred every 2 years to identify incident dementia, possible or probable AD, and non-AD dementia using standard research criteria. Covariates came from self-report and study measures. We used adjusted Cox proportional hazards models to examine the association between frailty and each outcome.
Results.
Over a mean follow-up of 6.5 years, 521 participants developed dementia (of which 448 developed AD). In the model adjusted for age, sex, education, and race, the hazard ratio for frailty was 1.78 (95% confidence interval [CI] 1.32–2.40). In the fully adjusted models, the hazard ratio for frailty was 1.20 for all-cause dementia (95% CI 0.85–1.69), 1.08 for AD (95% CI 0.74–1.57), and 2.57 for non-AD dementia (95% CI 1.08–6.11). For all-cause dementia, we found an interaction between baseline cognitive score and frailty (p = .02); hazard ratio for frailty was 1.78 for those with higher global cognition (95% CI 1.14–2.78) and 0.79 for those with lower global cognition (95% CI 0.50–1.26).
Conclusion.
Frailty was associated with dementia when adjusting only for demographic variables but not in the fully adjusted model. Frailty was associated with higher risk of developing non-AD dementia but not AD. Although frailty was not associated with all-cause dementia in the entire sample, an association did exist in participants with higher cognitive scores. Mechanisms underlying these associations remain to be elucidated.
doi:10.1093/gerona/glt013
PMCID: PMC3738027  PMID: 23419778
Dementia; Alzheimer’s disease; Frailty; Epidemiology
11.  Dementia before Death in Ageing Societies— The Promise of Prevention and the Reality 
PLoS Medicine  2006;3(10):e397.
Background
Dementia and severe cognitive impairment are very closely linked to ageing. The longer we live the more likely we are to suffer from these conditions. Given population increases in longevity it is important to understand not only risk and protective factors for dementia and severe cognitive impairment at given ages but also whether protection affects cumulative risk. This can be explored by examining the effect on cumulative risk by time of death of factors found consistently to reduce risk at particular ages, such as education and social status.
Methods and Findings
In this analysis we report the prevalence of dementia and severe cognitive impairment in the year before death in a large population sample. In the Medical Research Council Cognitive Function and Ageing Study (a 10-y population-based cohort study of individuals 65 and over in England and Wales), these prevalences have been estimated by age, sex, social class, and education. Differences have been explored using logistic regression. The overall prevalence of dementia at death was 30%. There was a strong increasing trend for dementia with age from 6% for those aged 65–69 y at time of death to 58% for those aged 95 y and above at time of death. Higher prevalences were seen for severe cognitive impairment, with similar patterns. People with higher education and social class had significantly reduced dementia and severe cognitive impairment before death, but the absolute difference was small (under 10%).
Conclusions
Reducing risk for dementia at a given age will lead to further extension of life, thus cumulative risk (even in populations at lower risk for given ages) remains high. Ageing of populations is likely to result in an increase in the number of people dying with dementia and severe cognitive impairment even in the presence of preventative programmes. Policy development and research for dementia must address the needs of individuals who will continue to experience these conditions before death.
The overall prevalence of dementia at death in this large study was 30%. Ageing of populations is likely to result in an increase in the number of people dying with dementia even in the presence of preventative programmes.
Editors' Summary
Background.
Severe cognitive impairment and its advanced form, dementia, are among the most difficult problems associated with aging in industrialized countries. Age-associated decline in mental functioning is also expected to become more common in developing countries as improvement of conditions that affect health leads to longer life expectancies. Although the risk of cognitive impairment is known to increase with age, the number of people who suffer from loss of mental abilities in the last years of their lives has not been well studied, as such persons are usually reported to have died from other causes. Further, because the very elderly are seldom included in prevention studies, it is not known whether factors found to reduce the risk of developing dementia by a given age will provide protection until the end of life.
Why Was This Study Done?
This study was designed to follow a representative population of aged people over several years to estimate the risk of developing cognitive impairment or dementia near the end of life and to determine whether factors such as education and social class, which may be protective earlier in life, can ultimately prevent decline in mental functioning.
What Did the Researchers Do and Find?
