Karla Lindquist

Inflammatory markers and cognition in well-functioning African-American and white elders

Background: Several lines of evidence suggest that inflammatory mechanisms contribute to AD. Objective: To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders. Methods: 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-α (TNFα) 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. Results: 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 ≤ 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 TNFα (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. Conclusions: 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.

Posttraumatic Stress Disorder and Risk of Dementia Among US Veterans

CONTEXT Posttraumatic stress disorder (PTSD) is highly prevalent among US veterans because of combat and may impair cognition. OBJECTIVE To determine whether PTSD is associated with the risk of developing dementia among older US veterans receiving treatment in the Department of Veterans Affairs medical centers. DESIGN A stratified, retrospective cohort study conducted using the Department of Veterans Affairs National Patient Care Database. SETTING Department of Veterans Affairs medical centers in the United States. PARTICIPANTS A total of 181 093 veterans 55 years or older without dementia from fiscal years 1997 through 2000 (53 155 veterans with and 127 938 veterans without PTSD). MAIN OUTCOME MEASURES During the follow-up period between October 1, 2000, and December 31, 2007, 31 107 (17.2%) veterans were ascertained to have newly diagnosed dementia according to International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS The mean baseline age of the veterans was 68.8 years, and 174 806 (96.5%) were men. Veterans with PTSD had a 7-year cumulative incident dementia rate of 10.6%, whereas those without had a rate of 6.6% (P < .001). With age as the time scale, Cox proportional hazards models indicated that patients with PTSD were more than twice as likely to develop incident dementia compared with those without PTSD (hazard ratio, 2.31; 95% confidence interval, 2.24-2.39). After multivariable adjustment, patients with PTSD were still more likely to develop dementia (hazard ratio, 1.77; 95% confidence interval, 1.70-1.85). Results were similar when we excluded those with a history of head injury, substance abuse, or clinical depression. CONCLUSIONS In a predominantly male veteran cohort, those diagnosed as having PTSD were at a nearly 2-fold-higher risk of developing dementia compared with those without PTSD. Mechanisms linking these important disorders need to be identified with the hope of finding ways to reduce the increased risk of dementia associated with PTSD.

Predictors of maintaining cognitive function in older adults: The Health ABC Study

Background: 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. Methods: 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 ≥0), minor decliners (slope <0 and >1 SD below mean), or major decliners (slope ≤1 SD below mean). Logistic regression was used to identify domain-specific factors associated with being a maintainer vs a minor decliner. Results: 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. Conclusion: 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.

Subtype of mild cognitive impairment and progression to dementia and death.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Development and Validation of a Functional Morbidity Index to Predict Mortality in Community-dwelling Elders

AbstractOBJECTIVE: Functional measures have a great appeal for prognostic instruments because they are associated with mortality, they represent the end-impact of disease on the patient, and information about them can be obtained directly from the patient. However, there are no prognostic indices that have been developed for community-dwelling elders based primarily on functional measures. Our objective in this study was to develop and validate a prognostic index for 2-year mortality in community-dwelling elders, based on self-reported functional status, age, and gender. DESIGN: Population-based cohort study from 1993 to 1995. SETTING: Community-dwelling elders within the United States. PARTICIPANTS: Subjects, age ≥70 (N=7,393), from the Asset and Health Dynamics Among the Oldest Old study. We developed the index in 4,516 participants (mean age 78, 84% white, 61% female), and validated it in 2,877 different participants (mean age 78, 73% white, 61% female). MAIN OUTCOME MEASURES: Prediction of 2-year mortality using risk factors such as activities of daily living, instrumental activities of daily living, additional measures of physical function, age, and gender. RESULTS: Overall mortality was 10% in the development cohort and 12% in the validation cohort. In the development cohort, 6 independent predictors of mortality were identified and weighted, using logistic regression models, to create a point scale: male gender, 2 points; age (76 to 80, 1 point;>80, 2 points); dependence in bathing, 1 point; dependence in shopping, 2 points; difficulty walking several blocks, 2 points; and difficulty pulling or pushing heavy objects, 1 point. We calculated risk scores for each patient by adding the points of each independent risk factor present. In the development cohort, 2-year mortality was 3% in the lowest risk group (0 to 2 points), 11% in the middle risk group (3 to 6 points), and 34% in the highest risk group (>7 points). In the validation cohort, 2-year mortality was 5% in the lowest risk group, 12% in the middle risk group, and 36% in the highest risk group. The c-statistics for the point system were 0.76 and 0.74 in the development and validation cohorts, respectively. CONCLUSIONS: This prognostic index, which relies solely on self-reported functional status, age, and gender, provides a simple and accurate method of stratifying community-dwelling elders into groups at varying risk of mortality.

