Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Premature or early bilateral oophorectomy: a 2021 update.

In this invited review, we discuss some unresolved and controversial issues concerning premature (<40 years) or early (40-45 years) bilateral oophorectomy. First, we clarify the terminology. Second, we summarize the long-term harmful consequences of bilateral oophorectomy. Third, we discuss the restrictive indications for bilateral oophorectomy in premenopausal women to prevent ovarian cancer that are justified by the current scientific evidence. Fourth, we explain the importance of estrogen replacement therapy when bilateral oophorectomy is performed. Hormone replacement therapy is indicated after bilateral oophorectomy until the age of expected natural menopause like in premature or early primary ovarian insufficiency. Fifth, we discuss the relationship between adverse childhood experiences, adverse adult experiences, mental health, gynecologic symptoms and bilateral oophorectomy. The acceptance and popularity of bilateral oophorectomy over several decades, and its persistence even in the absence of supporting scientific evidence, suggest that non-medical factors related to sex, gender, reproduction, cultural beliefs and socioeconomic structure are involved. We discuss some of these non-medical factors and the need for more research in this area.

Longitudinal Comparison of in Clinic and at Home Administration of the Cogstate Brief Battery and Demonstrated Practice Effects in the Mayo Clinic Study of Aging.

BACKGROUND: The Cogstate Brief Battery (CBB) is a computerized cognitive assessment that can be completed in clinic or at home. Design/Objective: This retrospective study investigated whether practice effects / performance trajectories of the CBB differ by location of administration. PARTICIPANTS/SETTING: Participants included 1439 cognitively unimpaired individuals age 50-75 at baseline participating in the Mayo Clinic Study of Aging (MCSA), a population-based study of cognitive aging. Sixty three percent of participants completed the CBB in clinic only and 37% completed CBB both in clinic and at home. MEASUREMENTS: The CBB consists of four subtests: Detection, Identification, One Card Learning, and One Back. Linear mixed effects models were used to evaluate performance trajectories in clinic and at home. RESULTS: Results demonstrated significant practice effects between sessions 1 to 2 for most CBB measures. Practice effects continued over subsequent testing sessions, to a lesser degree. Average practice effects/trajectories were similar for each location (home vs. clinic). One Card Learning and One Back accuracy performances were lower at home than in clinic, and this difference was large in magnitude for One Card Learning accuracy. Participants performed faster at home on Detection reaction time, although this difference was small in magnitude. CONCLUSIONS: Results suggest the location where the CBB is completed has an important impact on performance, particularly for One Card Learning accuracy, and there are practice effects across repeated sessions that are similar regardless of where testing is completed.

The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.

The 32-year relationship between cholesterol and dementia from midlife to late life.

BACKGROUND: Cellular and animal studies suggest that hypercholesterolemia contributes to Alzheimer disease (AD). However, the relationship between cholesterol and dementia at the population level is less clear and may vary over the lifespan. METHODS: The Prospective Population Study of Women, consisting of 1,462 women without dementia aged 38-60 years, was initiated in 1968-1969 in Gothenburg, Sweden. Follow-ups were conducted in 1974-1975, 1980-1981, 1992-1993, and 2000-2001. All-cause dementia was diagnosed according to DSM-III-R criteria and AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Cox proportional hazards regression examined baseline, time-dependent, and change in cholesterol levels in relation to incident dementia and AD among all participants. Analyses were repeated among participants who survived to the age of 70 years or older and participated in the 2000-2001 examination. RESULTS: Higher cholesterol level in 1968 was not associated with an increased risk of AD (highest vs lowest quartile: hazard ratio [HR] 2.82, 95% confidence interval [CI] 0.94-8.43) among those who survived to and participated in the 2000-2001 examination. While there was no association between cholesterol level and dementia when considering all participants over 32 years, a time-dependent decrease in cholesterol over the follow-up was associated with an increased risk of dementia (HR 2.35, 95% CI 1.22-4.58). CONCLUSION: These data suggest that midlife cholesterol level is not associated with an increased risk of AD. However, there may be a slight risk among those surviving to an age at risk for dementia. Declining cholesterol levels from midlife to late life may better predict AD risk than levels obtained at one timepoint prior to dementia onset. Analytic strategies examining this and other risk factors across the lifespan may affect interpretation of results.

Adiposity indicators and dementia over 32 years in Sweden.