Using standardized assessments of cognitive status, the researchers interviewed people age 65 and over at six sites representing rural and urban areas in the United Kingdom. Interviews were conducted at regular intervals over ten years. Of approximately 12,000 study participants who had died by the time of this report, just over 2,500 had an assessment for dementia within one year before dying. Of this group, those who died between ages 65 and 69 had a 6% chance of dying with dementia, and those who died above age 95 had a 58% chance of dying with dementia. When moderate and severe cognitive impairment were considered together, the rate in people above age 95 reached almost 80%. Women were more likely to develop dementia than men, even after taking into account the fact that women tend to live longer than men. A higher level of education was associated with only a slightly lower risk of dementia before death.
What Do These Findings Mean?
According to these results, as the number of aged persons increases (with improved health care, preventive medicine, and healthier lifestyles), the chances of developing dementia in the last years of life will continue to increase. Factors believed to protect against dementia at earlier times may be of little effect at the end of life. Planning for aging societies must therefore include not only research into treatments and preventive efforts to reduce the impact of dementia at the end of life, but also realistic allocation of resources to support individuals and their caregivers who must deal with the difficulties of cognitive decline.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030397.
Web site of the Medical Research Council Cognitive Function and Ageing Study
Web site of the Alzheimer's Association
Wikipedia entry on dementia (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030397
PMCID: PMC1626550  PMID: 17076551
12.  Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study 
PLoS Medicine  2009;6(11):e1000180.
Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation.
Background
Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).
Methods and Findings
A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).
Conclusions
Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Losing one's belongings and forgetting people's names is often a normal part of aging. But increasing forgetfulness can also be a sign of dementia, a group of symptoms caused by several disorders that affect the structure of the brain. The commonest form of dementia is Alzheimer disease. In this, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. Vascular dementia, in which problems with blood circulation deprive parts of the brain of oxygen, is also common. People with dementia have problems with two or more “cognitive” functions—thinking, language, memory, understanding, and judgment. As the disease progresses, they gradually lose their ability to deal with normal daily activities until they need total care, their personality often changes, and they may become agitated or aggressive. Dementia is rare before the age of 65 years but about a quarter of people over 85 years old have dementia. Because more people live to a ripe old age these days, the number of people with dementia is increasing. According to the latest estimates, about 35 million people now have dementia and by 2050, 115 million may have the disorder.
Why Was This Study Done?
There is no cure for dementia but many drugs designed to modulate specific abnormal (pathological) changes in the brain that can cause the symptoms of dementia are being developed. To assess the likely impact of these potentially expensive new therapies, experts need to know what proportion of dementia is associated with each type of brain pathology. Although some brain changes can be detected in living brains with techniques such as computed tomography brain scans, most brain changes can only be studied in brains taken from people after death (post mortem brains). In this study, which is part of the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), the researchers look for associations between dementia in elderly people and pathological changes in their post mortem brains and estimate the attributable-risk (AR) for dementia at death associated with specific pathological features in the brain. That is, they estimate the proportion of dementia directly attributable to each type of pathology.
What Did the Researchers Do and Find?
Nearly 20 years ago, the MRC CFAS interviewed more than 18,000 people aged 65 years or older recruited at six sites in England and Wales to determine their cognitive function and their ability to deal with daily activities. 20% of the participants, which included people with and without cognitive impairment, were then assessed in more detail and invited to donate their brains for post mortem examination. As of 2004, 456 individuals had donated their brains. The dementia status of these donors was established using data from their assessment interviews and death certificates, and from interviews with relatives and carers, and their brains were carefully examined for abnormal changes. The researchers then used statistical methods to estimate the AR for dementia at death associated with various abnormal brain changes. The main contributors to AR for dementia at death included age (18% of dementia at death was attributable to this factor), plaques (8%), and neurofibrillary tangles (11%) in a brain region called the neocortex, small blood vessel disease (12%), and multiple abnormal changes in blood vessels (9%).
What Do These Findings Mean?
These findings suggest that multiple abnormal brain changes determine the overall burden of dementia. Importantly, they also suggest that dementia is often associated with mixed pathological changes—many people with dementia had brain changes consistent with both Alzheimer disease and vascular dementia. Because people with dementia live for variable lengths of time during which the abnormal changes in their brain are likely to alter, it may be difficult to extrapolate these findings to living populations of elderly people. Furthermore, only a small percentage of the MRC CFAS participants have donated their brains so the findings of this study may not apply to the general population. Nevertheless, these findings suggest that the new therapies currently under development may do little to reduce the overall burden of dementia because most people's dementia involves multiple pathologies. Consequently, it may be necessary to develop a range of strategies and combination therapies to deal with the ongoing dementia epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000180.