Use of a Modified Informed Consent Process among Vulnerable Patients: A Descriptive Study

BACKGROUND: Little is known about patient characteristics associated with comprehension of consent information, and whether modifications to the consent process can promote understanding.OBJECTIVE: To describe a modified research consent process, and determine whether literacy and demographic characteristics are associated with understanding consent information.DESIGN: Descriptive study of a modified consent process: consent form (written at a sixth-grade level) read to participants, combined with 7 comprehension questions and targeted education, repeated until comprehension achieved (teach-to-goal).PARTICIPANTS: Two hundred and four ethnically diverse subjects, aged ≥50, consenting for a trial to improve the forms used for advance directives.MEASUREMENTS: Number of passes through the consent process required to achieve complete comprehension. Literacy assessed in English and Spanish with the Short Form Test of Functional Health Literacy in Adults (scores 0 to 36).RESULTS: Participants had a mean age of 61 years and 40% had limited literacy (s-TOHFLA<23). Only 28% of subjects answered all comprehension questions correctly on the first pass. After adjustment, lower literacy (P=.04) and being black (P=.03) were associated with requiring more passes through the consent process. Not speaking English as a primary language was associated with requiring more passes through the consent process in bivariate analyses (P<.01), but not in multivariable analyses (P>.05). After the second pass, most subjects (80%) answered all questions correctly. With a teach-to-goal strategy, 98% of participants who engaged in the consent process achieved complete comprehension.CONCLUSIONS: Lower literacy and minority status are important determinants of understanding consent information. Using a modified consent process, little additional education was required to achieve complete comprehension, regardless of literacy or language barriers.

Serum leptin level and cognition in the elderly: Findings from the Health ABC Study

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.

Impact of Age and Comorbidity on Colorectal Cancer Screening Among Older Veterans

