Kristine Yaffe

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

At present, about 33·9 million people worldwide have Alzheimer's disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184,000-492,000 cases in the USA.

Background Recent estimates suggesting that over half of Alzheimer's disease burden worldwide might be attributed to potentially modifiable risk factors do not take into account risk-factor non-independence. We aimed to provide specific estimates of preventive potential by accounting for the association between risk factors. Methods Using relative risks from existing meta-analyses, we estimated the population-attributable risk (PAR) of Alzheimer's disease worldwide and in the USA, Europe, and the UK for seven potentially modifiable risk factors that have consistent evidence of an association with the disease (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment). The combined PAR associated with the risk factors was calculated using data from the Health Survey for England 2006 to estimate and adjust for the association between risk factors. The potential of risk factor reduction was assessed by examining the combined effect of relative reductions of 10% and 20% per decade for each of the seven risk factors on projections for Alzheimer's disease cases to 2050. Findings Worldwide, the highest estimated PAR was for low educational attainment (19·1%, 95% CI 12·3–25·6). The highest estimated PAR was for physical inactivity in the USA (21·0%, 95% CI 5·8–36·6), Europe (20·3%, 5·6–35·6), and the UK (21·8%, 6·1–37·7). Assuming independence, the combined worldwide PAR for the seven risk factors was 49·4% (95% CI 25·7–68·4), which equates to 16·8 million attributable cases (95% CI 8·7–23·2 million) of 33·9 million cases. However, after adjustment for the association between the risk factors, the estimate reduced to 28·2% (95% CI 14·2–41·5), which equates to 9·6 million attributable cases (95% CI 4·8–14·1 million) of 33·9 million cases. Combined PAR estimates were about 30% for the USA, Europe, and the UK. Assuming a causal relation and intervention at the correct age for prevention, relative reductions of 10% per decade in the prevalence of each of the seven risk factors could reduce the prevalence of Alzheimer's disease in 2050 by 8·3% worldwide. Interpretation After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression. Funding National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough.

A concerted effort to tackle the global health problem posed by traumatic brain injury (TBI) is long overdue. TBI is a public health challenge of vast, but insufficiently recognised, proportions. Worldwide, more than 50 million people have a TBI each year, and it is estimated that about half the world's population will have one or more TBIs over their lifetime. TBI is the leading cause of mortality in young adults and a major cause of death and disability across all ages in all countries, with a disproportionate burden of disability and death occurring in low-income and middle-income countries (LMICs). It has been estimated that TBI costs the global economy approximately $US400 billion annually. Deficiencies in prevention, care, and research urgently need to be addressed to reduce the huge burden and societal costs of TBI. This Commission highlights priorities and provides expert recommendations for all stakeholders—policy makers, funders, health-care professionals, researchers, and patient representatives—on clinical and research strategies to reduce this growing public health problem and improve the lives of people with TBI. Traumatic brain injury: a priority for public health policyThe Lancet Neurology Commission1 draws attention to the devastating impact of traumatic brain injury (TBI) on patients and their families, and the huge public health burden and economic cost of TBI globally. About 50–60 million new TBI cases are estimated to occur annually, with 2·5 million occurring in the European Union.1 The burden of TBI is greatest in low-income and middle-income countries, where 90% of trauma-related deaths occur.2,3 The Commission sets priorities for prevention, clinical care, and research, calling for a combination of innovative research methods and global collaboration to address the huge but poorly recognised public health challenge of TBI, with steps to ensure that developments in care and progress in research are effectively translated into clinical practice and public health policy. Full-Text PDF Traumatic brain injury: a global challengeTraumatic brain injury (TBI) is a leading cause of death and disability worldwide, with enormous economic consequences. The Lancet Neurology Commission1 on TBI sets priorities and provides recommendations for future clinical practice, research, and policy to reduce this overwhelming burden. The Commission comes at a time when the global incidence of TBI is rising, access to care is severely lacking in many parts of the world, and methods of monitoring and diagnosis are frequently inadequate. Full-Text PDF Outcome assessment after traumatic brain injury – Authors' replyWe thank Thomas McMillan and colleagues for their thoughtful comments on assessment of outcomes, with many of which we fully agree. As with many outcome assessments in traumatic brain injury (TBI), the Glasgow Outcome Scale (GOS) is open to a wide variety of influences other than brain injury: factors related to acute TBI appear to explain at best 35% of the variance.1 The predictors, moderators, and mediators of outcome after TBI are incompletely understood. There is thus much progress to be made in identifying confounding covariates for the effects of interventions. Full-Text PDF Outcome assessment after traumatic brain injuryIn their wide ranging and impressive Commission of traumatic brain injury (TBI), Andrew Maas and colleagues1 recommend the development and validation of multidimensional outcome constructs that quantify overall burden of disability from TBI. Their observation that there are already nearly 1000 assessment instruments to consider is one of many challenges that need to be overcome to achieve this aim. Full-Text PDF The burden of traumatic brain injury in childrenOn Feb 21, the US Centers for Disease Control and Prevention (CDC), in collaboration with the National Institutes of Health, published the Report to Congress: The Management of Traumatic Brain Injury (TBI) in Children, to review the public health burden and to make recommendations for the future management and treatment of this population. In a field with such a lack of scientific research and evidence, the report has drawn on all existing resources and studies to comprehensively present the US experience. Full-Text PDF

Background:Whetherhearinglossisindependentlyassociatedwithacceleratedcognitivedeclineinolderadults is unknown. Methods:Westudied1984olderadults(meanage,77.4 years) enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State Examination [3MS] score, 80) who underwent audiometric testinginyear5.Participantswerefollowedupfor6years. Hearing was defined at baseline using a pure-tone average of thresholds at 0.5 to 4 kHz in the better-hearing ear. Cognitive testing was performed in years 5, 8, 10, and11andconsistedofthe3MS(measuringglobalfunction) and the Digit Symbol Substitution test (measuring executive function). Incident cognitive impairment was definedasa3MSscoreoflessthan80oradeclinein3MS score of more than 5 points from baseline. Mixedeffects regression and Cox proportional hazards regression models were adjusted for demographic and cardiovascular risk factors. Results: In total, 1162 individuals with baseline hearing loss (pure-tone average 25 dB) had annual rates of declinein3MSandDigitSymbolSubstitutiontestscoresthat were41%and32%greater,respectively,thanthoseamong individuals with normal hearing. On the 3MS, the annual score changes were 0.65 (95% CI, 0.73 to 0.56) vs 0.46(95%CI,0.55to0.36)pointsperyear(P=.004). On the Digit Symbol Substitution test, the annual score changes were 0.83 (95% CI, 0.94 to 0.73) vs 0.63 (95% CI, 0.75 to 0.51) points per year (P=.02). Comparedtothosewithnormalhearing,individualswithhearing loss at baseline had a 24% (hazard ratio, 1.24; 95% CI, 1.05-1.48) increased risk for incident cognitive impairment. Rates of cognitive decline and the risk for incident cognitiveimpairmentwerelinearlyassociatedwiththeseverity of an individual’s baseline hearing loss.

To evaluate if midlife cardiovascular risk factors are associated with risk of late-life dementia in a large, diverse cohort.The authors conducted a retrospective cohort study of 8,845 participants of a health maintenance organization who underwent health evaluations from 1964 to 1973 when they were between the ages of 40 and 44. Midlife cardiovascular risk factors included total cholesterol, diabetes, hypertension, and smoking. Diagnoses of dementia were ascertained by medical records from January 1994 to April 2003.The authors identified 721 participants (8.2%) with dementia. Smoking, hypertension, high cholesterol, and diabetes at midlife were each associated with a 20 to 40% increase in risk of dementia (fully adjusted Cox proportional hazards model: HR 1.24, 95% CI 1.04 to 1.48 for hypertension, HR 1.26, 95% CI 1.08 to 1.47 for smoking, HR 1.42, 95% CI 1.22 to 1.66 for high cholesterol, and HR 1.46, 95% CI 1.19 to 1.79 for diabetes). A composite cardiovascular risk score was created using all four risk factors and was associated with dementia in a dose-dependent fashion. Compared with participants having no risk factors, the risk for dementia increased from 1.27 for having one risk factor to 2.37 for having all four risk factors (fully adjusted model: HR 2.37, 95% CI 1.10 to 5.10).The presence of multiple cardiovascular risk factors at midlife substantially increases risk of late-life dementia in a dose dependent manner.

Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes.To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years.A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California.Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease.At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55).Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

Several studies have reported an association between the metabolic syndrome and cardiovascular disease. Despite an increasing awareness that cardiovascular risk factors increase risk of cognitive decline and dementia, there are few data on the metabolic syndrome and cognition.To determine if the metabolic syndrome is a risk factor for cognitive decline and if this association is modified by inflammation.A 5-year prospective observational study conducted from 1997 to 2002 at community clinics at 2 sites.A total of 2632 black and white elders (mean age, 74 years).Association of the metabolic syndrome (measured using National Cholesterol Education Program guidelines) and high inflammation (defined as above median serum level of interleukin 6 and C-reactive protein) with change in cognition (Modified Mini-Mental State Examination [3MS]) at 3 and 5 years. Cognitive impairment was defined as at least a 5-point decline.Compared with those without the metabolic syndrome (n = 1616), elders with the metabolic syndrome (n = 1016) were more likely to have cognitive impairment (26% vs 21%, multivariate adjusted relative risk [RR], 1.20; 95% confidence interval [CI], 1.02-1.41). There was a statistically significant interaction with inflammation and the metabolic syndrome (P = .03) on cognitive impairment. After stratifying for inflammation, those with the metabolic syndrome and high inflammation (n = 348) had an increased likelihood of cognitive impairment compared with those without the metabolic syndrome (multivariate adjusted RR, 1.66; 95% CI, 1.19-2.32). Those with the metabolic syndrome and low inflammation (n = 668) did not exhibit an increased likelihood of impairment (multivariate adjusted RR, 1.08; 95% CI, 0.89-1.30). Stratified multivariate random-effects models demonstrated that participants with the metabolic syndrome and high inflammation had greater 4-year decline on 3MS (P = .04) compared with those without the metabolic syndrome, whereas those with the metabolic syndrome and low inflammation did not (P = .44).These findings support the hypothesis that the metabolic syndrome contributes to cognitive impairment in elders, but primarily in those with high level of inflammation.

To evaluate any association between obesity in middle age, measured by body mass index and skinfold thickness, and risk of dementia later in life.Analysis of prospective data from a multiethnic population based cohort.Kaiser Permanente Northern California Medical Group, a healthcare delivery organisation.10,276 men and women who underwent detailed health evaluations from 1964 to 1973 when they were aged 40-45 and who were still members of the health plan in 1994.Diagnosis of dementia from January 1994 to April 2003. Time to diagnosis was analysed with Cox proportional hazard models adjusted for age, sex, race, education, smoking, alcohol use, marital status, diabetes, hypertension, hyperlipidaemia, stroke, and ischaemic heart disease.Dementia was diagnosed in 713 (6.9%) participants. Obese people (body mass index > or = 30) had a 74% increased risk of dementia (hazard ratio 1.74, 95% confidence interval 1.34 to 2.26), while overweight people (body mass index 25.0-29.9) had a 35% greater risk of dementia (1.35, 1.14 to 1.60) compared with those of normal weight (body mass index 18.6-24.9). Compared with those in the lowest fifth, men and women in the highest fifth of the distribution of subscapular or tricep skinfold thickness had a 72% and 59% greater risk of dementia, respectively (1.72, 1.36 to 2.18, and 1.59, 1.24 to 2.04).Obesity in middle age increases the risk of future dementia independently of comorbid conditions.

Depression is highly common throughout the life course and dementia is common in late life. Depression has been linked with dementia, and growing evidence implies that the timing of depression may be important in defining the nature of this association. In particular, earlier-life depression (or depressive symptoms) has consistently been associated with a more than twofold increase in dementia risk. By contrast, studies of late-life depression and dementia risk have been conflicting; most support an association, yet the nature of this association (for example, if depression is a prodrome or consequence of, or risk factor for dementia) remains unclear. The likely biological mechanisms linking depression to dementia include vascular disease, alterations in glucocorticoid steroid levels and hippocampal atrophy, increased deposition of amyloid-β plaques, inflammatory changes, and deficits of nerve growth factors. Treatment strategies for depression could interfere with these pathways and alter the risk of dementia. Given the projected increase in dementia incidence in the coming decades, understanding whether treatment for depression alone, or combined with other regimens, improves cognition is of critical importance. In this Review, we summarize and analyze current evidence linking late-life and earlier-life depression and dementia, and discuss the primary underlying mechanisms and implications for treatment.

It is unclear whether functional status before dialysis is maintained after the initiation of this therapy in elderly patients with end-stage renal disease (ESRD).Using a national registry of patients undergoing dialysis, which was linked to a national registry of nursing home residents, we identified all 3702 nursing home residents in the United States who were starting treatment with dialysis between June 1998 and October 2000 and for whom at least one measurement of functional status was available before the initiation of dialysis. Functional status was measured by assessing the degree of dependence in seven activities of daily living (on the Minimum Data Set-Activities of Daily Living [MDS-ADL] scale of 0 to 28 points, with higher scores indicating greater functional difficulty).The median MDS-ADL score increased from 12 during the 3 months before the initiation of dialysis to 16 during the 3 months after the initiation of dialysis. Three months after the initiation of dialysis, functional status had been maintained in 39% of nursing home residents, but by 12 months after the initiation of dialysis, 58% had died and predialysis functional status had been maintained in only 13%. In a random-effects model, the initiation of dialysis was associated with a sharp decline in functional status, indicated by an increase of 2.8 points in the MDS-ADL score (95% confidence interval [CI], 2.5 to 3.0); this decline was independent of age, sex, race, and functional-status trajectory before the initiation of dialysis. The decline in functional status associated with the initiation of dialysis remained substantial (1.7 points; 95% CI, 1.4 to 2.1), even after adjustment for the presence or absence of an accelerated functional decline during the 3-month period before the initiation of dialysis.Among nursing home residents with ESRD, the initiation of dialysis is associated with a substantial and sustained decline in functional status.

ContextNeuropsychiatric symptoms of dementia are common and associated with poor outcomes for patients and caregivers. Although nonpharmacological interventions should be the first line of treatment, a wide variety of pharmacological agents are used in the management of neuropsychiatric symptoms; therefore, concise, current, evidence-based recommendations are needed.ObjectiveTo evaluate the efficacy of pharmacological agents used in the treatment of neuropsychiatric symptoms of dementia.Evidence AcquisitionA systematic review of English-language articles published from 1966 to July 2004 using MEDLINE, the Cochrane Database of Systematic Reviews, and a manual search of bibliographies was conducted. Inclusion criteria were double-blind, placebo-controlled, randomized controlled trials (RCTs) or meta-analyses of any drug therapy for patients with dementia that included neuropsychiatric outcomes. Trials reporting only depression outcomes were excluded. Data on the inclusion criteria, patients, methods, results, and quality of each study were independently abstracted. Twenty-nine articles met inclusion criteria.Evidence SynthesisFor typical antipsychotics, 2 meta-analyses and 2 RCTs were included. Generally, no difference among specific agents was found, efficacy was small at best, and adverse effects were common. Six RCTs with atypical antipsychotics were included; results showed modest, statistically significant efficacy of olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical antipsychotics are associated with an increased risk of stroke. There have been no RCTs designed to directly compare the efficacy of typical and atypical antipsychotics. Five trials of antidepressants were included; results showed no efficacy for treating neuropsychiatric symptoms other than depression, with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs investigating valproate showed no efficacy. Two small RCTs of carbamazepine had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors generally showed small, although statistically significant, efficacy. Two RCTs of memantine also had conflicting results for treatment of neuropsychiatric symptoms.ConclusionsPharmacological therapies are not particularly effective for management of neuropsychiatric symptoms of dementia. Of the agents reviewed, the atypical antipsychotics risperidone and olanzapine currently have the best evidence for efficacy. However, the effects are modest and further complicated by an increased risk of stroke. Additional trials of cholinesterase inhibitors enrolling patients with high levels of neuropsychiatric symptoms may be warranted.