The US National Institute on Aging provides information for patients and carers about forgetfulness and about Alzheimer disease (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke provides information about dementia (in English and Spanish)
The UK National Health Service Choices Web site also provides detailed information for patients and their carers about dementia and about Alzheimer disease
MedlinePlus provides links to additional resources about dementia and Alzheimer disease (in English and Spanish)
More information about the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) is available
doi:10.1371/journal.pmed.1000180
PMCID: PMC2765638  PMID: 19901977
13.  A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts 
Background
The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.
Methods
To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case–control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Results
Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P heterogeneity = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P trend = .04). Restricted cubic spline regression confirmed a nonlinear association (P nonlinearity < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P interaction > .10).
Conclusions
In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.
doi:10.1093/jnci/djs474
PMCID: PMC3545904  PMID: 23243202
14.  Elevated c-reactive protein levels are associated with prevalent dementia in the oldest-old 
Background
C-reactive protein (CRP) is a nonspecific marker of inflammation that is increased in the brain and serum of patients with Alzheimer’s disease (AD) and has been associated with increased risk of developing dementia. Inflammation increases with age and the number of people reaching the age of 90 and older is growing, making the association between inflammation and dementia increasingly relevant. Using a cross-sectional design, we examined if high levels of serum CRP are associated with increased odds of prevalent dementia in the oldest-old.
Methods
Serum CRP levels of 305 participants (mean age 94.3 ± 2.9 years) from The 90+ Study, a longitudinal cohort study of people 90 and older, were evaluated with respect to all-cause dementia (DSM-IV criteria). CRP levels were divided into three categories: undetectable (< 0.5 mg/dL), detectable (0.5 – 0.7 mg/dL) and elevated (≥0.8 mg/dL). Odds ratios (OR) were calculated using logistic regression and adjusted for covariates.
Results
Relative to participants with undetectable CRP levels, participants with detectable or elevated CRP levels had increased odds of all-cause dementia (detectable: OR 3.0, 95% CI 1.2 – 7.3; elevated: OR 5.0, 95% CI 1.9 – 12.9). When participants were subdivided by gender, significantly increased odds ratios were seen only in women.
Conclusions
In the oldest-old, high CRP levels are associated with increased odds of all-cause dementia, particularly in women. Prospective studies are necessary to confirm if increased CRP levels are associated with increased risk of developing dementia in this age group.
doi:10.1016/j.jalz.2009.04.1230
PMCID: PMC2740472  PMID: 19560102
C-reactive protein; dementia; nonagenarian; serum; inflammation
15.  Occupational exposure to pesticides increases the risk of incident AD 
Neurology  2010;74(19):1524-1530.
Background:
Commonly used organophosphate and organochlorine pesticides inhibit acetylcholinesterase at synapses in the somatic, autonomic, and central nervous systems and may therefore have lasting effects on the nervous system. Few studies have examined the relationship of pesticide exposure and risk of dementia or Alzheimer disease (AD). We sought to examine the association of occupational pesticide exposure and the risk of incident dementia and AD in later life.
Methods:
Residents of the agricultural community of Cache County, UT, who were aged 65 years and older as of January 1995, were invited to participate in the study. At baseline, participants completed detailed occupational history questionnaires that included information about exposures to various types of pesticides. Cognitive status was assessed at baseline and after 3, 7, and 10 years. Standardized methods were used for detection and diagnosis of dementia and AD. Cox proportional hazards survival analyses were used to evaluate the risk of incident dementia and AD associated with pesticide exposure.
Results:
Among 3,084 enrollees without dementia, more men than women reported pesticide exposure (p < 0.0001). Exposed individuals (n = 572) had more years of education (p < 0.01) but did not differ from others in age. Some 500 individuals developed incident dementia, 344 with AD. After adjustment for baseline age, sex, education, APOE ε4 status, and baseline Modified Mini-Mental State Examination scores, Cox proportional hazards models showed increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09–1.76, and for AD (HR 1.42, 95% CI 1.06–1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05–2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99–2.24), which was nearly significant.
Conclusions:
Pesticide exposure may increase the risk of dementia and Alzheimer disease in late life.