Context Guidelines increasingly state that screening for cancer should be targeted to people who will live long enough to benefit from it. Content The investigators studied receipt of colorectal cancer screening in 27068 screen-eligible VA patients 70 years or older. Only 47% of patients with no comorbidity (5-year mortality rate, 19%) were screened, whereas 41% with severe comorbidity (5-year mortality rate, 55%) were screened. Rates were somewhat lower for older men but varied only slightly by life expectancy. Caution Some tests may have been done for diagnosis rather than screening. Implication In this population of elderly men, screening did not target healthier patients. The Editors Colorectal cancer screening guidelines recommend screening older adults who have substantial life expectancies according to age and comorbid conditions (1). For example, the U.S. Preventive Services Task Force recommends routine screening until age 75 years, whereas the Veterans Health Administration, the American Cancer Society, and the American Geriatrics Society (25) recommend colorectal cancer screening for older adults unless they are unlikely to live 5 years or have significant comorbid conditions that would preclude treatment. Targeting screening to healthy persons who are likely to live at least 5 years is recommended because randomized trials of fecal occult blood testing (FOBT) suggest that a difference in colorectal cancer mortality between screened and unscreened persons does not become noticeable until at least 5 years after screening (68). Therefore, persons with a life expectancy of 5 years or less are not likely to benefit from screening but remain at risk for harms that may occur immediately, such as complications from procedures and the treatment of clinically unimportant disease (9, 10). However, it remains unclear whether screening is being targeted to healthy older persons with substantial life expectancies and avoided in older persons with significant comorbidity, for whom the risks of screening outweigh the benefits. Previous studies of associations among age, comorbidity, and receipt of cancer screening have found that age is a stronger determinant of screening than comorbidity. For example, whereas advancing age is consistently associated with lower screening rates, worsening comorbidity has had little effect on the use of screening mammography, Papanicolaou smears, or prostate-specific antigen screening (1113). Previous studies of the relationship between colorectal cancer screening and comorbidity have been limited by small sample size, short follow-up times, and focus on FOBT rather than all types of colorectal cancer screening tests (14, 15). In addition, previous Veterans Affairs (VA) studies have not measured colorectal cancer screening performed outside the VA health care system by means of Medicare (1517). Having a better understanding of how comorbidity and age affect overall screening use is particularly important for colorectal cancer screening because the tests and follow-up procedures are often more invasive than those for other types of cancer and may result in substantial harms, such as major bleeding events, colon perforation, or strokeespecially in elderly persons with limited life expectancies (9, 18, 19). To characterize the use of colorectal cancer screening across a prognostic spectrum of advancing age and comorbidity, we examined VA data and Medicare claims for patients 70 years of age or older who were seen at 4 geographically diverse VA facilities. Specifically, we determined 2-year screening incidence and 5-year mortality rate for subgroups of older patients without significant comorbidity for whom guidelines recommend screening, as well as for subgroups of older patients with severe comorbidity for whom most guidelines agree that the risks of screening outweigh the benefits. Methods Data Sources and Patients We identified a cohort of screen-eligible patients on 1 January 2001 and followed them for 2 years for the performance of colorectal cancer screening. We obtained data for this cohort study from National VA Data Systems, clinical data extracted from the electronic record system (Veterans Health Information Systems and Technology Architectures) of 4 VA medical centers (Minneapolis, Minnesota; Durham, North Carolina; Portland, Oregon; and West Los Angeles, California), and Medicare claims. National VA data included the National Patient Care Database (which captures all inpatient and outpatient claims within the VA), Fee Basis Files (which capture claims for non-VA services paid for by the VA), and the Vital Status File (which captures mortality data for veterans) (20). Clinical data extracted from the 4 VA centers included text entered by clinicians in response to computerized clinical reminders about colorectal cancer screening (21). We used linked Medicare claims from the VA Information Resource Center to capture services provided to our cohort outside the VA by Medicare (22). On the basis of these data sources, we identified a cohort of 60933 patients 70 years of age or older who had at least 1 outpatient visit within the VA health care system or Medicare between 1 January 2000 and 31 December 2000 (the period during which we measured comorbidity) and at least 1 outpatient visit at 1 of the 4 VA centers between 1 January 2001 and 31 December 2002 (the period during which we measured the performance of colorectal cancer screening) (Figure 1). We selected the 4 VA centers for geographic diversity. We excluded 11817 (19%) patients who were enrolled in Medicare managed care at any point from 1 January 2000 to 31 December 2002, because they lacked Medicare claims. In addition, patients had to be eligible for screening to be included in our cohort. Therefore, we used VA and Medicare inpatient and outpatient claims from the 8-year period before the start of 2001 (dating back to 1 October 1992 for VA claims and 1 January 1999 for Medicare claims) to exclude 11200 (18%) patients with a history of colorectal cancer, colitis, colorectal polyps, colectomy, or colostomy and 8153 (13%) patients who had any history of a colonoscopy or had had a sigmoidoscopy or barium enema within 5 years and were therefore not due for screening at the start of 2001. We also used claims from the 6 months before their index test to exclude 2695 (4%) of patients who had signs or symptoms that would justify the performance of a test for nonscreening purposes (Figure 1). This left a final screen-eligible cohort of 27068 patients on 1 January 2001. Figure 1. Study flow diagram. Eligibility criteria included having been seen in an outpatient clinic at 1 of 4 Veterans Affairs (VA) centers between 1 January 2001 and 31 December 2002, which indicated that the VA was at least partially responsible for medical care, but data on colorectal cancer screening were gathered during the entire 2-year screening interval from both national VA and Medicare claims. Additional eligibility criteria included having at least 1 outpatient visit between 1 January and 31 December 2000 to define comorbidity as of 1 January 2001. *Defined by searching VA and Medicare inpatient and outpatient claims before 1 January 2001, dating as far back as 1 October 1992 for VA claims and 1 January 1999 for Medicare claims. Data Collection and Measurement Outcome Variables We assessed receipt of colorectal cancer screening between 1 January 2001 and 31 December 2002 for our cohort across the VA health care system and Medicare, because many elderly veterans use more than 1 VA center and most are enrolled in Medicare (23). We identified colorectal cancer screening in National VA Data Systems and linked Medicare payment data (hospital outpatient and physician/supplier files) by using International Classification of Disease, Ninth Revision (ICD-9), codes; Current Procedural Terminology (CPT) codes; and Level II Healthcare Common Procedure Coding System (HCPCS) codes for FOBT (CPT codes 82270, 82273, and 82274 and HCPCS code G0107), colonoscopy (ICD-9 codes 45.22, 45.23, 45.25, 45.41, 45.42, and 45.43; CPT codes 44388 to 44394, 45355, and 45378 to 45385; and HCPCS codes G0105, G0121), sigmoidoscopy (ICD-9 codes 45.24, 48.22 to 48.24, 48.26, 48.35, and 48.36; CPT codes 45300, 45303, 45305, 45308, 45309, 45315, 45320, 45330 to 45334, and 45337 to 45339; and HCPCS code G0104), or barium enema (ICD-9 code 87.64; CPT codes 74270 and 74280; and HCPCS codes G0106, G0120, and G0122) (2427). We assigned patients to 1 of the 4 screening procedures on the basis of their first test during 2001 through 2002. We chose a 2-year screening period to allow sufficient time for screening tests to be scheduled and performed; this is also the screening interval used in randomized trials of FOBT (6, 7). We obtained vital status through 31 December 2005 from the VA Vital Status File to determine 5-year mortality rates. The VA Vital Status File is similar to the National Death Index in terms of accuracy and completeness (28). We used 5-year mortality rates descriptively to identify conditions associated with having a life expectancy less than 5 years (5-year mortality rate >50%). Predictor Variables We assigned patients to 1 of 3 categories on the basis of their age on 1 January 2001: 70 to 74 years, 75 to 79 years, or 80 years or older. We defined the burden of comorbidity by using the Deyo adaptation of the Charlson Comorbidity Index (2931), a summary measure of 19 chronic disease diagnoses from administrative data that are selected and weighted according to their association with mortality. We calculated CharlsonDeyo scores from VA and Medicare inpatient and outpatient claims during the 12 months before the start of 2001 (3234). We categorized patients as having no significant comorbidity if they had a CharlsonDeyo score of 0, average comorbidity if they had a CharlsonDeyo score of 1 to 3, and severe comorbidity if they had a CharlsonDeyo score of 4 or greater. We chose th

