Showing papers by "Jeff D. Williamson published in 2022"

Association of Intensive vs Standard Blood Pressure Control With Cerebral Blood Flow: Secondary Analysis of the SPRINT MIND Randomized Clinical Trial.

Abstract: Importance Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion. Objective To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF). Design, Setting, and Participants This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure-lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021. Interventions Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg. Main Outcomes and Measures The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF. Results Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, -0.84 [95% CI, -2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05). Conclusions and Relevance Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease. Trial Registration ClinicalTrials.gov Identifier: NCT01206062.

Association of Antihypertensives That Stimulate vs Inhibit Types 2 and 4 Angiotensin II Receptors With Cognitive Impairment

Abstract: Key Points Question Are antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, associated with a lower risk of incident cognitive impairment? Findings In a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), this cohort study of 8685 patients found that prevalent use of medication regimens that contain exclusively angiotensin II receptor type 2 and 4–stimulating antihypertensives was associated with an approximately 25% lower risk of incident amnestic mild cognitive impairment or probable dementia during 4.8 years of follow-up. Meaning These results, if replicated in randomized clinical trials, suggest that certain antihypertensive medications could be used to prevent the development of cognitive decline.

Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease

Abstract: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

Longer-Term All-Cause and Cardiovascular Mortality With Intensive Blood Pressure Control: A Secondary Analysis of a Randomized Clinical Trial.

Abstract: Importance The Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure control reduced cardiovascular morbidity and mortality. However, the legacy effect of intensive treatment is unknown. Objective To evaluate the long-term effects of randomization to intensive treatment with the incidence of cardiovascular and all-cause mortality approximately 4.5 years after the trial ended. Design, Setting, and Participants In this secondary analysis of a multicenter randomized clinical trial, randomization began on November 8, 2010, the trial intervention ended on August 20, 2015, and trial close-out visits occurred through July 2016. Patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke were included from 102 clinic sites in the US and Puerto Rico. Analyses were conducted between October 2021 and February 2022. Interventions Randomization to systolic blood pressure (SBP) goal of less than 120 mm Hg (intensive treatment group; n = 4678) vs less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures Extended observational follow-up for mortality via the US National Death Index from 2016 through 2020. In a subset of 2944 trial participants, outpatient SBP from electronic health records during and after the trial were examined. Results Among 9361 randomized participants, the mean (SD) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a median (IQR) intervention period of 3.3 (2.9-3.9) years, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and all-cause mortality (HR, 0.83; 95% CI, 0.68-1.01). However, at the median (IQR) total follow-up of 8.8 (8.3-9.3) years, there was no longer evidence of benefit for cardiovascular mortality (HR, 1.02; 95% CI, 0.84-1.24) or all-cause mortality (HR, 1.08; 95% CI, 0.94-1.23). In a subgroup of participants, the estimated mean outpatient SBP among participants randomized to intensive treatment increased from 132.8 mm Hg (95% CI, 132.0-133.7) at 5 years to 140.4 mm Hg (95% CI, 137.8-143.0) at 10 years following randomization. Conclusions and Relevance The beneficial effect of intensive treatment on cardiovascular and all-cause mortality did not persist after the trial. Given increasing outpatient SBP levels in participants randomized to intensive treatment following the trial, these results highlight the importance of consistent long-term management of hypertension. Trial Registration ClinicalTrials.gov Identifier: NCT01206062.

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

Abstract: The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.

A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease

Abstract: Alzheimer's disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care.We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called "Alzheimer's Predictive Vector" (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO).The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer's related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype.This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.Alzheimer’s disease is the most common cause of dementia, impacting memory, thinking and behaviour. It can be challenging to diagnose Alzheimer’s disease which can lead to suboptimal patient care. During the development of Alzheimer’s disease the brain shrinks and the cells within it die. One method that can be used to assess brain function is magnetic resonance imaging, which uses magnetic fields and radio waves to produce images of the brain. In this study, we develop a method that uses magnetic resonance imaging data to identify differences in the brain between people with and without Alzheimer’s disease, including before obvious shrinkage of the brain occurs. This method could be used to help diagnose patients with Alzheimer’s Disease.