Several studies have suggested that physical activity is positively associated with cognitive function in elderly persons. Evidence about this association has been limited by the cross-sectional design of most studies and by the frequent lack of adjustment for potential confounding variables. We determined whether physical activity is associated with cognitive decline in a prospective study of older women.We studied 5925 predominantly white community-dwelling women (aged > or =65 years) who were recruited at 4 clinical centers and were without baseline cognitive impairment or physical limitations. We measured cognitive performance using a modified Mini-Mental State Examination at baseline and 6 to 8 years later. Physical activity was measured by self-reported blocks (1 block approximately 160 m) walked per week and by total kilocalories (energy) expended per week in recreation, blocks walked, and stairs climbed. Cognitive decline was defined as a 3-point decline or greater on repeated modified Mini-Mental State Examination.Women with a greater physical activity level at baseline were less likely to experience cognitive decline during the 6 to 8 years of follow-up: cognitive decline occurred in 17%, 18%, 22%, and 24% of those in the highest, third, second, and lowest quartile of blocks walked per week (P< .001 for trend). Almost identical results were obtained by quartile of total kilocalories expended per week. After adjustment for age, educational level, comorbid conditions, smoking status, estrogen use, and functional limitation, women in the highest quartile remained less likely than women in the lowest quartile to develop cognitive decline (for blocks walked: odds ratio, 0.66 [95% confidence interval, 0.54-0.82]; for total kilocalories: odds ratio, 0.74 [95% confidence interval, 0.60-0.90]).Women with higher levels of baseline physical activity were less likely to develop cognitive decline. This association was not explained by differences in baseline function or health status. This finding supports the hypothesis that physical activity prevents cognitive decline in older community-dwelling women.

The decision to institutionalize a patient with dementia is complex and is based on patient and caregiver characteristics and the sociocultural context of patients and caregivers. Most studies have determined predictors of nursing home placement primarily according to patient or caregiver characteristics alone.To develop and validate a prognostic model to determine the comprehensive predictors of placement among an ethnically diverse population of patients with dementia.The Medicare Alzheimer's Disease Demonstration and Evaluation study, a prospective study at 8 sites in the United States, with enrollment between December 1989 and December 1994 of 5788 community-living persons with advanced dementia.Time to nursing home placement throughout a 36-month follow-up period, assessed by interview and review of Medicare records, and its association with patient and caregiver characteristics, obtained by interview at enrollment.Patients were divided into a development (n = 3859) and validation (n = 1929) cohort. In the development cohort, the Kaplan-Meier estimates of nursing home placement throughout 1, 2, and 3 years were 22%, 40%, and 52%, respectively. After multivariate adjustment, patient characteristics that were associated with nursing home placement were as follows: black ethnicity (hazard ratio, 0.60; 95% confidence interval [CI], 0.48-0.74), Hispanic ethnicity (HR, 0.40; 95% CI, 0.28-0.56) (both ethnicities were inversely associated with placement), living alone (HR, 1.74; 95% CI, 1.49-2.02), 1 or more dependencies in activities of daily living (HR, 1.38; 95% CI, 1.20-1.60), high cognitive impairment (for Mini-Mental Status Examination score < or =20: HR, 1.52; 95% CI, 1.33-1.73), and 1 or more difficult behaviors (HR, 1.30; 95% CI, 1.11-1.52). Caregiver characteristics associated with patient placement were age 65 to 74 years (HR, 1.17; 95% CI, 1.01-1.37), age 75 years or older (HR, 1.55; 95% CI, 1.31-1.84), and high Zarit Burden Scale score (for highest quartile: HR, 1.73; 95% CI, 1.49-2.00). Patients were assigned to quartiles of risk based on this model. In the development cohort, patients in the first, second, third, and fourth quartile had a 25%, 42%, 64%, and 91% rate of nursing home placement at 3 years, respectively. In the validation cohort, the respective rates were 21%, 50%, 64%, and 89%. The C statistic for 3-year nursing home placement was 0.66 in the development cohort and 0.63 in the validation cohort.Patient and caregiver characteristics are both important determinants of long-term care placement for patients with dementia. Interventions directed at delaying placement, such as reduction of caregiver burden or difficult patient behaviors, need to take into account the patient and caregiver as a unit.

Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later.A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted.A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33-3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58-2.35). Those with high SAD (>25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98-3.81) vs those with low SAD (<25 cm) and normal BMI (18.5-24.9 kg/m(2)), whereas those both obese (BMI >30 kg/m(2)) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI, 2.85-4.55).Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity; therefore, mechanisms linking central obesity to dementia need to be unveiled.

Little is known about prevalence rates of DSM-IV disorders across age strata of older adults, including common conditions such as individual and coexisting mood and anxiety disorders.To determine nationally representative estimates of 12-month prevalence rates of mood, anxiety, and comorbid mood-anxiety disorders across young-old, mid-old, old-old, and oldest-old community-dwelling adults.The National Comorbidity Survey Replication (NCS-R) is a population-based probability sample of 9282 participants 18 years and older, conducted between February 2001 and April 2003. The NCS-R survey used the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview.Continental United States.We studied the 2575 participants 55 years and older who were part of NCS-R (43%, 55-64 years; 32%, 65-74 years; 20%, 75-84 years; 5%, >or=85 years). This included only noninstitutionalized adults, as all NCS-R participants resided in households within the community.Twelve-month prevalence of mood disorders (major depressive disorder, dysthymia, bipolar disorder), anxiety disorders (panic disorder, agoraphobia, specific phobia, social phobia, generalized anxiety disorder, posttraumatic stress disorder), and coexisting mood-anxiety disorder were assessed using DSM-IV criteria. Prevalence rates were weighted to adjust for the complex design to infer generalizability to the US population.The likelihood of having a mood, anxiety, or combined mood-anxiety disorder generally showed a pattern of decline with age (P < .05). Twelve-month disorders showed higher rates in women compared with men, a statistically significant trend with age. In addition, anxiety disorders were as high if not higher than mood disorders across age groups (overall 12-month rates: mood, 5% and anxiety, 12%). No differences were found between race/ethnicity groups.Prevalence rates of DSM-IV mood and anxiety disorders in late life tend to decline with age, but remain very common, especially in women. These results highlight the need for intervention and prevention strategies.

Several lines of evidence suggest that inflammatory mechanisms contribute to AD.To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders.The authors studied 3,031 African-American and white men and women (mean age 74 years) enrolled in the Health, Aging, and Body Composition Study. Serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) and plasma levels of tumor necrosis factor-alpha (TNFalpha) were measured at baseline; cognition was assessed with the Modified Mini-Mental State Examination (3MS) at baseline and at follow-up. Cognitive decline was defined as a decline of >5 points.In age-adjusted analyses, participants in the highest tertile of IL-6 or CRP performed nearly 2 points lower (worse) on baseline and follow-up 3MS (p < 0.001 for all) and declined by almost 1 point over the >2 years (p = 0.01 for IL-6 and p = 0.04 for CRP) compared with those in the lowest tertile. After multivariate adjustment, 3MS scores among participants in the highest tertile of IL-6 and CRP were similar at baseline but remained significantly lower at follow-up (p < or = 0.05 for both). Those in the highest inflammatory marker tertile were also more likely to have cognitive decline compared with the lowest tertile for IL-6 (26 vs 20%; age-adjusted odds ratio [OR] = 1.34; 95% CI 1.06 to 1.69) and for CRP (24 vs 19%; OR = 1.41; 95% CI 1.10 to 1.79) but not for TNFalpha (23 vs 21%; OR = 1.12; 95% CI 0.88 to 1.43). There was no significant interaction between race and inflammatory marker or between nonsteroidal anti-inflammatory drug use and inflammatory marker on cognition.Serum markers of inflammation, especially IL-6 and CRP, are prospectively associated with cognitive decline in well-functioning elders. These findings support the hypothesis that inflammation contributes to cognitive decline in the elderly.

To determine whether cardiorespiratory fitness at baseline is associated with maintenance of cognitive function over 6 years or with level of cognitive function on tests performed 6 years later in a longitudinal study of healthy older people.Prospective cohort.Community-based study of noninstitutionalized adults aged 55 and older living in Sonoma, California.Three hundred forty-nine cohort members without evidence of cardiovascular disease, musculoskeletal disability, or cognitive impairment at baseline.Cardiorespiratory fitness measures were based on a standard treadmill exercise test protocol and included peak oxygen consumption (peak VO2), treadmill exercise duration, and oxygen uptake efficiency slope (OUES). Cognitive function was evaluated at baseline with a modified Mini-Mental State Examination (mMMSE) and after 6 years of follow-up with a detailed cognitive test battery that included the full MMSE, three tests of attention/executive function, two measures of verbal memory, and two tests of verbal fluency.Participants with worse cardiorespiratory fitness at baseline experienced greater decline on the mMMSE over 6 years (mean mMMSE decline (95% confidence interval) by baseline peak VO2 tertile: lowest = -0.5 (-0.8 to -0.3), middle = -0.2 (-0.5-0.0), highest = 0.0 (-0.3-0.2), P =.002 for trend over tertiles). Participants with worse baseline cardiorespiratory fitness also performed worse on all cognitive tests conducted 6 years later. Results were similar for analyses based on peak VO2, treadmill exercise duration, and OUES. After adjustment for demographic and health-related covariates, measures of cardiorespiratory fitness were associated most strongly with measures of global cognitive function and attention/executive function.Baseline measures of cardiorespiratory fitness are positively associated with preservation of cognitive function over a 6-year period and with levels of performance on cognitive tests conducted 6 years later in healthy older adults. High cardiorespiratory fitness may protect against cognitive dysfunction in older people.

Many patients with dementia who live at home would require nursing home care if they did not have the assistance of family caregivers. However, caregiving sometimes has adverse health consequences for caregivers, including very high rates of depression. The goal of this study was to determine the patient and caregiver characteristics associated with depression among caregivers of patients with dementia.Cross-sectional study.Five thousand six hundred and twenty-seven patients with moderate to advanced dementia and their primary caregivers upon enrollment in the Medicare Alzheimer's Disease Demonstration (MADDE) at 8 locations in the United States.Caregiver depression was defined as 6 or more symptoms on the 15-item Geriatric Depression Scale. Patient characteristics measured included ethnicity and other demographic characteristics, income, activities of daily living (ADL) function, Mini-Mental Status Exam (MMSE) score, and behavioral problems. Caregiver characteristics measured included demographic characteristics, relationship to the patient, hours spent caregiving, and ADL and Instrumental Activities of Daily Living (IADL) function. We used chi2 and t tests to measure the bivariate relationships between patient and caregiver predictors and caregiver depression. We used logistic regression to determine the independent predictors of caregiver depression.Thirty-two percent of caregivers reported 6 or more symptoms of depression and were classified as depressed. Independent patient predictors of caregiver depression included younger age (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.33 to 2.76 in patients less than 65 years compared to patients over 85 years), white (OR, 1.53; 95% CI, 1.18 to 1.99) and Hispanic ethnicity (OR, 2.50; 95% CI, 1.69 to 3.70) compared to black ethnicity, education (OR, 1.16; 95% CI, 1.01 to 1.33 for those with less than a high school education), ADL dependence (OR, 1.55; 95% CI, 1.26 to 1.90 for patients dependent in 2 or more ADL compared to patients dependent in no ADL), and behavioral disturbance, particularly angry or aggressive behavior (OR, 1.47; 95% CI, 1.27 to 1.69 for patients with angry or aggressive behavior). Independent caregiver predictors of depression included low income (OR, 1.45; 95% CI, 1.18 to 1.77 for less than 10,000 dollars/per year, compared to >20,000 dollars per year), the relationship to the patient (OR, 2.73; 95% CI, 1.31 to 5.72 for wife, compared to son of male patient), hours spent caregiving (OR, 1.89; 95% CI, 1.51 to 2.38 for 40 to 79 hours/week compared to less than 40 hours/week), and functional dependence (OR, 2.53; 95% CI, 2.13 to 3.01 for ADL dependent compared to IADL independent).Caregiver depression is a complex process, influenced by ethnicity as well as diverse patient and caregiver characteristics. Efforts to identify and treat caregiver depression will need to be multidisciplinary and focus on multiple risk factors simultaneously.

Patients with major depression have elevated levels of inflammatory cytokines. We examined the link between inflammatory markers and depressed mood in a community-based sample of older people. Data are from 3024 well-functioning older persons, 70-79 years of age, participating in the Health, Aging and Body Composition study. Depressed mood was defined as a Center for Epidemiologic Studies Depression scale score of 16 or higher. Plasma concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP) were measured. Compared with the 2879 nondepressed subjects, the 145 persons with depressed mood had higher median plasma levels of IL-6 (2.04 vs. 1.83 pg/mL, p =.02), TNF-alpha (3.43 vs. 3.16 pg/mL, p =.05), and CRP (1.96 vs. 1.66 mg/L, p =.03). After adjustment for health and demographic variables, depressed mood was especially prevalent among persons who had a high (above median) plasma level for at least two of the inflammatory markers. Compared with those without high levels, for persons with a high level for two or all three markers the risk of depressed mood was 2.45 (95% confidence interval [CI] = 1.34-4.47) and 2.40 (95% CI = 1.27-4.53), respectively. The association between depressed mood and serum level of IL-6 was significantly stronger in men than in women. In old age, depressed mood is associated with high levels of inflammatory markers, suggesting that depressed mood is causing and/or caused by systemic inflammation.

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury.

Cholinesterase inhibitors are the primary treatment for the cognitive symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated with neuropsychiatric and functional deficits, but results from randomized controlled trials of cholinesterase inhibitors are conflicting.To conduct a systematic review and meta-analysis to quantify the efficacy of cholinesterase inhibitors for neuropsychiatric and functional outcomes in patients with mild to moderate AD.We performed a literature search of trials using MEDLINE (January 1966-December 2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the Cochrane Controlled Trials Register. We retrieved English- and non-English-language articles for review and collected references from bibliographies of reviews, original research articles, and other articles of interest. We searched for both published and unpublished trials, contacting researchers and pharmaceutical companies.We included 29 parallel-group or crossover randomized, double-blind, placebo-controlled trials of outpatients who were diagnosed as having mild to moderate probable AD and were treated for at least 1 month with a cholinesterase inhibitor. Sixteen trials included neuropsychiatric and 18 included functional measures.Two investigators (N.H.T. and J.H.) independently extracted study methods, sources of bias, and outcomes. Neuropsychiatric outcomes were measured with the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed with the weighted mean difference method. Functional outcomes were measured with several activities of daily living (ADL) and instrumental activities of daily living (IADL) scales and analyzed with the standardized mean difference method.For neuropsychiatric outcomes, 10 trials included the ADAS-noncog and 6 included the NPI. Compared with placebo, patients randomized to cholinesterase inhibitors improved 1.72 points on the NPI (95% confidence interval [CI], 0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points). For functional outcomes, 14 trials used ADL and 13 trials used IADL scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various cholinesterase inhibitors.These results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.

Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions.To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI.DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects.FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN.Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.

