Paul K. Crane

Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older

Context Some studies suggest that people with high levels of physical activity are less likely to develop dementia. Content All 1740 participants in this cohort study were 65 years of age or older and were cognitively intact at baseline. Over 6.2 years, the rate of dementia was 13.0 per 1000 person-years in those who exercised 3 or more times per week and 19.7 per 1000 person-years in those who exercised less than 3 times per week. Limitations The only measure of exercise intensity was self-reported frequency. The cohort was largely white and well-educated. Implications This study adds to the evidence that regular exercise is associated with a lower risk for dementia. However, the existing evidence does not prove that regular exercise is associated with a lower dementia risk. The Editors Alzheimer disease and other dementing illnesses are major sources of morbidity and mortality (1-3) that affect millions of persons in the increasingly aging society of the United States. Research designed to discover strategies to delay onset and progression of these potentially devastating illnesses is ongoing worldwide. Effective prevention strategies would result in substantial benefits through improved quality of life, prolonged independent life expectancy, and reduced economic cost and social burdens. Regular physical exercise is an important element in overall health promotion (4) and might also be an effective strategy to delay onset of dementia (5). A biological basis for how physical exercise might preserve brain function includes improved cerebral blood flow and oxygen delivery (6) and inducing fibroblast growth factor in the hippocampus (7). More recent evidence suggests that reduced loss of hippocampal brain tissue in the aging brain is related to level of physical fitness (8). Evidence from some longitudinal studies and randomized trials suggests that physical exercise enhances cognitive function in older adults (9-15), whereas other studies have failed to observe the benefits of physical exercise in preserving cognitive function (16-19). Many people regard Alzheimer disease as one of the most dreaded consequences of aging. If regular physical exercise were shown to be effective in reducing the risk or delaying the onset of dementing illnesses, it would be another compelling reason to promote physical exercise. Few population-based longitudinal studies have examined the role of physical exercise on the risk for dementia in elderly persons. One recent longitudinal study showed that physical exercise was associated with decreased risk for decline in cognitive function (odds ratio [OR], 0.58), Alzheimer disease (OR, 0.50), and any dementia (OR, 0.63) (11), whereas another longitudinal study showed no association between physical exercise and dementia (16). More recent studies showed that walking was associated with a reduced risk for dementia and Alzheimer disease in a cohort of Japanese-American men (20) and that engaging in more diverse physical activities was associated with a reduced risk for dementia in the Cardiovascular Health Study (21). The purpose of this study was 2-fold: 1) to determine whether regular exercise is associated with a reduced risk for incidence of dementia (in particular, Alzheimer disease) in a cohort followed biennially over 6 years and 2) to examine whether the association of physical exercise with incident dementia is modulated by other potential risk factors, such as depression, cardiovascular and cerebrovascular disease, diabetes, apolipoprotein E 4 allele, cognitive function, physical function, self-rated health, and lifestyle characteristics. Methods Study Sample The Adult Changes in Thought (ACT) study is a population-based, longitudinal study of aging and dementia. The ACT study was designed to determine the incidence of Alzheimer disease, other types of dementia, and cognitive impairment as well as to determine risk factors for these conditions. The details of the ACT study have been described elsewhere (22, 23). Briefly, a random sample of 6782 individuals was drawn from Seattle-area members of Group Health Cooperative (GHC), a consumer-governed health maintenance organization. The participants were 65 years of age and older when the study began in 1994 to 1996. Those who had an existing diagnosis of dementia, were current residents of a nursing home, or were participating in other studies were ineligible (n= 1360). Of 5422 eligible persons, 2581 participated and 2841 declined participation. Age, sex, and ethnicity of the remaining 2581 participants did not differ significantly from those who were excluded. Nonresponse has been described elsewhere (22). Declining to participate was more common among the oldest age group (>85 years), women, and African-American and minority groups (22). Additional details regarding the incident rates of dementia and Alzheimer disease from the ACT study have been published elsewhere and are consistent with rates reported in U.S. and European cohort studies (22). The institutional review boards of the University of Washington and Group Health Cooperative approved the ACT study. Participants received the Cognitive Ability Screening Instrument (CASI) (24) as initial screening for cognitive function and were interviewed with structured questionnaires to obtain data, including demographic characteristics, medical history, memory and general functioning, and potential epidemiologic risk factors. Persons scoring 86 or higher on the CASI were entered directly into the ACT cohort as being cognitively intact. (The CASI scores range from 0 to 100; a score of 86 corresponds to a Mini-Mental State Examination score of 25 to 26.) Persons with a score lower than 86 had additional medical record review and standardized clinical and neuropsychological evaluation for dementia. Persons who did not meet established criteria for dementia (25) were included in the ACT cohort. The current study sample was selected from the 2581 ACT participants to examine the temporal relationship of physical exercise preceding development of dementia. By design, we selected the 1895 persons whose CASI scores were above the 25th percentileCASI scores 91 to 100. We excluded 686 persons whose CASI scores were in the lowest quartileCASI scores 62 to 90because the lowest quartile group might include persons who had mild cognitive impairment or impending dementia (26). We did not collect information about the history of exercise before the participants entered the study. Therefore, in the group with low CASI scores, we could not be certain whether a reported low level of physical exercise preceded the development of dementia or was a consequence of the development of cognitive impairment or dementia. Of 1895 participants selected, 155 withdrew after the baseline visit and did not have a follow-up examination and were thus excluded from the analyses, leaving the analytic sample of 1740 persons. Incident Dementia We conducted biennial examinations to identify cases of incident dementia, when participants were rescreened with the CASI. Those who scored 86 or higher on the CASI remained in the ACT cohort. Scores on the CASI that were less than 86 at follow-up prompted a full standardized clinical examination. The results of rescreening by the CASI and by the clinical and neuropsychological examinations were reviewed at a consensus diagnosis conference that included at least the examining physician, a neuropsychologist, another study physician, and the study nurse. Persons who did not meet the criteria for dementia were considered as not having dementia and were followed in the ACT cohort (22, 23). Persons who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria (25) for dementia were considered to have incident dementia. Dementia type was determined by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimers Disease and Related Disorders Association (NINCDS-ADRDA) criteria (27) for Alzheimer disease and by the DSM-IV criteria (25) for other types of dementia. Level of physical activity was not considered at the consensus conference. Physical Exercise Physical exercise was assessed at baseline by asking participants the number of days per week they did each of the following activities for at least 15 minutes at a time during the past year: walking, hiking, bicycling, aerobics or calisthenics, swimming, water aerobics, weight training or stretching, or other exercise. The frequency of exercise was calculated by the times per week that participants engaged in any of these forms of exercise. In this study, persons who exercised at least 3 times a week, above the lowest quartile, were classified as exercising regularly. Baseline Variables as Potential Confounders Numerous factors may influence the relationship between exercise and risk for dementia, including physical functioning, cognitive function, depression, health conditions, and lifestyle characteristics. Physical function was assessed by a performance-based physical function (PPF) test (23), which consisted of 4 performance tests: 10-foot timed walk, time to stand from a seated position in a chair to a standing position 5 times, balance test, and grip strength in the dominant hand. Each test was scored from 0 to 4 points. The final PPF score was the sum of the scores for the 4 performance tests and ranged from 0 to 16; higher scores indicated better physical function. Details of the PPF test have been reported elsewhere (23). Cognitive function was assessed by using the CASI, which provides quantitative assessment of attention, concentration, orientation, short-term memory, long-term memory, language ability, visual construction, list-generating fluency, abstraction, and judgment (24). At baseline, depression was measured by using the 11-item Center for Epidemiologic Studies Depression (CES-D) scale (28). The CES-D scores ranged from 0 to 33, with higher scores represe

