Genetic variation in the KIBRA gene (rs17070145) has been associated with episodic memory, with T-allele non-carriers exhibiting poorer performance than T-allele carriers. In a recent positron emission tomography study, KIBRA T-allele non-carriers exhibited hypometabolism in brain regions previously shown to be metabolically affected by Alzheimer’s disease (AD). Further, non-carriers have been shown to be at increased risk for late-onset AD. To further investigate the impact of this KIBRA variant on brain structures associated with AD, we utilized diffusion-weighted imaging to determine whether T-allele non-carriers exhibit altered white matter microstructure in a cohort of late-middle-aged, cognitively normal adults. 98 participants (age=62.36±5.96 years) from the Wisconsin Registry for Alzheimer’s Prevention underwent multi-shell diffusion-weighted magnetic resonance imaging. Neurite Orientation Dispersion and Density Imaging was applied to produce the intracellular volume fraction of axons and dendrites, termed the neurite density index (NDI). Analysis of covariance, controlling for age and sex, was used to test for the genetic effect of non-carriers on NDI on a voxel-wise basis in SPM12. Significance was inferred at p<0.001 uncorrected with cluster extent >100 voxels. Compared with T-allele carriers, non-carriers demonstrated decreased NDI in the right precuneal and lateral occipital white matter, the left temporal part of the superior longitudinal fascicle, and bilaterally in the corpus callosum and superior occipito-frontal fascicles. This study provides novel diffusion MRI based evidence of altered white matter integrity in KIBRA T-allele non-carriers in brain areas known to be affected in AD. Specifically, decreased neurite density in the occipito-frontal fascicles and corpus callosum correspond with white matter pathology associated with the progression of AD. Furthermore, the reductions in white matter integrity in the superior longitudinal fascicle and precuneal cerebral white matter pose a possible mechanism underlying the shared metabolic signatures previously demonstrated in AD and KIBRA T-allele non-carriers. Our findings further strengthen KIBRA’s connection to the neurobiological processes involved in memory and susceptibility to AD, and suggest a potential protective role of KIBRA’s T-allele against the pathophysiological processes of AD.
Abstract Background While Black/African Americans and Latinx/Hispanics have nearly twice the risk of developing Alzheimer’s disease compared to Non‐Hispanic Whites, their involvement in clinical research and trials remains low. Due to the lack of data and underrepresentation in research, it is unknown if there are clinicopathological differences in Alzheimer’s disease or response to therapies. We have established specific recruitment goals for underrepresented groups in the aducanumab Phase 3b/4 confirmatory ENVISION study, which is a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study of participants with mild cognitive impairment and mild dementia stages of Alzheimer’s disease (Stages 3 and 4; NCT05310071), designed to better understand the efficacy and safety of aducanumab treatment for these populations. Method Epidemiological and clinical data by race/ethnicity in the United States (US) were obtained from systematic literature reviews and Clinical trial data were then used to characterize the clinicopathological profile of Alzheimer’s disease among diverse groups. Data from underrepresented participants were pooled and analyzed contemporaneous Alzheimer’s disease clinical trials to identify potential differences (i.e., heterogeneity) in clinical and biomarker outcomes. Result Based on epidemiological analyses, the ENVISION has an enrollment target of 18% for patient populations historically underrepresented in clinical trials in the US. Limited pooled clinical trial data suggests there may be greater heterogeneity in clinical and biomarker endpoints in underrepresented groups. Conclusion Research and clinical trial data from diverse patient populations with Alzheimer’s disease are lacking. Inclusive research is essential to advancing the mission to develop treatments for this devastating disease. Data‐driven recruitment goals have been established and analyses planned to address the safety and efficacy of aducanumab in historically underrepresented populations in the ENVISION study. This could serve as a model for evaluating differences in treatment outcomes across racial/ethnic groups.