GLOSSARY
= Modified Mini-Mental State Examination;
= Alzheimer disease;
= confidence interval;
= Dementia Questionnaire;
= Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;
= hazard ratio.
doi:10.1212/WNL.0b013e3181dd4423
PMCID: PMC2875926  PMID: 20458069
16.  Prognostic Effect of Circulating Adiponectin in a Randomized 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women at Risk for Breast Cancer 
Journal of Clinical Oncology  2011;30(2):151-157.
Purpose
Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer.
Patients and Methods
We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period.
Results
At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels.
Conclusion
Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.
doi:10.1200/JCO.2011.35.2237
PMCID: PMC3255561  PMID: 22162577
17.  THE ASSOCIATION OF NEUROPSYCHIATRIC SYMPTOMS IN MCI WITH INCIDENT DEMENTIA AND ALZHEIMER’S DISEASE 
Objectives
Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer’s disease (AD). Among persons with MCI, depression and anxiety have been associated with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD.
Design
Longitudinal cohort study followed annually (median 1.58 years)
Setting
National Alzheimer’s Coordinating Center (NACC) database combining clinical data from 29 Alzheimer’s Disease Centers (ADCs).
Participants
1821 participants with MCI
Measurements
1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes (CDR-Sum) 5) Mini-Mental State Exam (MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, CDR-Sum, and MMSE.
Results
527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS>0 was associated with increased risk of incident dementia (HR 1.47, 95% CI 1.17, 1.84) and AD (HR 1.45, 95% CI 1.14, 1.83). Baseline NPI>0 was associated with increased risk of incident dementia (HR 1.37. 95% CI 1.12, 1.66) and AD (HR 1.35,95% CI 1.09, 1.66).
Conclusions
Neuropsychiatric symptoms in MCI are associated with significantly increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.
doi:10.1016/j.jagp.2013.01.006
PMCID: PMC3428504  PMID: 23567400
18.  Atrial Fibrillation and Risk of Dementia: A Prospective Cohort study 
Background/Objectives
Atrial fibrillation may increase dementia risk, but prior studies yielded conflicting results. Many had low power or limited measures of dementia. We investigated whether atrial fibrillation is associated with increased risk of incident dementia or Alzheimer disease, beyond its effect on stroke.
Design
A prospective cohort study
Setting
An integrated healthcare delivery system
Participants
A population-based sample of 3,045 community-dwelling adults age 65 and older without dementia or clinical stroke, followed from 1994-2008.
Measurements
Atrial fibrillation was identified from health plan electronic data using International Classification of Diseases, version 9, codes from inpatient and outpatient encounters. Covariates came from self-report, study measures, and health plan data. Participants were screened every 2 years with the Cognitive Abilities Screening Instrument (score range, 0-100), with detailed neuropsychological and clinical assessment of those scoring less than 86. The outcomes of all-cause dementia and possible or probable Alzheimer disease were determined by a multidisciplinary consensus committee using standard research criteria.
Results
Atrial fibrillation was present in 132/3,045 (4.3%) participants at baseline and was diagnosed in 370 (12.2%) more over a mean of 6.8 years of follow-up. 572 participants (18.8%) developed dementia (449 with Alzheimer disease). The adjusted hazard ratio for all-cause dementia associated with atrial fibrillation was 1.38 (95% CI 1.10-1.73) and for possible or probable Alzheimer disease, 1.50 (95% CI 1.16-1.94). Results were similar for participants with or without clinically recognized stroke during follow-up and in sensitivity analyses examining only probable Alzheimer disease.
Conclusion
Atrial fibrillation is associated with higher risk of developing Alzheimer disease and dementia. Future studies should examine whether specific treatments including optimal anticoagulation can decrease this risk.
doi:10.1111/j.1532-5415.2011.03508.x
PMCID: PMC3289545  PMID: 21806558
atrial fibrillation; cardiac arrhythmia; dementia; Alzheimer disease; epidemiology
19.  Are sex and educational level independent predictors of dementia and Alzheimer's disease? Incidence data from the PAQUID project 
OBJECTIVES—To examine the age specific risk of Alzheimer's disease according to sex, and to explore the role of education in a cohort of elderly community residents aged 65 years and older.