Chronic spinal pain and physical-mental comorbidity in the United States: Results from the national comorbidity survey replication

This paper investigates comorbidity between chronic back and neck pain and other physical and mental disorders in the US population, and assesses the contributions of chronic spinal pain and comorbid conditions to role disability. A probability sample of US adults (n=5692) was interviewed. Chronic spinal pain, other chronic pain conditions and selected chronic physical conditions were ascertained by self‐report. Mood, anxiety and substance use disorders were ascertained with the Composite International Diagnostic Interview (CIDI). Role disability was assessed with questions about days out of role and with impaired role functioning. The 1 year prevalence of chronic spinal pain was 19.0%. The vast majority (87.1%) of people with chronic spinal pain reported at least one other comorbid condition, including other chronic pain conditions (68.6%), chronic physical conditions (55.3%), and mental disorders (35.0%). Anxiety disorders showed as strong an association with chronic spinal pain as did mood disorders. Common conditions not significantly comorbid with chronic spinal pain were diabetes, heart disease, cancer, and drug abuse. Chronic spinal pain was significantly associated with role disability after controlling for demographic variables and for comorbidities. However, comorbid conditions explained about one‐third of the gross association of chronic spinal pain with role disability. We conclude that chronic spinal pain is highly comorbid with other pain conditions, chronic diseases, and mental disorders, and that comorbidity plays a significant role in role disability associated with chronic spinal pain. The societal burdens of chronic spinal pain need to be understood and managed within the context of comorbid conditions.

Glucose Levels and Risk of Dementia

BACKGROUND Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes. METHODS We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension. RESULTS During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P=0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P=0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76). CONCLUSIONS Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)

Pathological Correlates of Dementia in a Longitudinal, Population-Based Sample of Aging

Previously published community‐ or population‐based studies of brain aging and dementia with autopsy were restricted to a single sex, a single ethnic group, Roman Catholic clergy, or focused pathological assessments. Our goal was to determine the independent pathological correlates associated with dementia in a typical US population.

Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data

Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.