Abstract Introduction Although cerebrovascular disease has long been known to co‐occur with Alzheimer's disease (AD), recent studies suggest an etiologic contribution to AD pathogenesis. We used four dimensional (4D)‐flow magnetic resonance imaging (MRI) to evaluate blood flow and pulsatility indices in the circle of Willis. We hypothesized decreased mean blood flow and increased pulsatility, metrics indicative of poor vascular health, would be associated with cerebral atrophy and an AD cerebrospinal fluid (CSF) profile. Methods A total of 312 patients along the AD continuum (172 middle aged, 60 cognitively healthy older, 44 mild cognitive impairment, and 36 AD) underwent MRI, CSF, and medical examinations. Regression was used to predict CSF biomarkers and atrophy from 4D‐flow and analysis of covariance to compare vascular health between groups. Results Decreased mean flow in the middle cerebral artery (MCA) and superior portion of the internal carotid artery (sICA) and increased pulsatility in the MCA were associated with greater brain atrophy. Decreased mean flow in the sICA was associated with lower amyloid beta 1–42 (Aβ 42 ) in the CSF, a pathologic biomarker profile associated with AD. Interestingly, although metrics of flow and pulsatility differed markedly across the AD spectrum, there were no significant differences in cardiovascular risk score, mean arterial pressure, and pulse pressure across the three age‐matched older cohorts. Discussion By measuring intracranial arterial health directly with 4D‐flow MRI, these data suggest that intracranial arterial health is compromised in symptomatic AD. Even after accounting for disease stage, cerebral artery health is associated with atrophy and an AD Aβ 42 profile, suggesting neurovascular health may contribute to the etiopathogenesis of AD.
OBJECTIVES To measure the burden of delirium in older adults with or without Alzheimer disease or related disorders (ADRDs). DESIGN Prospective, observational cohort. SETTING Inpatient hospital and study participants' homes. PARTICIPANTS A subset (n = 267) of older medical and surgical patients and their caregivers enrolled in the Better Assessment of Illness study. MEASUREMENTS Delirium burden was measured using the DEL‐B instrument (range = 0‐40, with higher scores indicating greater burden) in caregivers (DEL‐B‐C) and patients 1 month after hospitalization. Severity of cognitive impairment (Montreal Cognitive Assessment [MoCA]), delirium presence (Confusion Assessment Method [CAM]), and delirium severity (CAM‐Severity [CAM‐S]) were measured during hospitalization and at 1‐month follow‐up. ADRD diagnosis was determined by a clinical consensus process. RESULTS For patients with (n = 56) and without (n = 211) ADRD, both DEL‐B instruments had good internal consistency. DEL‐B‐C scores had a median (interquartile range) among caregivers of patients with and without ADRD of 9 (5‐15) and 5 (1‐11), respectively ( P < .05). If the patient developed delirium, caregivers experienced greater burden (β[delirium × ADRD] = −.29; P = .42), regardless of ADRD status. Further, caregiver burden was modestly correlated with patient MoCA scores (Spearman correlation coefficient, ρ = −0.18; P = .01). Patients with ADRD who developed delirium self‐reported less burden than those without ADRD (β[delirium × ADRD] = −.67; P = .044). As with caregivers, delirium burden was modestly correlated with patient MoCA score (ρ = −0.18; P = .005) and correlated with the CAM‐S in patients without ADRD (ρ = 0.38; P < .001) but not for patients with ADRD (ρ = −0.07; P = .61). CONCLUSIONS Delirium resulted in the same degree of increased caregiver burden regardless of whether a patient had ADRD, signifying delirium is equally stressful to caregivers, even among those with experience caring for someone with a chronic cognitive disorder. Delirium burden is only modestly associated with degree of cognitive impairment, suggesting that other aspects of delirium contribute to burden. J Am Geriatr Soc 67:2587–2592, 2019
Abstract Objectives: The purpose of this study was to investigate the longitudinal trajectory of self- and informant-subjective cognitive complaints (SCC), and to determine if SCC predict longitudinal changes in objective measures (OM) of cognitive function. Methods: The study included healthy and cognitively normal late middle-aged adults enriched with a family history of AD who were evaluated at up to three visits over a 4-year period. At each visit (Visit 1–3), self- and informant-SCC and OM were evaluated. Linear mixed models were used to determine if the longitudinal rate of change of self- and informant-SCC were associated with demographic variables, depressive symptoms, family history (FH), and apolipoprotein epsilon 4 (APOE4) status. The same modeling approach was used to examine the effect of Visit 1 SCC on longitudinal cognitive change after controlling for the same variables. Results: At Visit 1, more self-SCC were associated with fewer years of education and more depressive symptoms. SCC were also associated with poorer performance on cognitive measures, such that more self-SCC at Visit 1 were associated with poorer performance on memory and executive functioning measures at Visit 1, while more informant-SCC were associated with faster rate of longitudinal decline on a measure of episodic learning and memory. FH and APOE4 status were not associated with SCC. Discussion: Self- and informant-SCC showed an association with OM, albeit over different time frames in our late middle-aged sample. Additional longitudinal follow-up will likely assist in further clarifying these relationships as our sample ages and more pronounced cognitive changes eventually emerge. ( JINS , 2017, 23 , 617–626)
Background:Older surgical patients with Alzheimer's disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. Objective:Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. Methods:The Succe ssful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in 'AD-Signature' regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months 1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2–36. Results:Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, β = –0.030, 95% confidence interval [–0.060, –0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (β = –0.100 [–0.192, –0.007]). Conclusion:Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery.