METHODS—A community based cohort of elderly people was studied longitudinally for 5 years for the development of dementia. Dementia diagnoses were made according to the DSM III R criteria and Alzheimer's disease was assessed using the NINCDS-ADRDA criteria. Among the 3675 non-demented subjects initially included in the cohort, 2881participated in the follow up. Hazard ratios of dementia were estimated using a Cox model with delayed entry in which the time scale is the age of the subjects.
RESULTS—During the 5 year follow up, 190 incident cases of dementia, including 140 cases of Alzheimer's disease were identified. The incidence rates of Alzheimer's disease were 0.8/100 person-years in men and 1.4/100 person-years in women. However, the incidence was higher in men than in women before the age of 80 and higher in women than in men after this age. A significant interaction between sex and age was found. The hazard ratio of Alzheimer's disease in women compared with men was estimated to be 0.8 at 75 years and 1.7 at 85 years. The risks of dementia and Alzheimer's disease were associated with a lower educational attainment (hazard ratio=1.8, p<0.001). The increased risk of Alzheimer's disease in women was not changed after adjustment for education.
CONCLUSION—Women have a higher risk of developing dementia after the age of 80 than men. Low educational attainment is associated with a higher risk of Alzheimer's disease. However, the increased risk in women is not explained by a lower educational level.


PMCID: PMC1736218  PMID: 10071096
20.  Cardiorespiratory Fitness as a Predictor of Dementia Mortality in Men and Women 
There is evidence that physical activity may reduce the risk of developing Alzheimer’s disease and dementia. However, few reports have examined the physical activity-dementia association with objective measures of physical activity. Cardiorespiratory fitness (hereafter called fitness) is an objective reproducible measure of recent physical activity habits.
Purpose:
We sought to determine whether fitness is associated with lower risk for dementia mortality in women and men.
Methods:
We followed 14,811 women and 45,078 men, ages 20-88 at baseline, for an average of 17 years. All participants completed a preventive health examination at the Cooper Clinic in Dallas, Texas during 1970-2001. Fitness was measured with a maximal treadmill exercise test, with results expressed in maximal metabolic equivalents (METs). The National Death Index identified deaths through 2003. Cox proportional hazards models were used to examine the association between baseline fitness and dementia mortality, adjusting for age, sex, examination year, body mass index, smoking, alcohol use, abnormal ECGs, and health status.
Results:
There were 164 deaths with dementia listed as the cause during 1,012,125 person-years of exposure. Each 1-MET increase in fitness was associated with a 14% lower adjusted risk of dementia mortality (95% confidence interval, CI 6%-22%). With fitness expressed in tertiles, adjusted hazard ratios (HRs) for those in the middle and high fitness groups suggest their risk of dementia mortality was less than half that of those in the lowest fitness group (respectively: HR 0.44, CI 0.26-0.74; HR 0.49, CI 0.26-0.90).
Conclusion:
Greater fitness was associated with lower risk of mortality from dementia in a large cohort of men and women.
doi:10.1249/MSS.0b013e31822cf717
PMCID: PMC3908779  PMID: 21796048
physical fitness; cognitive function; Alzheimer’s disease; vascular dementia; metabolic equivalents (METs)
21.  Retinal vascular caliber and risk of dementia 
Neurology  2011;76(9):816-821.
Background:
Retinal vessels provide a unique opportunity to study both systemic and cerebrovascular disease. Smaller retinal arteriolar calibers are strongly related to hypertension, whereas larger retinal venular calibers are more related to inflammation, cerebral hypoperfusion, and cerebrovascular disease. Whether retinal vessel calibers are related to dementia remains unclear.
Methods:
We investigated whether retinal arteriolar and venular calibers are associated with risk of dementia, and its subtypes Alzheimer disease (AD) and vascular dementia, in the prospective population-based Rotterdam Study. Digitized retinal images were available in 5,553 participants aged 55 years or over and dementia-free at baseline (1990–1993). Participants were re-examined in 1993–1994, 1997–1999, and 2002–2004 and were continuously monitored for development of dementia.
Results:
During a mean follow-up of 11.6 years, 655 participants developed dementia. AD was diagnosed in 519 and vascular dementia in 73 participants. Larger venular calibers were associated with an increased risk of dementia, in particular vascular dementia (age- and sex-adjusted hazard ratio per SD increase: 1.31; 95% confidence interval 1.06–1.64), but not AD. The association remained significant after adjustment for stroke and cardiovascular risk factors. Smaller arteriolar calibers were also associated with an increased risk of vascular dementia, yet only when adjusted for venular calibers.