To investigate the association between diabetes and impaired fasting glucose (IFG) and cognition and risk of developing both dementia and mild cognitive impairment (MCI) in older women.The authors analyzed data from a 4-year randomized trial of raloxifene among 7,027 osteoporotic postmenopausal women (mean age, 66.3 years) at 178 sites. Diabetes was defined by history, fasting blood glucose > or =7.0 mmol/L (> or =126 mg/dL), or use of hypoglycemic agents; IFG was defined as fasting glucose <7.0 mmol/L but >6.11 mmol/L (110 mg/dL); all others were considered to have normal glucose (NG). The main outcome was baseline and 4-year change on five standardized cognitive tests (z scores with lower scores indicating worse performance) and risk of developing clinically significant impairment (dementia, mild cognitive impairment, or very low cognitive score).A total of 267 (3.8%) women had diabetes and 297 (4.2%) had IFG. Women with IFG had worse baseline cognitive scores compared to women with NG but better scores than diabetics (age-adjusted composite z score based on five tests: NG 0.40, 95% CI 0.30 to 0.49; IFG 0.14, 95% CI -0.36 to 0.64; diabetics -0.78, 95% CI -1.23 to -0.33; p < 0.001). There was greater 4-year decline among diabetics (age and treatment-adjusted composite z score: NG -0.05, 95% CI -0.16 to 0.05; IFG 0.11, 95% CI -0.53 to 0.75; diabetics -1.00, 95% CI -1.50 to -0.50; p = 0.001). Further adjustment for education, race, and depression led to similar results. Risk of developing cognitive impairment among women with IFG or diabetes was increased by almost twofold (age and treatment-adjusted OR = 1.64; 95% CI 1.03 to 2.61 for IFG; OR = 1.79; 95% CI 1.14 to 2.81 for diabetics).Diabetic as well as pre-diabetic women have impaired cognitive performance and greater risk of developing cognitive impairment.

<h3>Context</h3> Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons. <h3>Objectives</h3> To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease. <h3>Design</h3> Prospective, population-based, longitudinal study. <h3>Setting</h3> Random sample of adults 65 years or older recruited from 4 US communities. <h3>Participants</h3> Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (≥8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria. <h3>Main Outcome Measure</h3> Diagnosis of MCI. <h3>Results</h3> Depressive symptoms at baseline were associated with increased risk of MCI (10.0%, 13.3%, and 19.7% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics. <h3>Conclusion</h3> Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.

While limited literacy is common and its prevalence increases with age, no prospective study has assessed whether limited literacy is associated with mortality in older adults.To assess the association of limited literacy with mortality.Five-year prospective study from 1999 to 2004 of community-dwelling elders from Memphis, TN, and Pittsburgh, PA, who were from the Health, Aging, and Body Composition study. Subjects' literacy was assessed with the Rapid Estimate of Adult Literacy in Medicine. Scores were categorized into limited (0 to 8th grade reading level) or adequate literacy (> or = 9th grade reading level).Two thousand five hundred and twelve black and white elders without baseline functional difficulties or dementia.Time to death.Participants' mean age was 75.6 years, 48% were male, 38% were black, and 24% had limited literacy; the median follow-up time was 4.2 years. Compared with those with adequate literacy, those with limited literacy had a higher risk of death (19.7% vs 10.6%) with a hazard ratio (HR) of 2.03 (95% confidence intervals [CI], 1.62 to 2.55). After adjusting for demographics and socioeconomic status, co-morbid conditions, self-rated health status, health-related behaviors, health care access measures, and psychosocial status, limited literacy remained independently associated with mortality (HR 1.75; 95% CI, 1.27 to 2.41).Limited literacy is independently associated with a nearly 2-fold increase in mortality in the elderly. Given the growth of the aging population and the prevalence of chronic diseases, the mechanisms by which limited literacy is associated with mortality in the elderly warrant further investigation.

Previous studies suggest a link between chronic kidney disease (CKD) and cognitive impairment. Whether the longitudinal course of cognitive impairment differs among people with or without CKD is unknown. Data collected in 3034 elderly individuals who participated in the Health, Aging, and Body Composition study were analyzed. Cognitive function was assessed with the Modified Mini-Mental State Exam (3MS) at baseline and then 2 and 4 yr after baseline. Cognitive impairment was defined as a 3MS score &lt;80 or a decline in 3MS &gt;5 points after 2 or 4 yr of follow-up among participants with baseline 3MS scores ≥80. Participants with CKD, defined as an estimated GFR (eGFR) &lt;60 ml/min per 1.73 m², were further divided into two eGFR strata. Unadjusted mean baseline 3MS scores and mean declines in 3MS scores over 4 yr were significantly more pronounced for participants with lower baseline eGFR. More advanced stages of CKD were associated with an increased risk for cognitive impairment: Odds ratio (OR) 1.32 (95% confidence interval [CI] 1.03 to 1.69) and OR 2.43 (95% CI, 1.38 to 4.29) for eGFR 45 to 59 ml/min per 1.73 m² and &lt;45 ml/min per 1.73 m², respectively, adjusted for case mix, baseline 3MS scores, and other potential confounders. CKD is associated with an increased risk for cognitive impairment in the elderly that cannot be fully explained by other well-established risk factors. Studies aimed at understanding the mechanism(s) responsible for cognitive impairment in CKD and efforts to interrupt this decline are warranted.

Previous cross-sectional studies have observed alterations in activity rhythms in dementia patients but the direction of causation is unclear. We determined whether circadian activity rhythms measured in community-dwelling older women are prospectively associated with incident dementia or mild cognitive impairment (MCI).Activity rhythm data were collected from 1,282 healthy community-dwelling women from the Study of Osteoporotic Fractures (SOF) cohort (mean age 83 years) with wrist actigraphy for a minimum of three 24-hour periods. Each participant completed a neuropsychological test battery and had clinical cognitive status (dementia, MCI, normal) adjudicated by an expert panel approximately 5 years later. All analyses were adjusted for demographics, body mass index (BMI), functional status, depression, medications, alcohol, caffeine, smoking, health status, and comorbidities.After 4.9 years of follow-up, 195 (15%) women had developed dementia and 302 (24%) had developed MCI. Older women with decreased activity rhythms had a higher likelihood of developing dementia or MCI when comparing those in the lowest quartiles of amplitude (odds ratio [OR] = 1.57; 95% CI, 1.09-2.25) or rhythm robustness (OR = 1.57; 95% CI, 1.10-2.26) to women in the highest quartiles. An increased risk of dementia or MCI (OR = 1.83; 95% CI, 1.29-2.61) was found for women whose timing of peak activity occurred later in the day (after 3:51 PM) when compared to those with average timing (1:34 PM-3:51 PM).Older, healthy women with decreased circadian activity rhythm amplitude and robustness, and delayed rhythms have increased odds of developing dementia and MCI. If confirmed, future studies should examine whether interventions (physical activity, bright light exposure) that influence activity rhythms will reduce the risk of cognitive deterioration in the elderly.

<h3>Background</h3> Few strategies are available for the prevention of cognitive impairment in elderly persons. Serum lipoprotein levels may be important predictors of cognitive function, and drugs that lower cholesterol may be effective for the prevention of cognitive impairment. <h3>Objective</h3> To determine whether serum lipoprotein levels, the 4-year change in serum lipoprotein levels, and the use of statin drugs are associated with cognition in older women without dementia. <h3>Design, Setting, and Participants</h3> An observational study of 1037 postmenopausal women with coronary heart disease enrolled in the Heart and Estrogen/progestin Replacement Study (participants at 10 of 20 centers). <h3>Main Outcome Measure</h3> The Modified Mini-Mental State Examination was administered at the end of the study after 4 years of follow-up. Women whose score was less than 84 points (&gt;1.5 SDs below the mean) were classified as having cognitive impairment. Lipoprotein levels (total, high-density lipoprotein, and low-density lipoprotein [LDL] cholesterol and triglycerides) were measured at baseline and at the end of the study; statin use was documented at each visit. <h3>Results</h3> Compared with women in the lower quartiles, women in the highest LDL cholesterol quartile at cognitive testing had worse mean ± SD Modified Mini-Mental State Examination scores (93.7 ± 6.0 vs 91.9 ± 7.6;<i>P</i>= .002) and an increased likelihood of cognitive impairment (adjusted odds ratio, 1.76; 95% confidence interval, 1.04-2.97). A reduction in the LDL cholesterol level during the 4 years tended to be associated with a lower odds of impairment (adjusted odds ratio, 0.61; 95% confidence interval, 0.36-1.03) compared with women whose levels increased. Higher total and LDL cholesterol levels, corrected for lipoprotein(a) levels, were also associated with a worse Modified Mini-Mental State Examination score and a higher likelihood of impairment, whereas high-density lipoprotein cholesterol and triglyceride levels were not associated with cognition. Compared with nonusers, statin users had higher mean ± SD Modified Mini-Mental State Examination scores (92.7 ± 7.1 vs 93.7 ± 6.1;<i>P</i>= .02) and a trend for a lower likelihood of cognitive impairment (odds ratio, 0.67; 95% confidence interval, 0.42-1.05), findings that seemed to be independent of lipid levels. <h3>Conclusions</h3> High LDL and total cholesterol levels are associated with cognitive impairment, and lowering these lipoprotein levels may be a strategy for preventing impairment. The association between statin use and better cognitive function in women without dementia requires further study.

Traumatic brain injuries (TBIs) are clinically grouped by severity: mild, moderate and severe. Mild TBI (the least severe form) is synonymous with concussion and is typically caused by blunt non-penetrating head trauma. The trauma causes stretching and tearing of axons, which leads to diffuse axonal injury - the best-studied pathogenetic mechanism of this disorder. However, mild TBI is defined on clinical grounds and no well-validated imaging or fluid biomarkers to determine the presence of neuronal damage in patients with mild TBI is available. Most patients with mild TBI will recover quickly, but others report persistent symptoms, called post-concussive syndrome, the underlying pathophysiology of which is largely unknown. Repeated concussive and subconcussive head injuries have been linked to the neurodegenerative condition chronic traumatic encephalopathy (CTE), which has been reported post-mortem in contact sports athletes and soldiers exposed to blasts. Insights from severe injuries and CTE plausibly shed light on the underlying cellular and molecular processes involved in mild TBI. MRI techniques and blood tests for axonal proteins to identify and grade axonal injury, in addition to PET for tau pathology, show promise as tools to explore CTE pathophysiology in longitudinal clinical studies, and might be developed into diagnostic tools for CTE. Given that CTE is attributed to repeated head trauma, prevention might be possible through rule changes by sports organizations and legislators.

Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > 25 and < 30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD. Keywords: obesity, overweight, body mass index, Alzheimer disease, vascular dementia, dementia, adiposity, midlife

Dysfunction in 24-h circadian rhythms is a common occurrence in ageing adults; however, circadian rhythm disruptions are more severe in people with age-related neurodegenerative diseases, including Alzheimer's disease and related dementias, and Parkinson's disease. Manifestations of circadian rhythm disruptions differ according to the type and severity of neurodegenerative disease and, for some patients, occur before the onset of typical clinical symptoms of neurodegeneration. Evidence from preliminary studies suggest that circadian rhythm disruptions, in addition to being a symptom of neurodegeneration, might also be a potential risk factor for developing Alzheimer's disease and related dementias, and Parkinson's disease, although large, longitudinal studies are needed to confirm this relationship. The mechanistic link between circadian rhythms and neurodegeneration is still not fully understood, although proposed underlying pathways include alterations of protein homoeostasis and immune and inflammatory function. While preliminary clinical studies are promising, more studies of circadian rhythm disruptions and its mechanisms are required. Furthermore, clinical trials are needed to determine whether circadian interventions could prevent or delay the onset of neurodegenerative diseases.

To determine the association between vision and hearing impairment and subsequent cognitive and functional decline in community-residing older women.Prospective cohort study.Four metropolitan areas of the United States.A total of 6,112 women aged 69 and older participating in the Study of Osteoporotic Fractures (SOF) between 1992 and 1994.Five thousand three hundred forty-five participants had hearing measured, 1,668 had visual acuity measured, and 1,636 had both measured. Visual impairment was defined as corrected vision worse than 20/40. Hearing impairment was defined as the inability to hear a tone of 40 dB or greater at 2,000 hertz. Participants completed the modified Mini-Mental State Examination and/or a functional status assessment at baseline and follow-up. Cognitive and functional decline were defined as the amount of decline from baseline to follow-up that exceeded the observed average change in scores by at least 1 standard deviation.About one-sixth (15.7%) of the sample had cognitive decline; 10.1% had functional decline. In multivariate models adjusted for sociodemographic characteristics and chronic conditions, vision impairment at baseline was associated with cognitive (odds ratio (OR)=1.78, 95% confidence interval (CI)=1.21-2.61) and functional (OR=1.79, 95% CI=1.15-2.79) decline. Hearing impairment was not associated with cognitive or functional decline. Combined impairment was associated with the greatest odds for cognitive (OR=2.19, 95% CI=1.26-3.81) and functional (OR=1.87, 95% CI=1.01-3.47) decline.Sensory impairment is associated with cognitive and functional decline in older women. Studies are needed to determine whether treatment of vision and hearing impairment can decrease the risk for cognitive and functional decline.

Objective Dementia has a multifactorial etiology, but the importance of individual health and lifestyle related risk factors is often uncertain or based on few studies. The goal of this paper is to identify the major modifiable risk factors for dementia as a first step in developing an effective preventive strategy and promoting healthy late life cognitive functioning. Methods A mixed-method approach combined findings from a systematic literature review and a Delphi consensus study. The literature search was conducted in PubMed and updated an earlier review by the United States National Institutes of Health from 2010. We reviewed the available evidence from observational epidemiological studies. The online Delphi study asked eight international experts to rank and weigh each risk factor for its importance for dementia prevention. Results Out of 3127 abstracts, 291 were included in the review. There was good agreement between modifiable risk factors identified in the literature review and risk factors named spontaneously by experts. After triangulation of both methods and re-weighting by experts, strongest support was found for depression, (midlife) hypertension, physical inactivity, diabetes, (midlife) obesity, hyperlipidemia, and smoking, while more research is needed for coronary heart disease, renal dysfunction, diet, and cognitive activity. Conclusions Findings provide good support for several somatic and lifestyle factors and will be used to inform the design of a new multicenter trial into dementia prevention. Copyright © 2014 John Wiley & Sons, Ltd.

Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia.To clarify the timing and nature of the association between depression and dementia.We examined depressive symptoms assessed in midlife (1964-1973) and late life (1994-2000) and the risks of dementia, Alzheimer disease (AD), and vascular dementia (VaD) (2003-2009) in a retrospective cohort study. Depressive symptoms were categorized as none, midlife only, late life only, or both. Cox proportional hazards models (age as timescale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD, or VaD.Kaiser Permanente Medical Care Program of Northern California.Thirteen thousand five hundred thirty-five long-term Kaiser Permanente members.Any medical record diagnosis of dementia or neurology clinic diagnosis of AD or VaD.Subjects had a mean (SD) age of 81.1 (4.5) years in 2003, 57.9% were women, and 24.2% were nonwhite. Depressive symptoms were present in 14.1% of subjects in midlife only, 9.2% in late life only, and 4.2% in both. During 6 years of follow-up, 22.5% were diagnosed with dementia (5.5% with AD and 2.3% with VaD). The adjusted hazard of dementia was increased by approximately 20% for midlife depressive symptoms only (hazard ratio, 1.19 [95% CI, 1.07-1.32]), 70% for late-life symptoms only (1.72 [1.54-1.92]), and 80% for both (1.77 [1.52-2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a 2-fold increase in AD risk (hazard ratio, 2.06 [95% CI, 1.67-2.55]), whereas subjects with midlife and late-life symptoms had more than a 3-fold increase in VaD risk (3.51 [2.44-5.05]).Depressive symptoms in midlife or in late life are associated with an increased risk of developing dementia. Depression that begins in late life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.