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

Abstract: Alzheimer's disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer's Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

Dissection of the polygenic architecture of neuronal Aβ production using a large sample of individual iPSC lines derived from Alzheimer’s disease patients

Abstract: Genome-wide association studies have demonstrated that polygenic risks shape Alzheimer’s disease (AD). To elucidate the polygenic architecture of AD phenotypes at a cellular level, we established induced pluripotent stem cells from 102 patients with AD, differentiated them into cortical neurons and conducted a genome-wide analysis of the neuronal production of amyloid β (Aβ). Using such a cellular dissection of polygenicity (CDiP) approach, we identified 24 significant genome-wide loci associated with alterations in Aβ production, including some loci not previously associated with AD, and confirmed the influence of some of the corresponding genes on Aβ levels by the use of small interfering RNA. CDiP genotype sets improved the predictions of amyloid positivity in the brains and cerebrospinal fluid of patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Secondary analyses of exome sequencing data from the Japanese ADNI and the ADNI cohorts focused on the 24 CDiP-derived loci associated with alterations in Aβ led to the identification of rare AD variants in KCNMA1. Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.

Vascular and microstructural markers of cognitive pathology

Abstract: Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension , metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection.

Daily Low-Dose Aspirin and Risk of Serious Falls and Fractures in Healthy Older People: A Substudy of the ASPREE Randomized Clinical Trial.

Abstract: Importance Falls and fractures are frequent and deleterious to the health of older people. Aspirin has been reported to reduce bone fragility and slow bone loss. Objective To determine if daily low-dose aspirin (100 mg) reduces the risk of fractures or serious falls (fall-related hospital presentations) in healthy older men and women. Design, Setting, and Participants This substudy of a double-blind, randomized, placebo-controlled trial studied older adult men and women in 16 major sites across southeastern Australia. The ASPREE-FRACTURE substudy was conducted as part of the Australian component of the ASPREE trial. Between 2010 and 2014 healthy (free of cardiovascular disease, dementia or physical disability), community-dwelling volunteers aged 70 years or older were recruited to participate in the ASPREE trial. Potentially eligible participants were identified by medical practitioners and trial personnel and were then sent a letter of invitation to participate. Interested participants were screened for suitability. Eligible participants with medical practitioner authorization and adherent to a 4-week run-in medication trial were randomized. Data were analyzed from October 17, 2019, to August 31, 2022. Interventions Participants in the intervention group received a daily dose of oral 100 mg enteric-coated (low-dose) aspirin. The control group received a daily identical enteric-coated placebo tablet. Main Outcomes and Measures The primary outcome of ASPREE-FRACTURE was the occurrence of any fracture. The secondary outcome was serious fall resulting in hospital presentation. Results In total, 16 703 people with a median (IQR) age of 74 (72-78) years were recruited, and 9179 (55.0%) were women. There were 8322 intervention participants and 8381 control participants included in the primary and secondary outcome analysis of 2865 fractures and 1688 serious falls over the median follow-up of 4.6 years. While there was no difference in the risk of first fracture between the intervention and control participants (hazard ratio, 0.97; 95% CI, 0.87-1.06; P = .50), aspirin was associated with a higher risk of serious falls (total falls 884 vs 804; incidence rate ratio, 1.17; 95% CI, 1.03-1.33; P = .01). Results remained unchanged in analyses that adjusted for covariates known to influence fracture and fall risk. Conclusions and Relevance In this substudy of a randomized clinical trial, the failure of low-dose aspirin to reduce the risk of fractures while increasing the risk of serious falls adds to evidence that this agent provides little favorable benefit in a healthy, White older adult population. Trial Registration This substudy is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000347561).