Surgery is increasingly common in older adults. Mild cognitive impairment (MCI) and delirium, the most common surgical complication in older adults, are both associated with post-operative cognitive decline. Our study objective was to determine if patients with both delirium and MCI have the greatest post-operative cognitive decline compared to patients with only MCI, only delirium, or neither condition. The Successful Aging after Elective Surgery (SAGES) cohort (N=560) includes older adults (≥70 years) without dementia who underwent scheduled elective surgery. MCI was defined (as previously) by a pre-operative Modified Mini-Mental State Examination score ≤80 if education ≤8 years and ≤88 if education ≥9 years. Delirium was evaluated each postoperative day using the Confusion Assessment Method supplemented by medical chart review. Cognitive data was collected by a detailed neuropsychological battery administered at baseline; months 1, 2, and 6; and every 6 months thereafter. Cognitive outcomes included a General Cognitive Performance (GCP) measure and three z-score composites for executive function, language/semantic memory, and episodic memory. We used linear mixed effects models to examine cognitive decline from months 2-36, controlling for age, sex, and education. We compared cognitive slopes between patients with both MCI and delirium (MCI+/delirium+), MCI only (MCI+/delirium), or delirium only (MCI-/delirium+) to patients with neither MCI nor delirium (MCI-/delirium-). 366 (65%) were MCI-/Delirium-, 60 (11%) were MCI+/Delirium-, 95 (17%) were MCI-/Delirium+, and 39 (7%) were MCI+/Delirium+. The MCI+/Delirium+ group had the greatest difference in cognitive slopes (b) compared to the MCI-/Delirium- group (p<.001, Figures 1-3 for GCP (b = -1.06), executive function (b = -0.11), and language/semantic memory (b = -0.09). In contrast, only MCI-/Del+ showed significantly greater decline in episodic memory compared to MCI-/Delirium- (b = -0.07, p=.005; Figure 4). Additional slopes and group comparisons are provided in Table 1. General Cognitive Performance (GCP): Patients with MCI only (MCI+/Delirium-, green), Delirium only (MCI-/Delirium+, red), or both (MCI+/Delirium+, orange) exhibited greater decline in GCP than patients with neither MCI nor Delirium (MCI-/Delirium, blue). Patients with both MCI and Delirium declined the most. Note: Although patients were also evaluated preoperatively and at 1 month post-surgery, these time points were not analyzed in order to account for the strongest practice/retest effects commonly observed between the first 2-3 administrations. Executive Function Z-Score Cognitive Composite: Patients with MCI only (MCI+/Delirium-, green), Delirium only (MCI-/Delirium+, red), or both (MCI+/Delirium+, orange) exhibited greater decline in Executive Function than patients with neither MCI nor Delirium (MCI /Delirium, blue). Patients with both MCI and Delirium declined the most. Cognitive tests included in the composite: Trail Making Test Part B, Digit Symbol, Visual Search and Attention Task, Digit Span. Language/Semantic Memory Z-Score Cognitive Composite: Only patients with both MCI and delirium (MCI+/Delirium+, orange) exhibited greater decline in Episodic Memory than patients with neither MCI nor Delirium (MCI-/Delirium, blue). Patients with Delirium only (MCI- /Delirium+, red) or MCI only (MCI+/Delirium-, green) were not statistically different from patients with neither MCI nor Delirium. Cognitive tests included in the composite: Category Fluency, Boston Naming Test, F-A-S Fluency. Episodic Memory Z-Score Cognitive Composite: Only patients Delirium only (MCI- /Delirium+, red) exhibited greater decline in Episodic Memory than patients with neither MCI nor Delirium (MCI-/Delirium, blue). Patients with MCI only (MCI+/Delirium-, green) or both (MCI+/Delirium+, orange) were not statistically different from patients with neither MCI nor Delirium. Cognitive tests included in the composite: Hopkins Verbal Learning Test delayed and total. The greatest post-operative cognitive decline was observed in MCI patients who also developed post-operative delirium, suggesting that surgical patients with MCI may benefit most from known delirium prevention strategies. Greater recognition of both conditions, targeted delirium prevention, and development of interventions targeting the specific cognitive domains most affected could lessen the degree of post-operative cognitive decline in older surgical patients.
To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship.One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories.Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033).In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.