The association between objectively measured sleep and cognition among community-dwelling elderly persons remains understudied. This observational, cross-sectional analysis examined this association.Results are from 2932 women (mean age 83.5 years) in the Study of Osteoporotic Fractures between 2002 and 2004. Cognitive function was measured by Mini-Mental State Examination (MMSE) and Trail Making B Test (Trails B). Cognitive impairment was defined as MMSE < 26 or Trails B > 278 seconds. Sleep parameters measured objectively using actigraphy included total sleep time, sleep efficiency, sleep latency, wake after sleep onset (WASO), and total nap time.There were 305 women (10.6%) with MMSE < 26 and 257 women (9.3%) with Trails B > 278 seconds. Compared with women with sleep efficiency > or = 70%, those with <70% had a higher risk of cognitive impairment (MMSE < 26 multivariate odds ratio [MOR] = 1.61; 95% confidence interval [CI], 1.20-2.16; Trails B > 278 MOR = 1.96; 95% CI, 1.43-2.67). Higher sleep latency was associated with higher risk of cognitive impairment (per half hour: MMSE < 26 MOR = 1.23; 95% CI, 1.13-1.33; Trails B > 278 MOR = 1.13; 95% CI, 1.04-1.24), as was higher WASO (per half hour: MMSE < 26 MOR = 1.15; 95% CI, 1.06-1.23; Trails B > 278 MOR = 1.24; 95% CI, 1.15-1.34). Women who napped > or = 2 hours per day had a higher risk (MMSE < 26 MOR = 1.42; 95% CI, 1.05-1.93; Trails B > 278 MOR = 1.74; 95% CI, 1.26-2.40). There was no significant relationship for total sleep time.Objectively measured disturbed sleep was consistently related to poorer cognition, whereas total sleep time was not. This finding may suggest that it is disturbance of sleep rather than quantity that affects cognition.

The association between depressive disorders and subsequent cognitive decline is controversial. We tested the hypothesis that elderly women (aged 65 years and older) without dementia but with depressive symptoms have worse cognitive function and greater cognitive decline than women with few or no symptoms.As part of an ongoing prospective study, we evaluated 5781 elderly, mostly white, community-dwelling women. Women completed the Geriatric Depression Scale short form. Three cognitive tests--Trails B, Digit Symbol, and a modified Mini-Mental State Examination--were administered at baseline and approximately 4 years later. Baseline, follow-up, and change scores for the cognitive tests were analyzed by analysis of covariance and Kruskal-Wallis analysis; the odds of cognitive deterioration (> or =3-point decline on the modified Mini-Mental State Examination) were determined by logistic regression.At baseline, 211 (3.6%) of the women had 6 or more depressive symptoms. Only 16 (7.6%) of these women were receiving antidepressant medication. Increasing symptoms of depression were associated with worse performance at baseline and follow-up on all 3 tests of cognitive function (P<.001 for all comparisons). For example, the baseline Digit Symbol score (mean +/- SD) was 45.5 +/- 10.7 among women with 0 to 2 symptoms of depression, 40.3 +/- 10.7 for women with 3 to 5 symptoms, and 39.0 +/- 11.3 for women with 6 or more symptoms. After adjusting for the baseline score, cognitive change scores were also inversely associated with the number of depressive symptoms (P<.001 for all comparisons). Odds ratios for cognitive deterioration using 0 to 2 symptoms as the reference were 1.6 (95% confidence interval, 1.3-2.1) for 3 to 5 symptoms and 2.3 (95% confidence interval, 1.6-3.3) for 6 or more symptoms. Results were similar after being adjusted for education, age, health status, exercise, alcohol use, functional status, and clinic site.Depressive symptoms in older women are associated with both poor cognitive function and subsequent cognitive decline. Mechanisms underlying the association between these 2 common conditions need further exploration.

An increased cortisol response to challenge is associated with a variety of age-related disorders such as Alzheimer's disease, depression, diabetes, metabolic syndrome, and hypertension. Among the healthy elderly, an increased cortisol response to challenge may be a risk factor for developing these age-related disorders. We searched Pubmed, Embase, PsychInfo, Biosis, and Digital Dissertations (January 1966-June 2003) and included 45 parallel-group (young vs. old subjects) studies that used either a pharmacological or psychological challenge in healthy volunteers and measured cortisol response to challenge. We calculated effect sizes (Cohen's d) for the standardized mean differences between groups. Compared to younger controls (n=670, mean age 28 years +/-5), older subjects (n=625, 69+/-6) showed a larger cortisol response to challenge defined as stronger response to stimulation or less inhibition after a suppression test (d=0.42, 95% confidence interval (CI), 0.26-0.57). The effect of age on cortisol release was significantly stronger in women (d=0.65, 95% CI 0.34-0.97) than men (d=0.24, 95% CI 0.02-0.47). Our results demonstrate that aging increases the cortisol response to challenge. This effect of age on cortisol response is almost three-fold stronger in women than men. Prospective studies should explore whether the higher cortisol response in the elderly is a risk factor for developing neuropsychiatric and medical disorders.

Epidemiologic evidence regarding the importance of traumatic brain injury (TBI) as a risk factor for dementia is conflicting. Few previous studies have used patients with non-TBI trauma (NTT) as controls to investigate the influence of age and TBI severity.To quantify the risk of dementia among adults with recent TBI compared with adults with NTT.This retrospective cohort study was performed from January 1, 2005, through December 31, 2011 (follow-up, 5-7 years). All patients 55 years or older diagnosed as having TBI or NTT in 2005 and 2006 and who did not have baseline dementia or die during hospitalization (n = 164,661) were identified in a California statewide administrative health database of emergency department (ED) and inpatient visits.Mild vs moderate to severe TBI diagnosed by Centers for Disease Control and Prevention criteria using International Classification of Diseases, Ninth Revision (ICD-9)codes, and NTT, defined as fractures excluding fractures of the head and neck, diagnosed using ICD-9 codes.Incident ED or inpatient diagnosis of dementia (using ICD-9 codes) 1 year or more after initial TBI or NTT. The association between TBI and risk of dementia was estimated using Cox proportional hazards models before and after adjusting for common dementia predictors and potential confounders. We also stratified by TBI severity and age category (55-64, 65-74, 75-84, and ≥85 years).A total of 51,799 patients with trauma (31.5%) had TBI. Of these, 4361 (8.4%) developed dementia compared with 6610 patients with NTT (5.9%) (P < .001). We found that TBI was associated with increased dementia risk (hazard ratio [HR], 1.46; 95% CI, 1.41-1.52; P < .001). Adjustment for covariates had little effect except adjustment for age category (fully adjusted model HR, 1.26; 95% CI, 1.21-1.32; P < .001). In stratified adjusted analyses, moderate to severe TBI was associated with increased risk of dementia across all ages (age 55-64: HR, 1.72; 95% CI, 1.40-2.10; P < .001; vs age 65-74: HR, 1.46; 95% CI, 1.30-1.64; P < .001), whereas mild TBI may be a more important risk factor with increasing age (age 55-64: HR, 1.11; 95% CI, 0.80-1.53; P = .55; vs age 65-74: HR, 1.25; 95% CI, 1.04-1.51; P = .02; age interaction P < .001).Among patients evaluated in the ED or inpatient settings, those with moderate to severe TBI at 55 years or older or mild TBI at 65 years or older had an increased risk of developing dementia. Younger adults may be more resilient to the effects of recent mild TBI than older adults.

Although several risk factors for cognitive decline have been identified, much less is known about factors that predict maintenance of cognitive function in advanced age.We studied 2,509 well-functioning black and white elders enrolled in a prospective study. Cognitive function was measured using the Modified Mini-Mental State Examination at baseline and years 3, 5, and 8. Random effects models were used to classify participants as cognitive maintainers (cognitive change slope > or = 0), minor decliners (slope < 0 and > 1 SD below mean), or major decliners (slope < or = 1 SD below mean). Logistic regression was used to identify domain-specific factors associated with being a maintainer vs a minor decliner.Over 8 years, 30% of the participants maintained cognitive function, 53% showed minor decline, and 16% had major cognitive decline. In the multivariate model, baseline variables significantly associated with being a maintainer vs a minor decliner were age (odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.55-0.77 per 5 years), white race (OR = 1.72, 95% CI 1.30-2.28), high school education level or greater (OR = 2.75, 95% CI 1.78-4.26), ninth grade literacy level or greater (OR = 4.85, 95% CI 3.00-7.87), weekly moderate/vigorous exercise (OR = 1.31, 95% CI 1.06-1.62), and not smoking (OR = 1.84, 95% CI 1.14-2.97). Variables associated with major cognitive decline compared to minor cognitive decline are reported.Elders who maintain cognitive function have a unique profile that differentiates them from those with minor decline. Importantly, some of these factors are modifiable and thus may be implemented in prevention programs to promote successful cognitive aging. Further, factors associated with maintenance may differ from factors associated with major cognitive decline, which may impact prevention vs treatment strategies.

Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia.To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM.Prospective population-based study.We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher.Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records.During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0-4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%, P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5-6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results.Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia.

In elderly persons, antipsychotic drugs are clinically prescribed off-label for a number of disorders outside of their Food and Drug Administration (FDA)-approved indications (schizophrenia and bipolar disorder). The largest number of antipsychotic prescriptions in older adults is for behavioral disturbances associated with dementia. In April 2005, the FDA, based on a meta-analysis of 17 double-blind randomized placebo-controlled trials among elderly people with dementia, determined that atypical antipsychotics were associated with a significantly (1.6–1.7 times) greater mortality risk compared with placebo, and asked that drug manufacturers add a ‘black box’ warning to prescribing information for these drugs. Most deaths were due to either cardiac or infectious causes, the two most common immediate causes of death in dementia in general. Clinicians, patients, and caregivers are left with unclear choices of treatment for dementia patients with psychosis and/or severe agitation. Not only are psychosis and agitation common in persons with dementia but they also frequently cause considerable caregiver distress and hasten institutionalization of patients. At the same time, there is a paucity of evidence-based treatment alternatives to antipsychotics for this population. Thus, there is insufficient evidence to suggest that psychotropics other than antipsychotics represent an overall effective and safe, let alone better, treatment choice for psychosis or agitation in dementia; currently no such treatment has been approved by the FDA for these symptoms. Similarly, the data on the efficacy of specific psychosocial treatments in patients with dementia are limited and inconclusive. The goal of this White Paper is to review relevant issues and make clinical and research recommendations regarding the treatment of elderly dementia patients with psychosis and/or agitation. The role of shared decision making and caution in using pharmacotherapy for these patients is stressed.

Age-related peripheral hearing impairment (HI) is prevalent, treatable, and may be a risk factor for dementia in older adults. In prospective analysis, we quantified the association of HI with incident dementia and with domain-specific cognitive decline in memory, perceptual speed, and processing speed.Data were from the Health, Aging and Body Composition (Health ABC) study, a biracial cohort of well-functioning adults aged 70-79 years. Dementia was defined using a prespecified algorithm incorporating medication use, hospital records, and neurocognitive test scores. A pure-tone average in decibels hearing level (dBHL) was calculated in the better hearing ear using thresholds from 0.5 to 4kHz, and HI was defined as normal hearing (≤25 dBHL), mild (26-40 dBHL), and moderate/severe (>40 dBHL). Associations between HI and incident dementia and between HI and cognitive change were modeled using Cox proportional hazards models and linear mixed models, respectively.Three-hundred eighty seven (20%) participants had moderate/severe HI, and 716 (38%) had mild HI. After adjustment for demographic and cardiovascular factors, moderate/severe audiometric HI (vs. normal hearing) was associated with increased risk of incident dementia over 9 years (hazard ratio: 1.55, 95% confidence interval [CI]: 1.10, 2.19). Other than poorer baseline memory performance (difference of -0.24 SDs, 95% CI: -0.44, -0.04), no associations were observed between HI and rates of domain-specific cognitive change during 7 years of follow-up.HI is associated with increased risk of developing dementia in older adults. Randomized trials are needed to determine whether treatment of hearing loss could postpone dementia onset in older adults.

The incidence and prevalence of dementia are expected to increase several-fold in the coming decades. Given that the current pharmaceutical treatment of dementia can only modestly improve symptoms, risk factor modification remains the cornerstone for dementia prevention. Some of the most promising strategies for the prevention of dementia include vascular risk factor control, cognitive activity, physical activity, social engagement, diet, and recognition of depression. In observational studies, vascular risk factors—including diabetes, hypertension, dyslipidemia, and obesity—are fairly consistently associated with increased risk of dementia. In addition, people with depression are at high risk for cognitive impairment. Population studies have reported that intake of antioxidants or polyunsaturated fatty acids may be associated with a reduced incidence of dementia, and it has been reported that people who are cognitively, socially, and physically active have a reduced risk of cognitive impairment. However, results from randomized trials of risk factor modification have been mixed. Most promising, interventions of cognitive and physical activity improve cognitive performance and slow cognitive decline. Future studies should continue to examine the implication of risk factor modification in controlled trials, with particular focus on whether several simultaneous interventions may have additive or multiplicative effects.

Importance: The prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years, and strategies for maintaining cognitive function with age are critically needed.Physical or mental activity alone result in relatively small, domain-specific improvements in cognitive function in older adults; combined interventions may have more global effects.Objective: To examine the combined effects of physical plus mental activity on cognitive function in older adults.Design: Randomized controlled trial with a factorial design.

<h3>Background</h3> Serotonin transporters have recently been described in bone, raising the possibility that medications that block serotonin reuptake could affect bone metabolism. <h3>Methods</h3> We assessed current use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) and obtained serial bone mineral density (BMD) measurements in a cohort of 2722 older women (mean age, 78.5 years) participating in the Study of Osteoporotic Fractures, a prospective cohort study of community-dwelling women. Hip BMD was measured at the sixth examination and an average of 4.9 years later at the eighth examination. We categorized women as nonusers (used no SSRIs or TCAs at either examination; n = 2406), SSRI users (used SSRIs but no TCAs at either examination; n = 198), or TCA users (used TCAs but no SSRIs at either examination; n = 118). Depressive symptoms were identified using a cutoff score of at least 6 on the Geriatric Depression Scale. <h3>Results</h3> After adjustment for potential confounders, including the Geriatric Depression Scale score, mean total hip BMD decreased 0.47% per year in nonusers compared with 0.82% in SSRI users (<i>P</i>&lt;.001) and 0.47% in TCA users (<i>P</i> = .99). Higher rates of bone loss were also observed at the 2 hip subregions for SSRI users. Results were not substantially altered when women who scored at least 6 on the Geriatric Depression Scale were excluded from the analysis. <h3>Conclusion</h3> Use of SSRIs but not TCAs is associated with an increased rate of bone loss at the hip in this cohort of older women.

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis.

Interview with Dr. Eric Larson on new insights into the dementia epidemic. (14:37)Download Demographics will drive an increase in the number of dementia cases, but reports reveal declining age-specific prevalence or incidence among people born later in the first half of the 20th century, informing our understanding of potentially modifiable risk factors.

Growing evidence suggests an association between sleep-disordered breathing (SDB) and cognitive decline in elderly persons. However, results from population-based studies have been conflicting, possibly owing to different methods to assess SDB or cognitive domains, making it difficult to draw conclusions on this association.To provide a quantitative synthesis of population-based studies on the relationship between SDB and risk of cognitive impairment.PubMed, EMBASE, and PsychINFO were systematically searched to identify peer-reviewed articles published in English before January 2017 that reported on the association between SDB and cognitive function.We included cross-sectional and prospective studies with at least 200 participants with a mean participant age of 40 years or older.Data were extracted independently by 2 investigators. We extracted and pooled adjusted risk ratios from prospective studies and standard mean differences from cross-sectional studies, using random-effect models. This meta-analysis followed the PRISMA guidelines and also adhered to the MOOSE guidelines.Cognitive outcomes were based on standard tests or diagnosis of cognitive impairment. Sleep-disordered breathing was ascertained by apnea-hypopnea index or clinical diagnosis.We included 14 studies, 6 of which were prospective, covering a total of 4 288 419 men and women. Pooled analysis of the 6 prospective studies indicated that those with SDB were 26% (risk ratio, 1.26; 95% CI, 1.05-1.50) more likely to develop cognitive impairment, with no evidence of publication bias but significant heterogeneity between studies. After removing 1 study that introduced significant heterogeneity, the pooled risk ratio was 1.35 (95% CI, 1.11-1.65). Pooled analysis of the 7 cross-sectional studies suggested that those with SDB had slightly worse executive function (standard mean difference, -0.05; 95% CI, -0.09 to 0.00), with no evidence of heterogeneity or publication bias. Sleep-disordered breathing was not associated with global cognition or memory.Sleep-disordered breathing is associated with an increased risk of cognitive impairment and a small worsening in executive function. Further studies are required to determine the mechanisms linking these common conditions and whether treatment of SDB might reduce risk of cognitive impairment.