Prediction of disability-free survival in healthy older people

Abstract: Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6-77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people.Trial registration Clinicaltrials.gov (NCT01038583).

Can Preferentially Prescribing Angiotensin II Receptor Blockers (ARBs) over Angiotensin-Converting Enzyme Inhibitors (ACEIs) Decrease Dementia Risk and Improve Brain Health Equity?

Abstract: Currently, there are no effective disease-modifying treatments for Alzheimer’s disease and related de-mentias (ADRD) (National Institute on Aging, 2021). In this context, considerable attention has been given to prevention of ADRD. The 2020 report of the Lancet Commission on “Dementia Prevention, Intervention, and Care” estimated that modifying specific risk factors could prevent or delay up to 40% of ADRD globally (Liv-ingston et al., 2020). Hypertension was one of 12 risk factors identified, responsible for an estimated 2% of all ADRD cases globally, and is the only modifiable risk factor for ADRD with randomized trial evidence show-ing lower risk of cognitive impairment by an intervention that improves the risk factor (i.e., blood pressure [BP] lowering) (Livingston et al., 2020; SPRINT MIND Investigators et al., 2019). The Department of Health and Human Services recently added a new goal to its National Plan to Address Alzheimer’s Disease, which focused on reducing risk factors, including hypertension (Office of the Assistant Secretary for Planning and Evaluation, 2021).

Risk of Mild Cognitive Impairment or Probable Dementia in New Users of Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors

Abstract: Key Points Question Is initiation of angiotensin II receptor blockers (ARBs), compared with angiotensin-converting enzyme inhibitors (ACEIs), associated with a reduced risk of cognitive impairment, after controlling for potential pretreatment confounders? Findings This active-comparator, new-user design cohort study identified 2040 new users of ACEIs/ARBs from the Systolic Blood Pressure Intervention Trial (SPRINT). The overall risk of cognitive impairment was not appreciably different between new users of an ARB vs ACEI. Meaning The findings of this study suggest that pragmatic trials reflective of blood pressure management outside the clinical trial setting are warranted to further elucidate cognitive outcomes with ARBs vs ACEIs initiation.

Hypertensive Aspects of Cardiometabolic Disorders Are Associated with Lower Brain Microstructure, Perfusion, and Cognition.

Abstract: BACKGROUND Cardiometabolic disorders (hypertension, diabetes) are key modifiable risk factors for Alzheimer's disease and related disorders. They often co-occur; yet, the extent to which they independently affect brain structure and function is unclear. OBJECTIVE We hypothesized their combined effect is greater in associations with cognitive function and neuroimaging biomarkers of white matter (WM) health and cerebral perfusion in a diverse older adult cohort. METHODS Participants aged 50-85 years received: clinical evaluation, oral glucose tolerance testing, neuroimaging, cognitive testing, and adjudication. Neuroimaging included: T1 (gray [GM]/WM segmentation, regional volumes/thicknesses); FLAIR (WM hyperintensity volume [WMHv]; arterial spin labeling (cerebral blood flow); diffusion tensor imaging (fractional anisotropy [FA]); and neurite orientation dispersion and density imaging (Free Water). Hypertension (HTN) and impaired glucose tolerance (IGT) were staged and cardiometabolic status was categorized (HTN only, IGT only, IGT+HTN, neither). Multivariable linear regression modeled associations with cognitive and neuroimaging measures (covariates: age, gender, race). RESULTS MRI was available for 478 participants (35% mild cognitive impairment, 10% dementia) with mean age 70±8 years, 74% with HTN, 61% with IGT, and 15% self-identified as Black/African-American. IGT+HTN was significantly associated with cognitive impairment, higher WM Free Water and WMHv, lower FA, and lower GM perfusion compared to neither factor. HTN alone was associated with poorer cognition and lower GM perfusion. Cardiometabolic factors were not associated with GM macrostructure (volumes, temporal lobe cortical thickness) or cognitive status. CONCLUSION HTN and its co-occurrence with IGT (HTN+IGT) were associated with lower global cognitive performance and reduced GM perfusion and impaired WM microstructure.