BACKGROUND: High midlife and late-life adiposity may increase risk for dementia. Late-life decrease in body mass index (BMI) or body weight within several years of a dementia diagnosis has also been reported. Differences in study designs and analyses may provide different pictures of this relationship. METHODS: Thirty-two years of longitudinal body weight, BMI, waist circumference, and waist-to-hip ratio (WHR) data, from the Prospective Population Study of Women in Sweden, were related to dementia. A representative sample of 1,462 nondemented women was followed from 1968 at ages 38-60 years, and subsequently in 1974, 1980, 1992, and 2000, using neuropsychiatric, anthropometric, clinical, and other measurements. Cox proportional hazards regression models estimated incident dementia risk by baseline factors. Logistic regression models including measures at each examination were related to dementia among surviving participants 32 years later. RESULTS: While Cox models showed no association between baseline anthropometric factors and dementia risk, logistic models showed that a midlife WHR greater than 0.80 increased risk for dementia approximately twofold (odds ratio 2.22, 95% confidence interval 1.00-4.94, p = 0.049) among surviving participants. Evidence for reverse causality was observed for body weight, BMI, and waist circumference in years preceding dementia diagnosis. CONCLUSIONS: Among survivors to age 70, high midlife waist-to-hip ratio may increase odds of dementia. Traditional Cox models do not evidence this relationship. Changing anthropometric parameters in years preceding dementia onset indicate the dynamic nature of this seemingly simple relationship. There are midlife and late-life implications for dementia prevention, and analytical considerations related to identifying risk factors for dementia.

Regionally-specific diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Diffusion tensor imaging (DTI) studies have shown significant cross-sectional differences among normal controls (NC) mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients in several fiber tracts in the brain, but longitudinal assessment is needed. METHODS: We studied 75 participants (25 NC, 25 amnestic MCI, and 25 mild AD) at baseline and 3 months later, with both imaging and clinical evaluations. Fractional anisotropy (FA) was analyzed in regions of interest (ROIs) in: (1) fornix, (2) cingulum bundle, (3) splenium, and (4) cerebral peduncles. Clinical data included assessments of clinical severity and cognitive function. Cross-sectional and longitudinal differences in FA, within each ROI, were analyzed with generalized estimating equations (GEE). RESULTS: Cross-sectionally, AD patients had lower FA than NC (p<0.05) at baseline and 3 months in the fornix and anterior portion of the cingulum bundle. Compared to MCI, AD cases had lower FA (p<0.05) in these regions and the splenium at 0 and 3 months. Both the fornix and anterior cingulum correlated across all clinical cognitive scores; lower FA in these ROIs corresponded to worse performance. Over the course of 3 months, when the subjects were clinically stable, the ROIs were also largely stable. CONCLUSIONS: Using DTI, findings indicate FA is decreased in specific fiber tracts among groups of subjects that vary along the spectrum from normal to AD, and that this measure is stable over short periods of time. The fornix is a predominant outflow tract of the hippocampus and may be an important indicator of AD progression.

Effects of cardiovascular medications on rate of functional decline in Alzheimer disease.

BACKGROUND: Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD. METHODS: In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors. RESULTS: CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline. CONCLUSIONS: In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

Vascular factors predict rate of progression in Alzheimer disease.

BACKGROUND: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. OBJECTIVE: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. METHODS: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. RESULTS: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. CONCLUSION: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age.

High total cholesterol levels in late life associated with a reduced risk of dementia.

OBJECTIVE: To examine the longitudinal association between plasma total cholesterol and triglyceride levels and incident dementia. METHODS: Neuropsychiatric, anthropometric, laboratory, and other assessments were conducted for 392 participants of a 1901 to 1902 birth cohort first examined at age 70. Follow-up examinations were at ages 75, 79, 81, 83, 85, and 88. Information on those lost to follow-up was collected from case records, hospital linkage system, and death certificates. Cox proportional hazards regression examined lipid levels at ages 70, 75, and 79 and incident dementia between ages 70 and 88. RESULTS: Increasing cholesterol levels (per mmol/L) at ages 70 (hazard ratio [HR] 0.77, 95% CI: 0.61 to 0.96, p = 0.02), 75 (HR 0.70, CI: 0.52 to 0.93, p = 0.01), and 79 (HR 0.73, CI: 0.55 to 0.98, p = 0.04) were associated with a reduced risk of dementia between ages 79 and 88. Examination of cholesterol levels in quartiles showed that the risk reduction was apparent only among the highest quartile at ages 70 (8.03 to 11.44 mmol/L [311 to 442 mg/dL]; HR 0.31, CI: 0.11 to 0.85, p = 0.03), 75 (7.03 to 9.29 mmol/L [272 to 359 mg/dL]; HR 0.20, CI: 0.05 to 0.75, p = 0.02), and 79 (6.82 to 9.10 mmol/L [264 to 352 mg/dL]; HR 0.45, CI: 0.17 to 1.23, p = 0.12). Triglyceride levels were not associated with dementia. CONCLUSIONS: High cholesterol in late life was associated with decreased dementia risk, which is in contrast to previous studies suggesting high cholesterol in mid-life is a risk factor for later dementia. The conflicting results may be explained by the timing of the cholesterol measurements in relationship to age and the clinical onset of dementia.