Pain, Functional Limitations, and Aging

OBJECTIVES: To examine the relationship between functional limitations and pain across a spectrum of age, ranging from mid life to advanced old age.

Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort

BACKGROUND Older women treated with conjugated estrogens may have an increased risk of dementia, but the effect of naturally occurring sex hormones on cognition is not certain. METHODS Bioavailable estradiol and free testosterone level were obtained from 792 (55% men, 51% black) participants. We assessed cognition with the Modified Mini-Mental State Examination (3MS), Selective Reminding Test (SRT) and CLOX 1 at baseline and 2 years later. RESULTS Women in the lowest estradiol tertile were more likely than those in the highest tertile to decline (> or = 1.0 S.D. of change) on 3MS (25% versus 9%, adjusted odds ratio [OR] = 3.9; 95% confidence interval [CI] = 1.6-9.6) and on SRT (28% versus 12%, adjusted OR [95% CI] = 3.3 [1.4-7.9]) but not CLOX 1. There was a borderline association between low estradiol tertile and decline on SRT in men (22% versus 14%, adjusted OR [95% CI] = 1.9 [0.9-3.9]). Testosterone level was not associated with decline in cognition in either men or women. Findings did not differ by race. CONCLUSIONS Older women with low estradiol levels were more likely to experience decline in global cognitive function and verbal memory, and a similar trend was observed for verbal memory in men. This supports the hypothesis that endogenous sex hormones may play an important role in the maintenance of cognitive function in older adults.