Baseline hippocampal vascular reactivity predicts conversion to mild cognitive impairment: an analysis of the SPRINT‐MIND study

Abstract: Alzheimer’s disease (AD) is characterized by gradual decline to mild cognitive impairment (MCI) and dementia. Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could slow disease progression. Vascular reactivity, a measure of blood vessel elasticity and arterial stiffness, provides a quantitative neurobiological measure of cerebrovascular health. In the present study, we hypothesized that higher hippocampal and whole‐brain gray matter vascular reactivity would be associated with lower rate of conversion to MCI.

Mild behavioral impairment is associated with sleep apnea, insomnia and brain white matter hyperintensity burden

Abstract: Mild behavioral impairment (MBI) is a neurobehavioral syndrome associated with increased risk for Alzheimer’s disease (AD) and other neurodegenerative disorders. White matter hyperintensities (WMH) are brain lesions associated with cerebrovascular insult and contribute to cognitive decline across the cognitive spectrum (normal cognition, mild cognitive impairment (MCI) and dementia). Sleep disturbance is common among older adults with cognitive impairment and like MBI, is a modifiable AD risk factor that can affect brain structure including WMH. We sought to examine the prevalence of MBI and its relationship with sleep and WMH in a community cohort of older adults.

Development of an Advance Care Planning Portal-Based Tool for Community-Dwelling Persons Living With Cognitive Impairment: The ACPVoice Tool

Abstract: Background: Patient portals can be an innovative and efficient way to engage patients in advance care planning (ACP). However, comprehension and judgment in older adults with cognitive impairment presents several barriers and challenges to engaging in new technology. Our objective was to develop an ACP portal-based tool (ACPVoice) for community-dwelling persons living with cognitive impairment (PLCI) by engaging end-users in the design process. Methods: Two rounds of cognitive interviews were conducted to identify and resolve cognitive issues related to comprehension, judgment, response, and to assess content validity. Purposive sampling was used with the goal of enrolling 15 different participants (five with mild cognitive impairment and five dyads (those with mild dementia and their care partner) in each round to assess respondents’ understanding of questions related to advance care planning to be administered via the patient portal. Results: Twenty PLCI (mean age 78.4, 10 females [50%]) and ten care partners (mean age 60.9, 9 females [90%]) completed cognitive interviews between May 2021 and October 2021. The mean Mini-Mental State Examination score for PLCI was 25.6 (SD 2.6). Unclear wording and undefined vague and/or unfamiliar terms were the major issues identified. Revisions to item wording, response options, and instructions were made to improve question comprehension and response as well as navigational ease. Conclusion: Minor changes to the wording, format, and response options substantially improved respondents’ ability to interpret the item content of the ACPVoice tool. Dissemination and implementation of the ACPVoice tool could help to engage community-dwelling PLCI in ACP discussions.

Electronic health record screening for persons living with dementia in d-care

Abstract: Abstract Pragmatically identifying persons living with dementia (PLWD) for research is a persistent challenge, reflecting limitations in data elements. As part of the D-CARE study, the recruitment coordinator and analyst collaborated to create a screening algorithm to identify potentially eligible patients. A combination SAS/R script was applied on a monthly basis (Oct 2020-Dec 2021) to a clinical data warehouse, identifying living patients 50 years or older with ICD-10 codes for dementia or related conditions within the past two years, and an encounter within the past year. This process identified 6,478 unique patients, leading to the recruitment of 837 PLWD into the study (22% Black or Hispanic). Algorithmic components that enhanced recruitment efforts included the incorporation of data elements necessary to contact and enroll patients, formatting data consistent with reporting requirements, and tracking information on primary care provider, diagnosis dates with the set of providers that agreed to recruit for the trial.