Background Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction. Methodology/Principal Findings To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70–79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37–0.72), only IL-6 high (OR = 0.57, CI = 0.39–0.83) or only TNF-α high (OR = 0.67, CI = 0.46–0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL. Conclusions/Significance Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.

OBJECTIVE: To determine how physical activity at various ages over the life course is associated with cognitive impairment in late life. DESIGN: Cross‐sectional study. SETTING: Four U.S. sites. PARTICIPANTS: Nine thousand three hundred forty‐four women aged 65 and older (mean 71.6) who self‐reported teenage, age 30, age 50, and late‐life physical activity. MEASUREMENTS: Logistic regression was used to determine the association between physical activity status at each age and likelihood of cognitive impairment (modified Mini‐Mental State Examination (mMMSE) score &gt;1.5 standard deviations below the mean, mMMSE score≤22). Models were adjusted for age, education, marital status, diabetes mellitus, hypertension, depressive symptoms, smoking, and body mass index. RESULTS: Women who reported being physically active had a lower prevalence of cognitive impairment in late life than women who were inactive at each time (teenage: 8.5% vs 16.7%, adjusted odds ratio (AOR)=0.65, 95% confidence interval (CI)=0.53–0.80; age 30: 8.9% vs 12.0%, AOR=0.80, 95% CI=0.67–0.96); age 50: 8.5% vs 13.1%, AOR=0.71, 95% CI=0.59–0.85; old age: 8.2% vs 15.9%, AOR=0.74, 95% CI=0.61–0.91). When the four times were analyzed together, teenage physical activity was most strongly associated with lower odds of late‐life cognitive impairment (OR=0.73, 95% CI=0.58–0.92). However, women who were physically inactive as teenagers and became active in later life had lower risk than those who remained inactive. CONCLUSIONS: Women who reported being physically active at any point over the life course, especially as teenagers, had a lower likelihood of cognitive impairment in late life. Interventions should promote physical activity early in life and throughout the life course.

Traumatic brain injury (TBI) is common in both veteran and civilian populations. Prior studies have linked moderate and severe TBI with increased dementia risk, but the association between dementia and mild TBI, particularly mild TBI without loss of consciousness (LOC), remains unclear.To examine the association between TBI severity, LOC, and dementia diagnosis in veterans.This cohort study of all patients diagnosed with a TBI in the Veterans Health Administration health care system from October 1, 2001, to September 30, 2014, and a propensity-matched comparison group. Patients with dementia at baseline were excluded. Researchers identified TBIs through the Comprehensive TBI Evaluation database, which is restricted to Iraq and Afghanistan veterans, and the National Patient Care Database, which includes veterans of all eras. The severity of each TBI was based on the most severe injury recorded and classified as mild without LOC, mild with LOC, mild with LOC status unknown, or moderate or severe using Department of Defense or Defense and Veterans Brain Injury Center criteria. International Classification of Diseases, Ninth Revision codes were used to identify dementia diagnoses during follow-up and medical and psychiatric comorbidities in the 2 years prior to the index date.Dementia diagnosis in veterans who had experienced TBI with or without LOC and control participants without TBI exposure.The study included 178 779 patients diagnosed with a TBI in the Veterans Health Administration health care system and 178 779 patients in a propensity-matched comparison group. Veterans had a mean (SD) age of nearly 49.5 (18.2) years at baseline; 33 250 (9.3%) were women, and 259 136 (72.5%) were non-Hispanic white individuals. Differences between veterans with and without TBI were small. A total of 4698 veterans (2.6%) without TBI developed dementia compared with 10 835 (6.1%) of those with TBI. After adjustment for demographics and medical and psychiatric comobidities, adjusted hazard ratios for dementia were 2.36 (95% CI, 2.10-2.66) for mild TBI without LOC, 2.51 (95% CI, 2.29-2.76) for mild TBI with LOC, 3.19 (95% CI, 3.05-3.33) for mild TBI with LOC status unknown, and 3.77 (95% CI, 3.63-3.91) for moderate to severe TBI.In this cohort study of more than 350 000 veterans, even mild TBI without LOC was associated with more than a 2-fold increase in the risk of dementia diagnosis. Studies of strategies to determine mechanisms, prevention, and treatment of TBI-related dementia in veterans are urgently needed.

To determine if prevalent and incident diabetes mellitus (DM) increase risk of cognitive decline and if, among elderly adults with DM, poor glucose control is related to worse cognitive performance. DESIGN Prospective cohort study.Health, Aging, and Body Composition Study at 2 community clinics.A total of 3069 elderly adults (mean age, 74.2 years; 42% black; 52% female).Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. Diabetes mellitus status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c level was measured at years 1 (baseline), 4, 6, and 10 from fasting whole blood.At baseline, 717 participants (23.4%) had prevalent DM and 2352 (76.6%) were without DM, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs 90.9; DSST: 32.5 vs 36.3, respectively; t = 6.09; P = .001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: -6.0- vs -4.5-point decline; t = 2.66; P = .008; DSST: -7.9- vs -5.7-point decline; t = 3.69; P = .001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other 2 groups but were not statistically different from the group without DM. Multivariate adjustment for demographics and medical comorbidities produced similar results. Among participants with prevalent DM, glycosylated hemoglobin A1c level was associated with lower average mean cognitive scores (3MS: F = 8.2; P for overall = .003; DSST: F = 3.4; P for overall = .04), even after multivariate adjustment.Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests that severity of DM may contribute to accelerated cognitive aging.

Cognitive impairment, including dementia, is a common but poorly recognized problem among patients with end-stage renal disease (ESRD), affecting 16–38% of patients. Dementia is associated with high risks of death, dialysis withdrawal, hospitalization, and disability among patients with ESRD; thus, recognizing and effectively managing cognitive impairment may improve clinical care. Dementia screening strategies should take into account patient factors, the time available, the timing of assessments relative to dialysis treatments, and the implications of a positive screen for subsequent management (for example, transplantation). Additional diagnostic testing in patients with cognitive impairment, including neuroimaging, is largely based on the clinical evaluation. There is limited data on the efficacy and safety of pharmacotherapy for dementia in the setting of ESRD; therefore, decisions about the use of these medications should be individualized. Management of behavioral symptoms, evaluation of patient safety, and advance care planning are important components of dementia management. Prevention strategies targeting vascular risk factor modification, and physical and cognitive activity have shown promise in the general population and may be reasonably extrapolated to the ESRD population. Modification of ESRD-associated factors such as anemia and dialysis dose or frequency require further study before they can be recommended for treatment or prevention of cognitive impairment.

To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors.Cross-sectional.Chronic Renal Insufficiency Cohort Study.Eight hundred twenty-five adults aged 55 and older with CKD.Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m(2)) was estimated using the four-variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score < or =1 standard deviations from the mean).Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1-3.9), naming (AOR=1.9, 95% CI=1.0-3.3), attention (AOR=2.4, 95% CI=1.3-4.5), executive function (AOR=2.5, 95% CI=1.9-4.4), and delayed memory (AOR=1.5, 95% CI=0.9-2.6) but not on category fluency (AOR=1.1, 95% CI=0.6-2.0) than those with mild to moderate CKD (eGFR 45-59).In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.

Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer's disease (AD).The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I (2) statistic.Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I (2) = 0%-40%, p ≥ .16).An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.

Studies have linked midlife and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs, which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to middle adulthood and cognitive function at midlife.In a prospective study of 3381 adults (age, 18-30 years at baseline) with 25 years of follow-up, we assessed cognitive function at year 25 (2010-2011) with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol. Higher cumulative systolic and diastolic blood pressures and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These associations were significant primarily for exposures above recommended guidelines; cognitive test z scores were between 0.06 and 0.30 points less, on average, for each 1-SD increase in risk factor area under the curve after adjustment for age, race, sex, and education (P<0.05 for all). Fewer significant associations were observed for cholesterol.Cumulative exposure to CVRFs from early to middle adulthood, especially above recommended guidelines, was associated with worse cognition in midlife. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life require further investigation.

Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment.We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient.We identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), whereas nonsignificantly lower levels of zinc (P = .050) and vitamin D (P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD.The lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management.

Objective Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson disease (PD), but results are conflicting. Many studies do not account for confounding or reverse causation. We sought to address these concerns by quantifying risk of PD after TBI compared to non‐TBI trauma (NTT; defined as fractures). Methods Using inpatient/emergency department (ED) International Classification of Disease, Ninth Revision code data for California hospitals from 2005–2006, we identified patients aged ≥55 years with TBI (n = 52,393) or NTT (n = 113,406) and without baseline PD or dementia who survived hospitalization. Using Kaplan–Meier estimates and Cox proportional hazards models (adjusted for age, sex, race/ethnicity, income, comorbidities, health care use, and trauma severity), we estimated risk of PD after TBI during follow‐up ending in 2011. We also assessed interaction with mechanism of injury (fall vs nonfall) and effect of TBI severity (mild vs moderate/severe) and TBI frequency (1 TBI vs &gt;1 TBI). Results TBI patients were significantly more likely to be diagnosed with PD compared to NTT patients (1.7% vs 1.1%, p &lt; 0.001, adjusted hazard ratio [HR] = 1.44, 95% confidence interval [CI] = 1.31–1.58). Risk of PD was similar for TBI sustained via falls versus nonfalls (interaction p = 0.6). Assessment by TBI severity (mild TBI: HR = 1.24, 95% CI = 1.04–1.48; moderate/severe TBI: HR = 1.50, 95% CI = 1.35–1.66) and TBI frequency (1 TBI: HR = 1.45, 95% CI = 1.30–1.60; &gt;1 TBI: HR = 1.87, 95% CI = 1.58–2.21) revealed a dose response. Interpretation Among patients aged ≥55 years presenting to inpatient/ED settings with trauma, TBI is associated with a 44% increased risk of developing PD over 5 to 7 years that is unlikely to be due to confounding or reverse causation. Ann Neurol 2015;77:987–995

Background.In community-dwelling older adults, global cognitive function predicts longitudinal gait speed decline. Few prospective studies have evaluated whether specific executive cognitive deficits in aging may account for gait slowing over time.

Purpose of review Trouble falling or staying asleep, poor sleep quality, and short or long sleep duration are gaining attention as potential risk factors for cognitive decline and dementia, including Alzheimer's disease. Sleep-disordered breathing has also been linked to these outcomes. Here, we review recent observational and experimental studies investigating the effect of poor sleep on cognitive outcomes and Alzheimer's disease, and discuss possible mechanisms. Recent findings Observational studies with self-report and objective sleep measures (e.g. wrist actigraphy, polysomnography) support links between disturbed sleep and cognitive decline. Several recently published studies demonstrate associations between sleep variables and measures of Alzheimer's disease pathology, including cerebrospinal fluid measures of Aβ and PET measures of Aβ deposition. In addition, experimental studies suggest that sleep loss alters cerebrospinal fluid Aβ dynamics, decrements in slow-wave sleep may decrease the clearance of Aβ from the brain, and hypoxemia characteristic of sleep-disordered breathing increases Aβ production. Summary Findings indicate that poor sleep is a risk factor for cognitive decline and Alzheimer's disease. Although mechanisms underlying these associations are not yet clear, healthy sleep appears to play an important role in maintaining brain health with age, and may play a key role in Alzheimer's disease prevention.

Lower plasma β-amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia.To determine if plasma β-amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve.We studied 997 black and white community-dwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow-up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n = 550) were female; and 54.0% (n = 538) were black.Association of near-baseline plasma β-amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results.Low β-amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest β-amyloid tertile: mean change in 3MS score, -6.59 [95% confidence interval [CI], -5.21 to -7.67] points; middle tertile: -6.16 [95% CI, -4.92 to -7.32] points; and highest tertile: -3.60 [95% CI, -2.27 to -4.73] points; P < .001). Results were similar after multivariate adjustment for age, race, education, diabetes, smoking, and apolipoprotein E [APOE ] e4 status and after excluding the 72 participants with incident dementia. Measures of cognitive reserve modified this association whereby among those with high reserve (at least a high school diploma, higher than sixth-grade literacy, or no APOE e4 allele), β-amyloid 42/40 was less associated with multivariate adjusted 9-year decline. For example, among participants with less than a high school diploma, the 3MS score decline was -8.94 (95% CI, -6.94 to -10.94) for the lowest tertile compared with -4.45 (95% CI, -2.31 to -6.59) for the highest tertile, but for those with at least a high school diploma, 3MS score decline was -4.60 (95% CI,-3.07 to -6.13) for the lowest tertile and -2.88 (95% CI,-1.41 to -4.35) for the highest tertile (P = .004 for interaction). Interactions were also observed for literacy (P = .005) and for APOE e4 allele (P = .02).Lower plasma β-amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over 9 years, and this association is stronger among those with low measures of cognitive reserve.

<h3>Objective</h3> Our aim was to assess risk of Parkinson disease (PD) following traumatic brain injury (TBI), including specifically mild TBI (mTBI), among care recipients in the Veterans Health Administration. <h3>Methods</h3> In this retrospective cohort study, we identified all patients with a TBI diagnosis in Veterans Health Administration databases from October 2002 to September 2014 and age-matched 1:1 to a random sample of patients without TBI. All patients were aged 18 years and older without PD or dementia at baseline. TBI exposure and severity were determined via detailed clinical assessments or ICD-9 codes using Department of Defense and Defense and Veterans Brain Injury Center criteria. Baseline comorbidities and incident PD more than 1 year post-TBI were identified using ICD-9 codes. Risk of PD after TBI was assessed using Cox proportional hazard models adjusted for demographics and medical/psychiatric comorbidities. <h3>Results</h3> Among 325,870 patients (half with TBI; average age 47.9 ± 17.4 years; average follow-up 4.6 years), 1,462 were diagnosed with PD during follow-up. Compared to no TBI, those with TBI had higher incidence of PD (no TBI 0.31%, all-severity TBI 0.58%, mTBI 0.47%, moderate-severe TBI 0.75%). In adjusted models, all-severity TBI, mTBI, and moderate-severe TBI were associated with increased risk of PD (hazard ratio [95% confidence interval]: all-severity TBI 1.71 [1.53–1.92]; mTBI 1.56 [1.35–1.80]; moderate-severe TBI 1.83 [1.61–2.07]). <h3>Conclusions</h3> Among military veterans, mTBI is associated with 56% increased risk of PD, even after adjusting for demographics and medical/psychiatric comorbidities. This study highlights the importance of TBI prevention, long-term follow-up of TBI-exposed veterans, and the need to determine mechanisms and modifiable risk factors for post-TBI PD.