Strike while the iron is hot: can stepped-care treatments resurrect relapsing smokers?

The efficacies of 2 group counseling step-up treatments for smoking cessation, cognitive-behavioral/skill training therapy (CBT) and motivational interviewing/supportive (MIS) therapy, were compared with brief intervention (BI) treatment in a sample of 677 smokers. Differential efficacy of the 2 step-up treatments was also tested in smokers at low and high risk for relapse (no smoking vs. any smoking during the first postquit week. respectively). All participants received 8 weeks of nicotine patch therapy. BI consisted of 3 brief individual cessation counseling sessions; CBT and MIS participants received BI treatment and 6 group counseling sessions. Neither CBT nor MIS treatment improved long-term abstinence rates relative to BI. Limited support was found for the hypothesis that high-risk smokers would benefit more from MIS than CBT. Other hypotheses were not supported.

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding.

RATIONALE: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. OBJECTIVE: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? METHODS: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. RESULTS: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. CONCLUSIONS: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.

Differential effects of response-contingent and response-independent nicotine in rats.

Passive administration of nicotine activates the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system. However, little is known about the effects of self-administered nicotine. Drug-naive rats were trained to respond for food reinforcement and then tested in one, 1-h session in which they received response-contingent i.v. nicotine or response-independent i.v. nicotine or saline. Blood draws were taken immediately prior to the session, 15 min after the first infusion and immediately after the session. Both response-contingent and response-independent nicotine (RI/N) increased corticosterone within 15 min, however, corticosterone levels returned to baseline in animals receiving response-contingent nicotine (RC/N) by the end of the session while remaining elevated in those receiving RI/N. Furthermore, only RI/N increased plasma epinephrine and norepinephrine levels; RC/N produced no effect. These differences indicate that nicotine's acute effects are powerfully modified by the presence of a contingency relationship between drug administration and the animal's behavior and that this relationship develops very rapidly.

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.

RATIONALE: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. OBJECTIVE: Here, we attempt to establish and characterize nicotine SA on a PR. METHODS: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0. 09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. RESULTS: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. CONCLUSIONS: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement.

Acquisition of nicotine self-administration in rats: the effects of dose, feeding schedule, and drug contingency.

The studies presented here were designed to further clarify the nature of nicotine self-administration (SA) based on a limited access model in which rats are food restricted, receive operant training using food reinforcement, and are then tested in daily 1-h drug sessions. We examined the effects of dose, feeding schedule, and contingency of drug delivery on acquisition of nicotine SA. Two doses of nicotine bitartrate, 0.03 and 0.06 mg/kg per infusion (free base), supported the transition from food-reinforced to drug-reinforced responding, although the pattern of behavior differed between these doses. In contrast, 0.01 mg/kg per infusion failed to maintain nicotine SA. In a second study, animals were divided into three groups according to feeding schedule. Rats that were both weight restricted and food deprived showed the highest level of SA behavior, although neither food deprivation nor weight restriction was necessary to establish SA. In the third experiment, rats that were switched from food to nicotine as the response-dependent reinforcer maintained higher response rates throughout a 9-day period than animals switched to response-independent (i.e., yoked) nicotine which showed minimal responding after day 1. Furthermore, the differences between self-administering and yoked animals emerged during the first session, suggesting that nicotine may serve as a reinforcer during the first drug exposure in naive animals. These results indicate that acquisition of nicotine SA can be influenced by both dose of nicotine and feeding schedule and that, in animals previously trained on a food-reinforced operant, active lever pressing is maintained only when nicotine delivery is contingent upon responding.