Abstract 12463: Low-Density-Lipoprotein Cholesterol and Mortality Outcomes Among Healthy Older Adults Not Taking Lipid-Lowering Agents: A Cohort Study With 12,334 Participants

Abstract: Introduction: Clinical uncertainty remains about the relationship between cholesterol levels and risk of death in older persons. Hypothesis: Lower low-density lipoprotein (LDL) cholesterol level was associated with a decreased mortality risk from cardiovascular disease (CVD) and an increased mortality risk due to non-CVD causes in primary prevention older populations. Methods: We examined the relationship between LDL cholesterol levels and mortality outcomes in a cohort of older individuals aged ≥65 years enrolled into a clinical trial. At baseline, participants had no diagnosed dementia, physical disability or CVD events, and were not taking lipid-lowering agents. Multivariable Cox proportional-hazards models were used to examine associations of LDL cholesterol with all-cause, CVD, cancer, and combined non-CVD/non-cancer mortality. Restricted cubic splines were used to depict non-linear relationships. Results: Among 12,334 participants included in this analysis [mean (SD) age: 75.2 (4.6) years; 54% females], who were followed for a median of 6.9 (5.7-8.0) years, 1250 (10%) died (24% due to CVD, 43% cancer, and 33% non-CVD/non-cancer). There was a U-shaped relation linking LDL cholesterol and all-cause mortality (nadir: 3.3mmol/L) and a curvilinear relation for other mortality outcomes. Each 1-mmol/L higher LDL cholesterol was associated with a lower risk of all-cause mortality (HR=0.91, 95% CI 0.85-0.98), cancer mortality (0.83, 0.74-0.94) and non-CVD/non-cancer mortality (0.81, 0.71-0.93), but a higher risk of CVD mortality (1.19, 1.03-1.38). Reduced risks of all-cause and non-CVD/non-cancer mortality were only significant in males and but not females (P values for sex interaction <0.05). When deaths in the five years after baseline were excluded, the HRs for all-cause, cancer, non-CVD/non-cancer and CVD mortality were 1.03, 1.05, 0. 91 and 1.21 respectively (all P>0.10). Conclusions: Higher LDL cholesterol is associated with a greater risk of CVD mortality in older adults. Reduced risks for non-CVD mortality were likely driven by reverse causality, evidenced by the absence of associations after excluding deaths that occurred within the initial five years of follow-up.

Using an Electronic Health Record and Deficit Accumulation to Pragmatically Identify Candidates for Optimal Prescribing in Patients With Type 2 Diabetes.

Abstract: Objective Despite guidelines recommending less stringent glycemic goals for older adults with type 2 diabetes, overtreatment is prevalent. Pragmatic approaches for prioritizing patients for optimal prescribing are lacking. We describe glycemic control and medication patterns for older adults with type 2 diabetes in a contemporary cohort, exploring variability by frailty status. Research Design and Methods This was a cross-sectional observational study based on electronic health record (EHR) data, within an accountable care organization (ACO) affiliated with an academic medical center/health system. Participants were ACO-enrolled adults with type 2 diabetes who were ≥65 years of age as of 1 November 2020. Frailty status was determined by an automated EHR-based frailty index (eFI). Diabetes management was described by the most recent A1C in the past 2 years and use of higher-risk medications (insulin and/or sulfonylurea). Results Among 16,973 older adults with type 2 diabetes (mean age 75.2 years, 9,154 women [53.9%], 77.8% White), 9,134 (53.8%) and 6,218 (36.6%) were classified as pre-frail (0.10 < eFI ≤0.21) or frail (eFI >0.21), respectively. The median A1C level was 6.7% (50 mmol/mol) with an interquartile range of 6.2-7.5%, and 74.1 and 38.3% of patients had an A1C <7.5% (58 mmol/mol) and <6.5% (48 mmol/mol), respectively. Frailty status was not associated with level of glycemic control (P = 0.08). A majority of frail patients had an A1C <7.5% (58 mmol/mol) (n = 4,544, 73.1%), and among these patients, 1,755 (38.6%) were taking insulin and/or a sulfonylurea. Conclusion Treatment with insulin and/or a sulfonylurea to an A1C levels <7.5% is common in frail older adults. Tools such as the eFI may offer a scalable approach to targeting optimal prescribing interventions.