<h3>Objective:</h3> To determine whether anemia is associated with incident dementia in older adults. <h3>Methods:</h3> We studied 2,552 older adults (mean age 76.1 years; 38.9% black; 51.8% female) participating in the Health, Aging, and Body Composition study and free of dementia at baseline. We defined anemia using WHO criteria (hemoglobin concentration &lt;13 g/dL for men and &lt;12 g/dL for women). Dementia diagnosis was determined by dementia medication use, hospital records, or a change in Modified Mini-Mental State (3MS) score of more than 1.5 SD from mean. Discrete time Cox proportional hazard regression models were used to examine the hazard for developing dementia associated with anemia. <h3>Results:</h3> Of 2,552 participants, 392 (15.4%) older adults had anemia at baseline. Over 11 years of follow-up, 455 (17.8%) participants developed dementia. In the unadjusted model, those with baseline anemia had an increased risk of dementia (23% vs 17%, hazard ratio = 1.64; 95% confidence interval 1.30, 2.07) compared to those without anemia. The association remained significant after adjusting for demographics, <i>APOE</i> ε4, baseline 3MS score, comorbidities, and renal function. Additional adjustment for other anemia measures (mean corpuscular volume, red cell distribution width), erythropoietin, and C-reactive protein did not appreciably change the results. There was no interaction by sex and race on risk of developing dementia. <h3>Conclusion:</h3> Among older adults, anemia is associated with an increased risk of developing dementia. Findings suggest that further study of anemia as a risk factor for dementia and a target for intervention for cognitive health is warranted.

Sex differences in dementia risk are unclear, but some studies have found greater risk for women.To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.Sex.The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61).The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

Abstract More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two‐thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex‐ and gender‐related disparities of risk for AD.

Study Objectives: To examine associations of objectively and subjectively measured sleep with subsequent cognitive decline.Design: A population-based longitudinal study.Setting: Six centers in the United States.Participants: Participants were 2,822 cognitively intact community-dwelling older men (mean age 76.0 ± 5.3 y) followed over 3.4 ± 0.5 y.Interventions: None.Measurements and Results: Objectively measured sleep predictors from wrist actigraphy: total sleep time (TST), sleep efficiency (SE), wake after sleep onset (WASO), number of long wake episodes (LWEP).Self-reported sleep predictors: sleep quality (Pittsburgh Sleep Quality Index [PSQI]), daytime sleepiness (Epworth Sleepiness Scale [ESS]), TST.Clinically significant cognitive decline: five-point decline on the Modified Mini-Mental State examination (3MS), change score for the Trails B test time in the worse decile.Associations of sleep predictors and cognitive decline were examined with logistic regression and linear mixed models.After multivariable adjustment, higher levels of WASO and LWEP and lower SE were associated with an 1.4 to 1.5-fold increase in odds of clinically significant decline (odds ratio 95% confidence interval) Trails B test: SE < 70% versus SE ≥ 70%: 1.53 (1.07, 2.18); WASO ≥ 90 min versus WASO < 90 min: 1.47 (1.09, 1.98); eight or more LWEP versus fewer than eight: 1.38 (1.02, 1.86).3MS: eight or more LWEP versus fewer than eight: 1.36 (1.09, 1.71), with modest relationships to linear change in cognition over time.PSQI was related to decline in Trails B performance (3 sec/y per standard deviation increase).Conclusions: Among older community-dwelling men, reduced sleep efficiency, greater nighttime wakefulness, greater number of long wake episodes, and poor self-reported sleep quality were associated with subsequent cognitive decline.

Blood pressure (BP) and cholesterol are major modifiable risk factors for cardiovascular disease (CVD), but effects of exposures during young adulthood on later life CVD risk have not been well quantified. The authors sought to evaluate the independent associations between young adult exposures to risk factors and later life CVD risk, accounting for later life exposures. The authors pooled data from 6 U.S. cohorts with observations spanning the life course from young adulthood to later life, and imputed risk factor trajectories for low-density lipoprotein (LDL) and high-density lipoprotein cholesterols, systolic and diastolic BP starting from age 18 years for every participant. Time-weighted average exposures to each risk factor during young (age 18 to 39 years) and later adulthood (age ≥40 years) were calculated and linked to subsequent risks of coronary heart disease (CHD), heart failure (HF), or stroke. A total of 36,030 participants were included. During a median follow-up of 17 years, there were 4,570 CHD, 5,119 HF, and 2,862 stroke events. When young and later adult risk factors were considered jointly in the model, young adult LDL ≥100 mg/dl (compared with <100 mg/dl) was associated with a 64% increased risk for CHD, independent of later adult exposures. Similarly, young adult SBP ≥130 mm Hg (compared with <120 mm Hg) was associated with a 37% increased risk for HF, and young adult DBP ≥80 mm Hg (compared with <80 mm Hg) was associated with a 21% increased risk. Cumulative young adult exposures to elevated systolic BP, diastolic BP and LDL were associated with increased CVD risks in later life, independent of later adult exposures.

Previous estimates suggested that 1 in 3 cases of Alzheimer disease and related dementia (ADRDs) in the US are associated with modifiable risk factors, the most prominent being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences by sex or race and ethnicity.To update estimates of the proportion of ADRDs in the US that are associated with modifiable risk factors and to assess for differences by sex and race and ethnicity.For this cross-sectional study, risk factor prevalence and communality were obtained from the nationally representative US Behavioral Risk Factor Surveillance Survey data from January 2018 to December 2018, and relative risks for each risk factor were extracted from meta-analyses. Data were analyzed from December 2020 to August 2021. Respondents included 378 615 noninstitutionalized adults older than 18 years. The number before exclusion was 402 410. Approximately 23 795 (~6%) had missing values on at least 1 of the variables of interest.Physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss.Individual and combined population-attributable risks (PARs) associated with ADRDs, accounting for nonindependence between risk factors.Among 378 615 individuals, 171 161 (weighted 48.7%) were male, and 134 693 (weighted 21.1%) were 65 years and older. Race and ethnicity data were self-reported and defined by the US Behavioral Risk Factor Surveillance System Data; 6671 participants (weighted 0.9%) were American Indian and Alaska Native, 8043 (weighted 5.1%) were Asian, 29 956 (weighted 11.7%) were Black, 28 042 (weighted 16.0%) were Hispanic (any race), and 294 394 (weighted 64.3%) were White. Approximately 1 in 3 of ADRD cases (36.9%) in the US were associated with 8 modifiable risk factors, the most prominent of which were midlife obesity (17.7%; 95% CI, 17.5-18.0), physical inactivity (11.8%; 95% CI, 11.7-11.9), and low educational attainment (11.7%; 95% CI, 11.5-12.0). Combined PARs were higher in men (35.9%) than women (30.1%) and differed by race and ethnicity: American Indian and Alaska Native individuals, 39%; Asian individuals, 16%; Black individuals, 40%; Hispanic individuals (any race), 34%; and White individuals, 29%. The most prominent modifiable risk factors regardless of sex were midlife obesity for American Indian and Alaska Native individuals, Black individuals, and White individuals; low education for Hispanic individuals; and physical inactivity for Asian individuals.The findings suggest that risk factors associated with ADRDs have changed over the past decade and differ based on sex and race and ethnicity. Alzheimer risk reduction strategies may be more effective if they target higher-risk groups and consider current risk factor profiles.

The racial and ethnic diversity of the US, including among patients receiving their care at the Veterans Health Administration (VHA), is increasing. Dementia is a significant public health challenge and may have greater incidence among older adults from underrepresented racial and ethnic minority groups.To determine dementia incidence across 5 racial and ethnic groups and by US geographical region within a large, diverse, national cohort of older veterans who received care in the largest integrated health care system in the US.Retrospective cohort study within the VHA of a random sample (5% sample selected for each fiscal year) of 1 869 090 participants aged 55 years or older evaluated from October 1, 1999, to September 30, 2019 (the date of final follow-up).Self-reported racial and ethnic data were obtained from the National Patient Care Database. US region was determined using Centers for Disease Control and Prevention (CDC) regions from residential zip codes.Incident diagnosis of dementia (9th and 10th editions of the International Classification of Diseases). Fine-Gray proportional hazards models were used to examine time to diagnosis, with age as the time scale and accounting for competing risk of death.Among the 1 869 090 study participants (mean age, 69.4 [SD, 7.9] years; 42 870 women [2%]; 6865 American Indian or Alaska Native [0.4%], 9391 Asian [0.5%], 176 795 Black [9.5%], 20 663 Hispanic [1.0%], and 1 655 376 White [88.6%]), 13% received a diagnosis of dementia over a mean follow-up of 10.1 years. Age-adjusted incidence of dementia per 1000 person-years was 14.2 (95% CI, 13.3-15.1) for American Indian or Alaska Native participants, 12.4 (95% CI, 11.7-13.1) for Asian participants, 19.4 (95% CI, 19.2-19.6) for Black participants, 20.7 (95% CI, 20.1-21.3) for Hispanic participants, and 11.5 (95% CI, 11.4-11.6) for White participants. Compared with White participants, the fully adjusted hazard ratios were 1.05 (95% CI, 0.98-1.13) for American Indian or Alaska Native participants, 1.20 (95% CI, 1.13-1.28) for Asian participants, 1.54 (95% CI, 1.51-1.57) for Black participants, and 1.92 (95% CI, 1.82-2.02) for Hispanic participants. Across most US regions, age-adjusted dementia incidence rates were highest for Black and Hispanic participants, with rates similar among American Indian or Alaska Native, Asian, and White participants.Among older adults who received care at VHA medical centers, there were significant differences in dementia incidence based on race and ethnicity. Further research is needed to understand the mechanisms responsible for these differences.

Mild cognitive impairment (MCI) represents a common cognitive state between normal cognitive aging and dementia. There is limited information about the heterogeneity of MCI and how this heterogeneity may influence the clinical course of MCI. We determined the longitudinal course of subtypes of MCI and assessed the rate of progression to dementia and to death.As part of the Alzheimer's Disease Research Centers of California, we studied 327 patients with MCI (250 with amnestic MCI, 34 with single nonmemory MCI, and 43 with multiple domain MCI) who were followed longitudinally. We determined if subtype of MCI was independently associated with time to dementia diagnosis and time to death using Cox proportional hazard models, and type of dementia using Fisher's exact test.Mean age of the patients with MCI was 72.9 +/- 9.3 years and mean Mini-Mental State Examination score was 25.7 +/- 4.3. After a mean follow-up of 3.1 years, 199 (65%) progressed to dementia and 80 (24%) died. After multivariate adjustment, compared to those with amnestic MCI, patients with single nonmemory or multiple subtype MCI were less likely to receive a diagnosis of dementia (HR = 0.60; 95% CI 0.35-1.05 and HR = 0.71; 95% CI 0.44-1.14) but more likely to die (HR = 2.57; 95% CI 1.13-5.84 and HR = 1.73; 95% CI 0.72-4.18), but these results were of borderline statistical significance. There were significant differences in the type of dementia diagnosed across MCI subtypes (p = 0.006). Among the patients who progressed to Alzheimer's disease, 76% had prior amnestic MCI; of the patients who progressed to vascular dementia, 50% had prior amnestic MCI; all patients who progressed to a frontal dementia syndrome had single nonmemory MCI previously.The majority of patients with MCI progressed to dementia and a significant proportion died. Subtype of MCI may influence rates of progression to death and to dementia and has a major influence on subsequent type of dementia diagnosis.

<h3>Background</h3> A few studies have examined change in cognitive performance by diabetes status with disparate results. We examined the 4-year change in cognitive performance among older adults according to glucose tolerance status. <h3>Methods</h3> Three cognitive tests (Mini-Mental State Examination, Verbal Fluency [VF] test, and Trail-Making Test B) were measured 4 years apart in 999 white men and women aged 42 to 89 years, who were enrolled in the Rancho Bernardo Study. Participants were classified with normal (NGT), impaired (IGT) or diabetic glucose tolerance. Sex-specific linear regression models adjusted for age, education, depression score, apolipoprotein E ϵ4 allele, and current estrogen use. We checked for mediation by further adjusting for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels; blood pressure; glycohemoglobin level; and microalbuminuria, retinopathy, stroke, or coronary heart disease. <h3>Results</h3> At baseline, mean cognitive function scores did not differ between glucose tolerance groups. Women with diabetes mellitus had a 4-fold increased risk of a major cognitive decline on the VF test after 4 years compared with nondiabetic women. After multivariate adjustment, VF test scores at follow-up for women were 15.2 ± 0.6 for those with diabetes, 16.7 ± 0.4 for those with IGT, and 17.2 ± 0.2 for those with NGT (<i>P</i>= .007). Glycohemoglobin attenuated this effect, but lipid levels, blood pressure, and microvascular or macrovascular disease did not. Performance on Mini-Mental State Examination and Trail-Making Test B did not differ by baseline glucose status. <h3>Conclusions</h3> Elderly white women with diabetes had a more rapid decline in performance on the VF test compared with women with IGT or NGT. Better glucose control might ameliorate this decline.

Performance measures of physical function (gait speed, chair stands, standing balance) and cognitive function [Teng-modified Mini-Mental Status Exam (3MS) and digit symbol substitution test (DSST)] were assessed at baseline in 3,075 participants in the Health, Aging and Body Composition Study. Each physical function measure was examined for the strength and magnitude of association with cognitive function. All physical function measures were associated with both the 3MS and DSST scores (p < 0.001), and in multivariate analysis each relationship was independent of demographic characteristics, weight, physical activity and comorbid health conditions of participants. The association of motor performance was consistently greater for the DSST than the 3MS and, among the motor tests, gait speed retained a significant association with both cognitive measures independent of demographic, weight, physical activity and comorbid health conditions. In this large cohort of high-functioning older adults, the correlation between physical and cognitive function was not entirely explained by demographics. Longitudinal studies are needed to determine the direction of causality in this relationship.

Reduced sleep has been reported to predict obesity in children and young adults. However, studies based on self-report have been unable to identify an association in older populations. In this study, the cross-sectional associations between sleep duration measured objectively and measures of weight and body composition were assessed in two cohorts of older adults. Wrist actigraphy was performed for a mean (s.d.) of 5.2 (0.9) nights in 3055 men (age: 67–96 years) participating in the Osteoporotic Fractures in Men Study (MrOS) and 4.1 (0.8) nights in 3052 women (age: 70–99 years) participating in the Study of Osteoporotic Fractures (SOF). A subgroup of 2862 men and 455 women also underwent polysomnography to measure sleep apnea severity. Compared to those sleeping an average of 7–8 h per night, and after adjusting for multiple risk factors and medical conditions, a sleep duration of less than 5 h was associated with a body mass index (BMI) that was on average 2.5 kg/m2 (95% confidence interval (CI): 2.0–2.9) greater in men and 1.8 kg/m2 (95% CI: 1.1–2.4) greater in women. The odds of obesity (BMI ⩾30 kg/m2) was 3.7-fold greater (95% CI: 2.7–5.0) in men and 2.3-fold greater in women (95% CI: 1.6–3.1) who slept less than 5 h. Short sleep was also associated with central body fat distribution and increased percent body fat. These associations persisted after adjusting for sleep apnea, insomnia and daytime sleepiness. In older men and women, actigraphy-ascertained reduced sleep durations are strongly associated with greater adiposity.