Association Between Acute Care and Critical Illness Hospitalization and Cognitive Function in Older Adults

CONTEXT Studies suggest that many survivors of critical illness experience long-term cognitive impairment but have not included premorbid measures of cognitive functioning and have not evaluated risk for dementia associated with critical illness. OBJECTIVES To determine whether decline in cognitive function was greater among older individuals who experienced acute care or critical illness hospitalizations relative to those not hospitalized and to determine whether the risk for incident dementia differed by these exposures. DESIGN, SETTING, AND PARTICIPANTS Analysis of data from a prospective cohort study from 1994 through 2007 comprising 2929 individuals 65 years old and older without dementia at baseline residing in the community in the Seattle area and belonging to the Group Health Cooperative. Participants with 2 or more study visits were included, and those who had a hospitalization for a diagnosis of primary brain injury were censored at the time of hospitalization. Individuals were screened with the Cognitive Abilities Screening Instrument (CASI) (score range, 0-100) every 2 years at follow-up visits, and those with a score less than 86 underwent a clinical examination for dementia. MAIN OUTCOME MEASURES Score on the CASI at follow-up study visits and incident dementia diagnosed in study participants, adjusted for baseline cognitive scores, age, and other risk factors. RESULTS During a mean (SD) follow-up of 6.1 (3.2) years, 1601 participants had no hospitalization, 1287 had 1 or more noncritical illness hospitalizations, and 41 had 1 or more critical illness hospitalizations. The CASI score was assessed more than 45 days after discharge for 94.3% of participants. Adjusted CASI scores averaged 1.01 points lower for visits following acute care illness hospitalization compared with follow-up visits not following any hospitalization (95% confidence interval [CI], -1.33 to -0.70; P < .001) and 2.14 points lower on average for visits following critical illness hospitalization (95% CI, -4.24 to -0.03; P = .047). There were 146 cases of dementia among those not hospitalized, 228 cases of dementia among those with 1 or more noncritical illness hospitalizations, and 5 cases of dementia among those with 1 or more critical illness hospitalizations. The adjusted hazard ratio for incident dementia was 1.4 following a noncritical illness hospitalization (95% CI, 1.1 to 1.7; P = .001) and 2.3 following a critical illness hospitalization (95% CI, 0.9 to 5.7; P = .09). CONCLUSIONS Among a cohort of older adults without dementia at baseline, those who experienced acute care hospitalization and critical illness hospitalization had a greater likelihood of cognitive decline compared with those who had no hospitalization. Noncritical illness hospitalization was significantly associated with the development of dementia.

Electronic Medical Records for Genetic Research: Results of the eMERGE Consortium

Clinical data captured in electronic medical records accurately identify cases and controls for genome-wide association studies. Where Electronic Records and Genomics Meet There has been a surge of interest in using electronic medical records in hospitals and clinics to capture information about patients that is normally buried in doctors’ handwritten notes. Indeed, the U.S. government has made the implementation of electronic medical records a priority area and has instigated standards for the recording and use of these records. The clinical data captured in electronic medical records including diagnoses, medical tests, and medications provide accurate clinical information that will improve patient care. With the ability to sequence the genomes of individuals faster and cheaper than ever before, it may be possible in the future to include the genome sequences of patients in their electronic medical records. A consortium called the Electronic Medical Records and Genomics Network (eMERGE) has set out to investigate whether clinical data captured in electronic medical records could be used to accurately identify patients with particular diseases for inclusion in genome-wide association studies (GWAS). GWAS scrutinize the genomes of individuals with particular diseases to identify tiny genetic variations that are associated with the risk of developing that disease. Here, the eMERGE consortium reports its study of the electronic medical records from five clinical centers and how accurately it identified patients with one of five diseases: dementia, cataracts, peripheral arterial disease, type 2 diabetes, and cardiac conduction defects. The investigators show that even though the electronic medical records were of different types and did not all use natural language processing to extract information from the records, they were able to obtain robust positive and negative values for identifying patients with these diseases with sufficient accuracy for use in GWAS. They conclude that widespread adoption of electronic medical records will provide real-world clinical data that will be valuable for GWAS and other types of genetic research. Clinical data in electronic medical records (EMRs) are a potential source of longitudinal clinical data for research. The Electronic Medical Records and Genomics Network (eMERGE) investigates whether data captured through routine clinical care using EMRs can identify disease phenotypes with sufficient positive and negative predictive values for use in genome-wide association studies (GWAS). Using data from five different sets of EMRs, we have identified five disease phenotypes with positive predictive values of 73 to 98% and negative predictive values of 98 to 100%. Most EMRs captured key information (diagnoses, medications, laboratory tests) used to define phenotypes in a structured format. We identified natural language processing as an important tool to improve case identification rates. Efforts and incentives to increase the implementation of interoperable EMRs will markedly improve the availability of clinical data for genomics research.

Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study

IMPORTANCE Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia. OBJECTIVE To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia. DESIGN, SETTING, AND PARTICIPANTS Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses. EXPOSURES Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time. MAIN OUTCOMES AND MEASURES Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities. RESULTS The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses. CONCLUSIONS AND RELEVANCE Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.

The coming epidemic of obesity in elderly Americans

Objectives: To estimate the prevalence of obesity in elderly Americans in 2010 and to discuss the health and economic implications of these estimates.

Subjective memory deterioration and future dementia in people aged 65 and older

Objectives: To study whether subjective memory deterioration is associated with future dementia in older people.