Conclusions:
Retinal venular widening is associated with an increased risk of vascular dementia. Our findings are in line with previous observations in stroke and cerebral small-vessel disease and suggest that the association between larger retinal venular calibers and dementia may reflect cerebral hypoperfusion and subsequent ischemia.
doi:10.1212/WNL.0b013e31820e7baa
PMCID: PMC3053331  PMID: 21288987
22.  Psychosocial Factors That Shape Patient and Carer Experiences of Dementia Diagnosis and Treatment: A Systematic Review of Qualitative Studies 
PLoS Medicine  2012;9(10):e1001331.
A systematic review of qualitative studies conducted by Frances Bunn and colleagues identifies and describes the experiences of patients and caregivers on receiving and adapting to a diagnosis of dementia.
Background
Early diagnosis and intervention for people with dementia is increasingly considered a priority, but practitioners are concerned with the effects of earlier diagnosis and interventions on patients and caregivers. This systematic review evaluates the qualitative evidence about how people accommodate and adapt to the diagnosis of dementia and its immediate consequences, to guide practice.
Methods and Findings
We systematically reviewed qualitative studies exploring experiences of community-dwelling individuals with dementia, and their carers, around diagnosis and the transition to becoming a person with dementia. We searched PubMed, PsychINFO, Embase, CINAHL, and the British Nursing Index (all searched in May 2010 with no date restrictions; PubMed search updated in February 2012), checked reference lists, and undertook citation searches in PubMed and Google Scholar (ongoing to September 2011). We used thematic synthesis to identify key themes, commonalities, barriers to earlier diagnosis, and support identified as helpful. We identified 126 papers reporting 102 studies including a total of 3,095 participants. Three overarching themes emerged from our analysis: (1) pathways through diagnosis, including its impact on identity, roles, and relationships; (2) resolving conflicts to accommodate a diagnosis, including the acceptability of support, focusing on the present or the future, and the use or avoidance of knowledge; and (3) strategies and support to minimise the impact of dementia. Consistent barriers to diagnosis include stigma, normalisation of symptoms, and lack of knowledge. Studies report a lack of specialist support particularly post-diagnosis.
Conclusions
There is an extensive body of qualitative literature on the experiences of community-dwelling individuals with dementia on receiving and adapting to a diagnosis of dementia. We present a thematic analysis that could be useful to professionals working with people with dementia. We suggest that research emphasis should shift towards the development and evaluation of interventions, particularly those providing support after diagnosis.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Dementia is a decline in mental ability severe enough to interfere with daily life. Alzheimer disease is the most common type of dementia. People with dementia usually have problems with two or more cognitive functions—thinking, language, memory, understanding, and judgment. Dementia is rare before the age of 65, but about a quarter of people over 85 have dementia. Because more people live longer these days, the number of patients with dementia is increasing. It is estimated that today between 40 and 50 million people live with dementia worldwide. By 2050, this number is expected to triple.
One way to study what dementia means to patients and their carers (most often spouses or other family members) is through qualitative research. Qualitative research aims to develop an in-depth understanding of individuals' experiences and behavior, as well as the reasons for their feelings and actions. In qualitative studies, researchers interview patients, their families, and doctors. When the studies are published, they usually contain direct quotations from interviews as well as summaries by the scientists who designed the interviews and analyzed the responses.
Why Was This Study Done?
This study was done to better understand the experiences and attitudes of patients and their carers surrounding dementia diagnosis. It focused on patients who lived and were cared for within the community (as opposed to people living in senior care facilities or other institutions). Most cases of dementia are progressive, meaning symptoms get worse over time. Diagnosis often happens at an advanced stage of the disease, and some patients never receive a formal diagnosis. This could have many possible reasons, including unawareness or denial of symptoms by patients and people close to them. The study was also trying to understand barriers to early diagnosis and what type of support is useful for newly diagnosed patients and carers.
What Did the Researchers Do and Find?