Recent studies have suggested that estrogen may improve cognitive function or prevent cognitive decline in older women. Little research has been conducted on exogenous or endogenous sex hormones and cognition in older men, yet it has been hypothesized that testosterone, either directly or by conversion to estrogens, may improve cognitive function. We investigated whether serum level of testosterone and estradiol is associated with cognition in older community-dwelling men.A cross-sectional study.Population-based listings in the Monongahela Valley near Pittsburgh, Pennsylvania.Three hundred ten men (mean age +/- standard deviation = 73.0 +/- 7.1) who were part of a cohort study.We measured cognitive function using the Mini-Mental State Examination (MMSE), Trails B, and Digit Symbol. Sex hormone levels were determined by radioimmunoassay from serum obtained at the time of cognitive testing and analyzed by tertile.No consistent association between total testosterone level and cognitive test scores was observed. However, men with high bioavailable (loosely protein-bound) testosterone had better cognitive test scores on all three tests (P < or =.001). Total estradiol levels were associated with worse cognitive scores on Digit Symbol (P <.001) and Trails B (P =.002), but bioavailable estradiol levels were not associated with cognitive function. Level of sex hormone binding globulin (SHBG) was negatively associated with cognitive scores on all three tests (P < or =.001). After adjusting for age and education, the statistical significance lessened for bioavailable testosterone (MMSE, P =.086; Digit Symbol, P =.047; Trails B, P =.076) and became nonsignificant for SHBG (all cognitive tests P>.10).Our findings support the hypothesis that higher levels of bioavailable testosterone, but not of bioavailable estradiol, are associated with better cognitive function in older men. In addition, bioavailable measures of testosterone may better reflect hormone levels available to the brain and thus be more closely associated with central nervous system outcomes such as cognition. Future studies, especially randomized trials, should be undertaken to determine whether testosterone may protect against cognitive decline in older men.

Previous studies have found no association between serum concentrations of total oestradiol and cognitive function, but these measurements may not reflect concentrations of hormone available to the brain. We tested the hypothesis that concentrations of non-protein-bound (free) and loosely bound (bioavailable) sex hormones are associated with cognitive function in older women.We measured cognitive performance with a modified mini mental status examination (mMMSE) at baseline (1986-88) and 6 years later in 425 women (65 years or older). Concentrations of non-protein-bound and bioavailable oestradiol and total and non-protein-bound testosterone were measured by RIA in serum samples taken at baseline.Initial cognitive scores did not differ by tertile of non-protein-bound oestradiol, bioavailable oestradiol, or testosterone. Cognitive impairment (a decrease of 3 points or more in mMMSE score) occurred in five (5%) of 94 women in the high tertile for non-protein-bound oestradiol and in 17 (16%) of 106 in the low tertile (odds ratio 0.3 [95% CI 0.1-0.8]). After adjustment for age, years of education, body-mass index, current oestrogen use, history of surgical menopause, and baseline mMMSE score, the odds ratio was 0.3 (0.1-0.9). The results were similar for bioavailable oestradiol (five [5%] vs 15 [15%]; adjusted odds ratio 0.3 [0.1-1.0]). There was no association between risk of cognitive impairment and serum testosterone.Women with high serum concentrations of non-protein-bound and bioavailable oestradiol, but not testosterone, were less likely to develop cognitive impairment than women with low concentrations. This finding supports the hypothesis that higher concentrations of endogenous oestrogens prevent cognitive decline.

OBJECTIVE— Recent evidence suggests that the metabolic syndrome and inflammation affect cognitive decline in old age and that they reinforce each other. However, it is not known what the roles of the individual components of the metabolic syndrome on cognition are. RESEARCH DESIGN AND METHODS— The sample consisted of 1,183 participants in the Longitudinal Aging Study Amsterdam who were aged 65–88 years. Metabolic syndrome (U.S. National Cholesterol Education Program definition) and its individual components and the inflammatory markers C-reactive protein (CRP) and α1-antichymotrypsin (ACT) were assessed. Cognitive assessments included general cognition (Mini-Mental State Examination), memory (verbal learning test), fluid intelligence (Raven's Matrices), and information processing speed (coding task). RESULTS— Of the sample, 36.3% had metabolic syndrome. Metabolic syndrome was significantly associated with all cognitive measures (P &amp;lt; 0.05). Of the individual components, hyperglycemia was most strongly and significantly associated with cognitive function (multivariate adjusted models; B values, indicating differences in scores between both groups, ranging from −0.38 to −1.21). There was a significant interaction between metabolic syndrome and inflammation on cognition (P &amp;lt; 0.01–0.09). Metabolic syndrome was negatively associated with cognition in subjects with high inflammation (highest tertile for both CRP and ACT; B values ranging from −0.86 to −1.94, P &amp;lt; 0.05), whereas an association was absent in subjects with low inflammation (B values ranging from −0.10 to −0.70). CONCLUSIONS— Subjects with metabolic syndrome showed poorer cognitive performance than subjects without metabolic syndrome, especially those with high levels of inflammation. Hyperglycemia was the main contributor of the association of metabolic syndrome with cognition.

We compared the predictive value of cerebral perfusion as measured by arterial-spin labeling magnetic resonance imaging (ASL-MRI) with MRI-derived hippocampal volume for determining future cognitive and functional decline and subsequent conversion from mild cognitive impairment to dementia. Forty-eight mild cognitive impairment subjects received structural and ASL-MRI scans at baseline and clinical and neuropsychologic assessments annually. Thirteen subjects became demented during the period of longitudinal observation (2.7+/-1.0 y). Cox regression analyses suggest that baseline hippocampal volume [relative risk (RR)=0.99, P=0.004], baseline right inferior parietal (RR=0.64, P=0.01) and right middle frontal (RR=0.73, P=0.01) perfusion were associated with conversion to dementia. Results from linear mixed effects modeling suggest that baseline perfusion from the right precuneus predicted subsequent declines in Clinical Dementia Rating Sum of Boxes (P=0.002), Functional Activates Questionnaire (P=0.01), and selective attention (ie, Stroop switching, P=0.009) whereas baseline perfusion from the right middle frontal cortex predicted subsequent episodic memory decline (ie, total recognition discriminability score from the California Verbal Learning Test, P=0.03). These results suggest that hypoperfusion as detected by ASL-MRI can predict subsequent clinical, functional, and cognitive decline and may be useful for identifying candidates for future Alzheimer disease treatment trials.

Background: Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control.Methods: Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n=1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs).Results: Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia.Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95%

BACKGROUND : The purpose of this study was to evaluate the cross‐sectional and longitudinal association of oral estrogen replacement therapy (ERT) and cognitive function in an older, nondemented sample of women. METHODS : In a prospective cohort of 9651 white women aged 65 years and older enrolled in the Study of Osteoporotic Fractures, a modified Mini‐Mental Status Exam (mMMSE), and digit symbol substitution and Trails B tests were administered twice, 4 to 6 years apart. History and current use of oral ERT was documented. Age, educational attainment, and activity limitations were the primary covariates in the analyses; in addition, stroke and depression scores were adjusted in subsets of women with available data. RESULTS : Current and past users of ERT had better initial scores on the mMMSE than did never users, P &lt; .05 and .001, respectively, with better scores for current estrogen hormone users being most apparent among the older and less educated women. The percentages of women scoring ≤23 of a possible 26 on the mMMSE were 14.3 for current users, 14.5 for past users, and 20.5 for never users, P &lt; .001. However, only past users exhibited smaller declines upon retesting in mMMSE and Trails B performance, P &lt; .05, than did never users. Educational attainment predicted both initial test scores and change scores and was, next to age, the most powerful predictor of cognitive function. CONCLUSIONS : Current oral ERT does not protect against age‐related declines in cognitive function in older nondemented women, whereas formal education does protect, even though it had been completed many years earlier. The influence of education in late‐life on cognitive function should be tested. J Am Geriatr Soc 47:518–523, 1999.

Several studies support a role for cardiovascular risk factors in cognitive aging. The metabolic syndrome, a constellation of cardiovascular risk factors, is common in elderly people. A growing but conflicting body of literature suggests that the metabolic syndrome may be associated with cognitive impairment.To investigate the association between the metabolic syndrome and its components and incident cognitive impairment in older women.We prospectively determined if the metabolic syndrome and its components were associated with a 4-year risk of developing cognitive impairment (dementia, mild cognitive impairment, or low global cognitive test score).The study was conducted at 180 clinical centers in 25 countries.A total of 4895 older women (mean age, 66.2 years) with osteoporosis who were part of an ancillary study to determine clinically relevant cognitive impairment were included in this study. These women were free of baseline cognitive impairment and had metabolic syndrome component measures.Clinically significant cognitive impairment was defined to include women with clinically adjudicated dementia or MCI and women who had a Short Blessed test score greater than 6 (consistent with impairment), but whose cases were not clinically adjudicated. Logistic regression analysis was used to examine the association between presence of the metabolic syndrome and development of clinically significant cognitive impairment.A total of 497 women (10.2%) had the metabolic syndrome and, of these, 36 (7.2%) developed cognitive impairment compared with 181 (of 4398 or 4.1%) without the syndrome (age-adjusted odds ratio, 1.66; 95% confidence interval, 1.14-2.41). The mean (SD) number of metabolic syndrome components for all women was 1.0 (1.1); 518 women (10.6%) were obese, 895 (18.3%) had hypertriglyceridemia, 1200 (24.5%) had low high-density lipoprotein cholesterol levels, 1944 (39.7%) had high blood pressure, and 381 (7.8%) had high fasting blood glucose levels. There was a 23.0% age-adjusted increase in the risk of developing cognitive impairment (odds ratio, 1.23; 95% confidence interval, 1.09-1.39) per unit increase in the number of components. Further multivariable adjustment somewhat reduced the effect.We found an association between the metabolic syndrome and the number of components and risk of developing cognitive impairment in older women. Additional studies are needed to determine if screening and close management of these at-risk elderly women would diminish the incidence of cognitive impairment.

Leptin is a peptide hormone secreted by adipocytes. It has been shown to modulate production and clearance of amyloid beta (Abeta) in rodent models. We sought to determine if serum leptin was associated with cognitive decline in the elderly. We studied 2871 well-functioning elders, aged 70-79, who were enrolled in a prospective study. Serum leptin concentrations were measured at baseline and analyzed by mean+/-1S.D. Clinically significantly cognitive decline over 4 years was defined as > or =5-point drop on the Modified Mini Mental State Exam (3MS). Compared to those in the lower leptin groups, elders in the high leptin group had less cognitive decline, 20.5% versus 24.7% (OR=0.79; 95% CI 0.61-1.02, p=0.07). After adjustment for demographic and clinical variables, including body mass index and total percent body fat, those in the high leptin group had significantly less likelihood of cognitive decline, OR=0.66 (95% CI 0.48-0.91). We conclude that in elderly individuals, higher serum leptin appears to protect against cognitive decline, independent of comorbidites and body fat.

This investigation examined whether raloxifene, a selective estrogen receptor modulator, affects the risk for Alzheimer's disease.The Multiple Outcomes of Raloxifene Evaluation was a randomized, placebo-controlled trial among postmenopausal women with osteoporosis. The effect of raloxifene (60 or 120 mg/day) on vertebral fractures was the primary outcome. Development of mild cognitive impairment and dementia was a secondary outcome. Women were given clinical and cognitive evaluations at baseline and annually. After 3 years, among the 5,386 women enrolled at participating sites, those who had clinical symptoms of dementia or scored in the lowest 10th percentile on cognitive screening were evaluated by a blinded dementia specialist and had brain scans and laboratory tests to evaluate dementia etiology. Dementia was diagnosed by a blinded adjudication committee.Of the 5,386 women, 5,153 (95.7%) were classified as cognitively normal, 181 (3.4%) had mild cognitive impairment, and 52 (1.0%) had dementia, 36 with Alzheimer's disease. Compared to those taking placebo, women receiving 120 mg/day of raloxifene had a 33% lower risk of mild cognitive impairment (relative risk, 0.67; 95% confidence interval [CI], 0.46-0.98) and somewhat lower risks of Alzheimer's disease (relative risk=0.52, 95% CI=0.22-1.21) and any cognitive impairment (relative risk=0.73, 95% CI=0.53-1.01). Risks of mild cognitive impairment, Alzheimer's disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene.Raloxifene at a dose of 120 mg/day, but not 60 mg/day, resulted in reduced risk of cognitive impairment in postmenopausal women.

To investigate the effect of metabolic syndrome on cognitive function in an elderly Latino population and to determine whether inflammation modifies this association.A longitudinal cohort study.Sacramento area and the surrounding California counties from 1998 to 1999.One thousand six hundred twenty-four Latinos aged 60 and older who participated in the Sacramento Area Latino Study of Aging.Baseline metabolic syndrome was calculated using the Third Adult Treatment Panel of the National Cholesterol Education Program. Cognitive function was measured using the Modified Mini-Mental State Examination (3MS) and the Delayed Word-List Recall (DelRec), a verbal memory test. The effect of metabolic syndrome on cognitive change scores was examined using random effects models; in addition, the effect of the individual components of the syndrome on cognitive change was examined.Of the 1,624 participants, 718 (44%) had metabolic syndrome at baseline. Those with metabolic syndrome had worse 3-year change scores on 3MS (P=.04) and DelRec (P=.03). Multivariate adjustment attenuated the results for DelRec but not for 3MS. This association was especially pronounced in participants with a high serum level of inflammation, resulting in an average 3MS score 0.64 points lower per year (P=.03) for those with metabolic syndrome. Individual components of metabolic syndrome were not associated with cognitive decline except for elevated glucose on the DelRec (P=.02) and high blood pressure on 3MS (P=.05).Metabolic syndrome and inflammation may both contribute to cognitive decline in older people of diverse backgrounds. The results also suggest that, in elderly Latinos, the composite measure of metabolic syndrome is a greater risk for cognitive decline than its individual components.

To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years.Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients.Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores.The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

Yaffe, Kristine; Krueger, Kathryn; Sarkar, Somnath; Grady, Deborah; Barrett-Connor, Elizabeth; Cox, David A.; Nickelsen, Thomas for the Multiple Outcomes of Raloxifene Evaluation Investigators

Objective The authors assessed the magnitude of discrepancy between patients' and caregivers' ratings of the patients' quality of life and sought to determine whether the discrepancies are associated with patient characteristics, caregiver characteristics, or the type of relationship between the patient and caregiver. Methods A sample of 91 patients with mild-to-moderately severe dementia and their primary family caregiver rated five domains of the patients' subjective quality of life. Results Agreement between patients and caregivers was low. Caregivers rated patients' quality of life lower than patients rated their own in all five domains. Discrepancies between patients' and caregivers' ratings were not associated with the patients' cognitive performance, level of functioning, nor caregivers' reports of aggressive, attention-seeking, or sexually inappropriate behaviors, nor whether the caregiver lived with or was married to the patient. However, discrepancies were associated with level of caregiver burden and the patients' report of depressive symptoms. Patients with depression reported low quality of life, which matched caregivers' low rating of patients' quality of life. Caregivers who reported higher levels of burden rated patients' quality of life lower than did patients in all five domains of quality of life. Conclusions Discrepancies between dementia patients' and their caregivers' ratings of the patients' quality of life are associated with increased levels of caregiver burden, rather than lower levels of patients' functioning. The results of this study support the direct assessment of mild-to-moderate dementia patients about their subjective quality of life. The authors assessed the magnitude of discrepancy between patients' and caregivers' ratings of the patients' quality of life and sought to determine whether the discrepancies are associated with patient characteristics, caregiver characteristics, or the type of relationship between the patient and caregiver. A sample of 91 patients with mild-to-moderately severe dementia and their primary family caregiver rated five domains of the patients' subjective quality of life. Agreement between patients and caregivers was low. Caregivers rated patients' quality of life lower than patients rated their own in all five domains. Discrepancies between patients' and caregivers' ratings were not associated with the patients' cognitive performance, level of functioning, nor caregivers' reports of aggressive, attention-seeking, or sexually inappropriate behaviors, nor whether the caregiver lived with or was married to the patient. However, discrepancies were associated with level of caregiver burden and the patients' report of depressive symptoms. Patients with depression reported low quality of life, which matched caregivers' low rating of patients' quality of life. Caregivers who reported higher levels of burden rated patients' quality of life lower than did patients in all five domains of quality of life. Discrepancies between dementia patients' and their caregivers' ratings of the patients' quality of life are associated with increased levels of caregiver burden, rather than lower levels of patients' functioning. The results of this study support the direct assessment of mild-to-moderate dementia patients about their subjective quality of life.