Visual impairment predicts physical function decline: the health, aging, and body composition (health abc) study

Abstract: Abstract The relationship between visual impairment (VI) and decline in physical function with age is poorly understood. We constructed separate linear mixed models to evaluate the relationship of self-reported (visual function question (VFQ) score) or performance-based (visual acuity (VA); log contrast sensitivity (LCS); stereoacuity (SA)) VI with change in performance on the Short Physical Performance Battery (SPPB) over 8 years in 2219 Health ABC participants. Mean age was 75.5 years (range 71-82); 52.4% were female, and 37.4% were black. For all measures of visual function, better vision was associated with loss of approximately -0.3 SPPB units/year which was similar to the unadjusted change in SPPB over time (-0.328 units/year 95%CI (-0.35, -0.31)). Participants with LCS ≤1.3 log units experienced 58% faster rate of decline versus those with better LCS (test of difference in slopes p< 0.0001). Those with poor VA ≥20/50 showed a 50% greater decline in SPPB (p=0.0029), and those with low SA ≤85 arcsec demonstrated a 33% faster decline (p< 0.001) relative to those with better visual function. Compared to the slope at the mean VFQ score, a 1 standard deviation lower score was associated with 23% greater decline in SPPB (p< 0.0001). The difference in SPPB slopes remained significant across VI measures after adjusting for longitudinal decline associated with age, sex, and black race (all p< 0.05). Both self-reported and performance-based VI predicted faster declines in SPPB over time. Whether older adults with VI might benefit from targeted intervention to prevent declining mobility function remains to be evaluated.

Relationship of self-reported and performance-based visual function with performance-based measures of physical function: the Health ABC study.

Abstract: BACKGROUND To assess the relationship between self-reported and performance-based visual impairment (VI) and lower extremity physical function. METHODS Cross-sectional analysis of 2219 Health ABC participants who completed vision testing and the Short Physical Performance Battery (SPPB). Linear regression models used either self-reported (weighted visual function question (VFQ) score)) or performance-based (visual acuity (VA), log contrast sensitivity (LCS), Frisby stereoacuity (SA)) to predict SPPB or its components-gait speed, chair stands, or standing balance-with and without covariate adjustment. RESULTS Mean age was 73.5 years (range 69-80); 52.4% were female and 37.4% African American. All VI measures were strongly associated with SPPB in unadjusted and adjusted models (p<0.001). A self-reported VFQ score 1 standard deviation lower than the mean (mean 87.8 out of 100) demonstrated a -0.241(95% CI:-0.325, -0.156) adjusted difference in SPPB. After controlling for covariates, VA of <20/40 (41%) demonstrated a -0.496(-0.660, -0.331) lower SPPB score while SA score>85 arcsec (30%) had a -0.449(-0.627, -0.271) adjusted SPPB score versus those with better visual function. LCS<1.55 (28.6%) was associated with a -0.759(-0.938, -0.579) lower and LCS≤1.30 (8%) with a -1.216(-1.515, -0.918) lower adjusted SPPB score relative to better LCS. In a final multivariable model containing multiple vision measures, LCS remained independently associated with SPPB and all components, while SA remained associated with balance (all p<0.05). CONCLUSIONS Both self-reported and performance-based VI are strongly associated with poor lower extremity physical function. These findings may identify a subgroup of older adults with co-existing visual and physical dysfunction who may benefit from targeted screening and intervention to prevent disability.