The researchers conducted a systematic search for published qualitative research studies that reported on the experience, beliefs, feelings, and attitudes surrounding dementia diagnosis. They identified and reviewed 102 such studies. Among the quotations and summaries of the individual studies, they looked for prominent and recurring themes. They also compared and contrasted the respective experiences of patients and carers.
Overall, they found that the complexity and variety of responses to a diagnosis of dementia means that making the diagnosis and conveying it to patients and carers is challenging. Negative connotations associated with dementia, inconsistent symptoms, and not knowing enough about the signs and symptoms were commonly reported barriers to early dementia diagnosis. It was often the carer who initiated the search for help from a doctor, and among patients, willingness and readiness to receive a diagnosis varied. Being told one had dementia had a big impact on a patient's identity and often caused feelings of loss, anger, fear, and frustration. Spouses had to adjust to increasingly unequal relationships and the transition to a role as carer. The strain associated with this often caused health problems in the carers as well. On the other hand, studies examining the experience of couples often reported that they found ways to continue working together as a team.
Adjusting to a dementia diagnosis is a complex process. Initially, most patients and carers experienced conflicts, for example, between autonomy and safety, between recognizing the need for help but reluctance to accept it, or between living in the present and dealing with anxiety about and preparing for the future. As these were resolved and as the disease progressed, the attitudes of patients and carers towards dementia often became more balanced and accepting. Many patients and their families adopted strategies to cope with the impact of dementia on their lives in order to manage the disease and maintain some sort of normal life. These included practical strategies involving reminders, social strategies such as relying on family support, and emotional strategies such as using humor. At some point many patients and carers reported that they were able to adopt positive mindsets and incorporate dementia in their lives.
The studies also pointed to an urgent need for support from outside the family, both right after diagnosis and subsequently. General practitioners and family physicians have important roles in helping patients and carers to get access to information, social and psychological support, and community care. The need for information was reported to be ongoing and varied, and meeting it required a variety of sources and formats. Key needs for patients and carers mentioned in the studies include information on financial aids and entitlements early on, and continued access to supportive professionals and specialists.
What Do These Findings Mean?
Qualitative studies to date on how patients and carers respond to a diagnosis of dementia provide a fairly detailed picture of their experiences. The summary provided here should help professionals to understand better the challenges patients and carers face around the time of diagnosis as well as their immediate and evolving needs. The results also suggest that future research should focus on the development and evaluation of ways to meet those needs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001331.
Wikipedia has pages on dementia and qualitative research (note that Wikipedia is a free online encyclopedia that anyone can edit)
Alzheimer Europe, an umbrella organization of 34 Alzheimer associations from 30 countries across Europe, has a page on the different approaches to research
The UK Department of Health has pages on dementia, including guidelines for carers of people with dementia
MedlinePlus also has information about dementia
doi:10.1371/journal.pmed.1001331
PMCID: PMC3484131  PMID: 23118618
23.  Combined Use of Serum Adiponectin and Tumor Necrosis Factor-Alpha Receptor 2 Levels Was Comparable to 2-Hour Post-Load Glucose in Diabetes Prediction 
PLoS ONE  2012;7(5):e36868.
Background
Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction.
Methods
We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte–fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples.
Results
Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, “adiponectin + TNF-α R2” improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the “CDP + 2-hour post-OGTT glucose” model (AUC  = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC  = 0.829 [95% CI: 0.808–0.849]).
Conclusions
The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.
doi:10.1371/journal.pone.0036868
PMCID: PMC3353952  PMID: 22615828
24.  Depressive symptoms and risk of dementia 
Neurology  2010;75(1):35-41.
Objectives:
Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period.
Methods:
In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of ≥16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE ε4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD).
Results:
During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D ≥16) had more than a 50% increased risk for dementia (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment.
Conclusions:
Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.
GLOSSARY
= Alzheimer disease;
= Clinical Dementia Rating;
= Center for Epidemiologic Studies Depression Scale;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= hazard ratio;
= mild cognitive impairment;
= Mini-Mental State Examination.
doi:10.1212/WNL.0b013e3181e62138
PMCID: PMC2906404  PMID: 20603483
25.  Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer 
Journal of Clinical Oncology  2010;29(1):32-39.
Purpose
Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality.
Patients and Methods
We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models.
Results
Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer–specific or all-cause mortality.
Conclusion
Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.
doi:10.1200/JCO.2009.26.4473
PMCID: PMC3055857  PMID: 21115858

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