<b><i>Objectives:</i></b> To explore the atrophy rate of entorhinal cortex (ERC) in AD and normal aging and assess the value of rate measurement of ERC atrophy for classifying subjects with AD from cognitively normal (CN) control subjects. <b><i>Methods:</i></b> Twenty-one AD patients and 23 CN subjects had MRI scans and clinical evaluations twice within 1.8 ± 0.6 years. ERC volumes were manually measured on volumetric T1-weighted MR images. <b><i>Results:</i></b> Patients with AD had a greater annual percentage volume change of ERC than CN subjects on both sides (left: 6.8 ± 4.3%/year for AD vs 1.4 ± 2.5%/year for CN [F_1,42 = 25.6, <i>p</i> &lt; 0.001]; right: 6.3 ± 3.3%/year for AD vs 1.4 ± 2.3%/year for CN [F_1,42 = 25.6, <i>p</i> &lt; 0.001]). Furthermore, increased ERC atrophy rate was correlated (<i>r</i> = −0.56, <i>p</i> = 0.01) with decreased memory performance in AD. CN subjects had on average annual ERC atrophy rates greater than zero (<i>p</i> &lt; 0.01). Baseline volume of ERC predicted atrophy rate of ERC (left: <i>r</i> = −0.53, <i>p</i> &lt; 0.01; right: <i>r</i> = −0.42, <i>p</i> &lt; 0.05) in CN subjects but not in AD subjects. Using ERC baseline volumes alone resulted in 77% overall correct classification (<i>p</i> &lt; 0.01) between AD and CN subjects, with 76% sensitivity and 78% specificity and an area under receiver operator characteristic (ROC) curve of 0.83. Adding annual atrophy rate of ERC to the model accounted for most of the variance (<i>p</i> &lt; 0.01), diminishing contributions from baseline volume and yielding 82% overall classification, with 76% sensitivity and 86% specificity and an area under the ROC curve of 0.93. <b><i>Conclusion:</i></b> ERC volume loss over time may be a better indicator for AD than cross-sectional measurements.

To test the hypothesis that lower 25-hydroxyvitamin D [25(OH)D] levels are associated with a greater likelihood of cognitive impairment and risk of cognitive decline.We measured 25(OH)D and assessed cognitive function using the Modified Mini-Mental State Examination (3MS) and Trail Making Test Part B (Trails B) in a cohort of 1,604 men enrolled in the Osteoporotic Fractures in Men Study and followed them for an average of 4.6 years for changes in cognitive function.In a model adjusted for age, season, and site, men with lower 25(OH)D levels seemed to have a higher odds of cognitive impairment, but the test for trend did not reach significance (impairment by 3MS: odds ratio [OR] 1.84, 95% confidence interval [CI] 0.81-4.19 for quartile [Q] 1; 1.41, 0.61-3.28 for Q2; and 1.18, 0.50-2.81 for Q3, compared with Q4 [referent group; p trend = 0.12]; and impairment by Trails B: OR 1.66, 95% CI 0.98-2.82 for Q1; 0.96, 0.54-1.69 for Q2; and 1.30, 0.76-2.22 for Q3, compared with Q4 [p trend = 0.12]). Adjustment for age and education further attenuated the relationships. There was a trend for an independent association between lower 25(OH)D levels and odds of cognitive decline by 3MS performance (multivariable OR 1.41, 95% CI 0.89-2.23 for Q1; 1.28, 0.84-1.95 for Q2; and 1.06, 0.70-1.62 for Q3, compared with Q4 [p = 0.10]), but no association with cognitive decline by Trails B.We found little evidence of independent associations between lower 25-hydroxyvitamin D level and baseline global and executive cognitive function or incident cognitive decline.

There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD).To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men.Twenty-four-week, randomized, double-blind, placebo-controlled, parallel-group study.Memory disorders clinics as well as general neurology and medicine clinics from University of California medical centers at Los Angeles, San Francisco, and Irvine.Sixteen male patients with AD and 22 healthy male control subjects. Healthy elderly control men were recruited from the community through advertisements as well as through the university-based clinics.Testosterone and placebo, in the form of hydroalcoholic gel (75 mg), were applied daily to the skin of the participants.Instruments assessing cognitive functioning (Alzheimer's Disease Assessment Scale-Cognitive Subscale, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation, Developmental Test of Visual-Motor Integration), neuropsychiatric symptoms (Neuropsychiatric Inventory), global functioning (Clinician's Interview-Based Impression of Change), and quality of life (Quality of Life-Alzheimer Disease Scale).For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale (P = .01). No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group (P = .09) compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo.Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.

To determine if atrophy rates were higher for entorhinal cortex (ERC) than for hippocampus in Alzheimer disease (AD), to determine the relationship between hippocampal atrophy rate and memory impairment, and to compare atrophy rates of ERC and hippocampus in differentiating between patients with AD and cognitively normal (CN) controls.Twenty patients with AD and 25 CN subjects had MRI scans and clinical evaluations twice approximately 1.9 years apart. ERC volumes were measured manually and hippocampal volumes were measured semiautomatically on volumetric T1-weighted MR images.In AD, the atrophy rate of ERC (7.1 +/- 3.2%/year) was higher (p < 0.02) than that of hippocampus (5.9 +/- 2.4%/year). Furthermore, memory deficit in mild AD, measured with the Delayed List Verbal Recall test, correlated significantly with atrophy rates of both ERC (r = -0.61) and hippocampus (r = -0.59). Atrophy rates of ERC and hippocampus were comparable in differentiating between AD and CN. Using atrophy rates of ERC or hippocampus to detect a 20% treatment effect with 90% power (p < 0.05) would require about 100 completed patients per arm in a 2-year study.The finding in AD that the atrophy rate in the entorhinal cortex is higher than in the hippocampus is consistent with the view that AD pathology begins in the entorhinal cortex.

Given the anticipated exponential increase in both the incidence and prevalence of dementia, it is critical to identify preventative strategies and improved treatments for this disorder. The metabolic syndrome is comprised of 5 cardiovascular risk factors that include abdominal obesity, hypertriglyceridemia, low high-density lipoprotein levels, hypertension, and hyperglycemia. The prevalence of the metabolic syndrome, similar to that for cognitive disorders, increases dramatically with age. Several possible mechanisms may explain an association between the metabolic syndrome and cognitive decline including microvascular and macrovascular disease, inflammation, adiposity, and insulin resistance. Although some of the individual components of the metabolic syndrome have been linked to risk of developing dementia and cognitive impairment, few studies have looked at the components of the metabolic syndrome as a whole. We found, in 3 separate studies involving elders of different ethnicities, that the metabolic syndrome is a risk factor for accelerated cognitive aging. This was especially true for elders with the metabolic syndrome and with elevated serum level of inflammation. If metabolic syndrome is associated with increased risk of developing cognitive impairment, regardless of mechanism, then early identification and treatment of these individuals might offer avenues for disease course modification.

Context: Vitamin D deficiency and frailty are common with aging, but the association between these conditions is uncertain.

Gait speed is cross-sectionally associated with attention and psychomotor speed in older community dwellers. It is unclear if gait speed predicts decline in these cognitive domains over time.Usual gait speed (m/s) over 6 m was measured at baseline in 2,776 Health, Aging and Body Composition Study participants (mean age +/- SD 73.5 +/- 2.8 years, 53% women, 37% blacks). The Digit Symbol Substitution Test (DSST) was administered at baseline and after 5 years to assess attention and psychomotor speed. We used multivariate logistic regression models to calculate the risk of DSST 5-year decline [>1 SD from mean change (9 points)] across quartiles of gait speed, adjusting for demographics, weight, physical activity, comorbidities, depression and Modified Mini-Mental State Examination.After 5 years, 389 (17.1%) participants declined in DSST. Compared to those in the highest quartile of gait speed (>1.35 m/s), participants in the lowest quartile (<1.05 m/s) were more likely to decline in DSST independently of the considered covariates (OR 1.74, 95% CI 1.21-2.51, adjusted p for trend across quartiles = 0.006).In this cohort of older community dwellers, gait speed independently predicted a decline in DSST after 5 years.

Although end-stage renal disease has been associated with cognitive impairment, the relation between lesser degrees of chronic kidney disease (CKD) and cognitive impairment is less well understood.Data for 1,015 women enrolled at 10 of the 20 Heart Estrogen/Progestin Replacement Study clinical sites were analyzed. All participants were younger than 80 years and had established coronary artery disease at study entry. Participants underwent 6 standard tests of cognitive function evaluating various domains. Unadjusted, residual age- and race-adjusted, and multivariable-adjusted linear and logistic regression models were used. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease regression equation. In addition to analyses across the spectrum of GFRs, CKD was categorized as mild (estimated GFR [eGFR], 45 to 60 mL/min/1.73 m2), moderate (eGFR, 30 to 44 mL/min/1.73 m2), and severe (eGFR, <30 mL/min/1.73 m2) according to a modification of recently established classification guidelines.Mean eGFR was 57 +/- 14 mL/min/1.73 m2. In multivariable analyses, eGFR was associated significantly with impairment in global cognition, executive function, language, and memory (approximately 15% to 25% increase in risk for dysfunction/10-mL/min/1.73 m2 decrement in eGFR). Associations among eGFR and cognitive function were independent of residual effects of age and race (2 key determinants of GFR) and the contributions of education, lifestyle factors, stroke, diabetes, and other laboratory variables.CKD is associated with cognitive impairment in menopausal women with coronary artery disease.

Objective: It is unclear why late-life mood and anxiety disorders are highly undertreated, despite being common among older adults. Thus this study examined prevalence of and key factors associated with nonuse of mental health services among older community-dwelling adults with these disorders. Methods: The sample included 348 participants aged 55 years or older who met 12-month criteria for DSM-IV mood and anxiety disorders and responded to the National Comorbidity Survey Replication (NCS-R), a population-based probability sample. Analyses included frequency measures and logistic regression with weights and complex design-corrected statistical tests. Key factors associated with not using mental health services were determined in a final multivariable model based on a systematic approach that accounted for a comprehensive list of potential predictors. Results: Approximately 70% of older adults with mood and anxiety disorders did not use services. Those who were from racial-ethnic minority groups, were not comfortable with discussing personal problems, were married or cohabitating, and had middle- versus high-income status had increased odds of not using mental health services. In addition, respondents with mild versus serious disorders, no chronic pain complaints, and low versus high perceived cognitive impairment had greater odds of nonuse. Conclusions: Results indicate that improvements are needed in the following areas to combat the very high number of mood and anxiety disorders that go untreated in older Americans: awareness of need, comfort in discussing personal problems with a health care professional, and screening and other prevention efforts. (Psychiatric Services 63:66–72, 2012)

OBJECTIVES: To investigate the association between objectively measured sleep‐disordered breathing (SDB) and cognitive impairment in community‐dwelling older women and to determine whether the apolipoprotein E (APOE) ɛ4 allele modifies this association. DESIGN: Cross‐sectional. SETTING: Participants' homes and two sites of the Study of Osteoporotic Fractures (SOF). PARTICIPANTS: Four hundred forty‐eight women with a mean age±standard deviation (SD) of 82.8±3.4. MEASUREMENTS: Participants completed the Mini‐Mental State Examination (MMSE), Trail Making Test Part B (Trails B), and polysomnography (PSG). SDB indices were the apnea–hypopnea index (AHI), the central apnea index (CAI), and oxygen saturation (SaO 2 ) nadir less than 80%. APOE ɛ4 was determined for a subset of 242 women. Cognitive impairment was defined as 1.5 SDs or more from the sample mean on either cognitive test (MMSE or Trails B). RESULTS: All SDB indices were associated with cognitive impairment according to the MMSE (AHI (per SD, odds ratio (OR)=1.4, 95% confidence interval (CI)=1.03–1.9), AHI of ≥30 (OR=3.4, 95% CI=1.4–8.1), SaO 2 nadir &lt;80% (OR=2.7, 95% CI=1.1–6.6), and CAI (per SD, OR=1.4, 95% CI=1.1–1.7)). Weaker, nonsignificant associations emerged between SDB and Trails B. In women who completed genotyping, each SD increase in AHI was associated with 70% greater odds of cognitive impairment according to the MMSE (OR=1.7, 95% CI=1.2–2.6). Women with the ɛ4 allele had a nearly five times greater odds of impairment (per SD, OR=4.6, 95% CI‐1.0–20.7); the association was smaller and nonsignificant in women without the ɛ4 allele (per SD, OR=1.5, 95% CI‐0.9–2.4; P for interaction=.08). CONCLUSION: SDB is an important risk factor for cognitive impairment in older women, especially those with the APOE ɛ4 allele. Mechanisms linking these disorders need to be identified.

Objectives To examine the association between sleep architecture, sleep‐disordered breathing, and cognition in older men. Design Population‐based cross‐sectional study. Setting Six clinical sites in the United States. Participants Two thousand nine hundred nine community‐dwelling men aged 67 and older who were not selected on the basis of sleep problems or cognitive impairment. Measurements Predictors were measured using in‐home polysomnography: sleep architecture, nocturnal hypoxemia (any sleep time with arterial oxygen saturation &lt;80%), apnea–hypopnea index ( AHI ), and arousal index. Cognitive outcomes were measured using the modified Mini‐Mental State Examination (3 MS ), Trail‐Making Test Part B ( TMT ‐B), and the Digit Vigilance Test ( DVT ). Results Analyses adjusted for age, race, education, body mass index, lifestyle, comorbidities, and medication use showed that participants who spent less percentage of time in rapid eye movement ( REM ) sleep had lower levels of cognition; participants in the lowest quartile (&lt;14.8%) took an average of 5.9 seconds longer on the TMT ‐B and 20.1 seconds longer on the DVT than those in the highest quartile (≥23.7%). Similarly, greater percentage of time spent in Stage 1 sleep was related to poorer cognitive function. Participants in the highest quartile of Stage 1 sleep (≥8.6%) had worse cognitive scores on average than those in the lowest quartile (&lt;4.0%). Those with nocturnal hypoxemia took an average of 22.3 seconds longer to complete the DVT than those without, but no associations were found with 3 MS or the TMT ‐B. Conclusion Spending less percentage of time in REM sleep and greater percentage of time in Stage 1 sleep and having higher levels of nocturnal hypoxemia were associated with poorer cognition in older men. Further studies are needed to clarify the direction of these associations and to explore potential mechanisms.

Identifying factors associated with functional declines in older adults is important given the aging of the population. We investigated if hearing impairment is independently associated with objectively measured declines in physical functioning in a community-based sample of older adults.Prospective observational study of 2,190 individuals from the Health, Aging, and Body Composition study. Participants were followed annually for up to 11 visits. Hearing was measured with pure-tone audiometry. Physical functioning and gait speed were measured with the Short Physical Performance Battery (SPPB). Incident disability and requirement for nursing care were assessed semiannually through self-report.In a mixed-effects model, greater hearing impairment was associated with poorer physical functioning. At both Visit 1 and Visit 11, SPPB scores were lower in individuals with mild (10.14 [95% CI 10.04-10.25], p < .01; 7.35 [95% CI 7.12-7.58], p < .05) and moderate or greater hearing impairment (10.04 [95% CI 9.90-10.19], p < .01; 7.00 [95% CI 6.69-7.32], p < .01) than scores in normal hearing individuals (10.36 [95% CI 10.26-10.46]; 7.71 [95% CI 7.49-7.92]). We observed that women with moderate or greater hearing impairment had a 31% increased risk of incident disability (Hazard ratio [HR] =1.31 [95% CI 1.08-1.60], p < .01) and a 31% increased risk of incident nursing care requirement (HR = 1.31 [95% CI 1.05-1.62], p = .02) compared to women with normal hearing.Hearing impairment is independently associated with poorer objective physical functioning in older adults, and a 31% increased risk for incident disability and need for nursing care in women.