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2 Cognitive Heterogeneity and Risk of Progression in Data-Driven Subtle Cognitive Decline Phenotypes
- Kelsey R Thomas, Katherine J Bangen, Alexandra J Weigand, Gema Ortiz, Kayla S Walker, David P Salmon, Mark W Bondi, Emily C Edmonds
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 103-104
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Objective:
There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer’s disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of <129 across subgroups.
Participants and Methods:A hierarchical cluster analysis was conducted using 11 baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer’s Disease Research Center (age M=71.93 years, SD=7.51; 55.9% women; 15.6% Hispanic/Latino/a/x/e). A discriminate function analysis was then conducted to test whether the individual neuropsychological scores predicted cluster-group membership. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score <129, by cluster group.
Results:Cluster analysis identified 5 groups: All-Average (n=139), Low-Visuospatial (n=46), Low-Executive (n=51), Low-Memory/Language (n=83), and Low-All Domains (n=46). The discriminant function analysis using the neuropsychological measures to predict group membership into these 5 clusters correctly classified 85.2% of the participants. Subgroups had unique demographic and clinical characteristics. Relative to the All-Average group, the Low-Visuospatial (hazard ratio [HR] 2.39, 95% CI [1.03, 5.56], p=.044), Low-Memory/Language (HR 4.37, 95% CI [2.24, 8.51], p<.001), and Low-All Domains (HR 7.21, 95% CI [3.59, 14.48], p<.001) groups had greater risk of progression to MCI/dementia. The Low-Executive group was also twice as likely to progress to MCI/dementia compared to the AllAverage group, but did not statistically differ (HR 2.03, 95% CI [0.88,4.70], p=.096). A similar pattern of results was found for progression to DRS score <129, with the Low-Executive (HR 2.82, 95% CI [1.26, 6.29], p=.012), Low-Memory/Language (HR 3.70, 95% CI [1.80, 7.56], p<.001) and Low-All Domains (HR 5.79, 95% CI [2.74, 12.27], p<.001) groups at greater risk of progression to a DRS score <129 than the All-Average group. The Low-Visuospatial group was also twice as likely to progress to DRS <129 compared to the All-Average group, but did not statistically differ (HR 2.02, 95% CI [0.80, 5.06], p=.135).
Conclusions:Our results add to a growing literature documenting heterogeneity in the earliest cognitive and pathological presentations associated with Alzheimer’s disease and related disorders. Participants with subtle memory/language, executive, and visuospatial weaknesses all declined at faster rates than the All-Average group, suggesting that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. These results have important implications for early identification of individuals at risk for MCI/dementia. Given that the same classification approach may not be optimal for everyone, determining profiles of subtle cognitive difficulties in CU individuals and implementing neuropsychological test batteries that assess multiple cognitive domains may be a key step towards an individualized approach to early detection and fewer missed opportunities for early intervention.
6 Pulse Pressure and APOE ε4 Dose Interact to Affect Cerebral Blood Flow in Older Adults Without Dementia
- Lauren Edwards, Kelsey R Thomas, Alexandra J Weigand, Emily C Edmonds, Alexandra L Clark, Einat K Brenner, Daniel A Nation, Lisa Delano-Wood, Mark W Bondi, Katherine J Bangen
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 107-108
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Objective:
Alterations in cerebral blood flow (CBF) are associated with risk of cognitive decline and Alzheimer’s disease (AD). Although apolipoprotein E (APOE) ε4 and greater vascular risk burden have both been linked to reduced CBF in older adults, less is known about how APOE ε4 status and vascular risk may interact to influence CBF. We aimed to determine whether the effect of vascular risk on CBF varies by gene dose of APOE ε4 alleles (i.e., number of e4 alleles) in older adults without dementia.
Participants and Methods:144 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent arterial spin labeling (ASL) and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure assessment. Vascular risk was assessed using pulse pressure (systolic blood pressure -diastolic blood pressure), which is thought to be a proxy for arterial stiffening. Participants were classified by number of APOE ε4 alleles (n0 alleles = 87, m allele = 46, n2 alleles = 11). CBF in six FreeSurfer-derived a priori regions of interest (ROIs) vulnerable to AD were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regression models tested the interaction between categorical APOE ε4 dose (0, 1, or 2 alleles) and continuous pulse pressure on CBF in each ROI, adjusting for age, sex, cognitive diagnosis (cognitively unimpaired vs. mild cognitive impairment), antihypertensive medication use, cerebral metabolism (FDG-PET composite), reference CBF region (precentral gyrus), and AD biomarker positivity defined using the ADNI-optimized phosphorylated tau/ß-amyloid ratio cut-off of > 0.0251 pg/ml.
Results:A significant pulse pressure X APOE ε4 dose interaction was found on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex (ps < .005). Among participants with two e4 alleles, higher pulse pressure was significantly associated with lower CBF (ps < .001). However, among participants with zero or one ε4 allele, there was no significant association between pulse pressure and CBF (ps > .234). No significant pulse pressure X APOE ε4 dose interaction was found in the inferior temporal cortex, rostral middle frontal gyrus, or medial orbitofrontal cortex (ps > .109). Results remained unchanged when additionally controlling for general vascular risk assessed via the modified Hachinski Ischemic Scale.
Conclusions:These findings demonstrate that the cross-sectional association between pulse pressure and region-specific CBF differs by APOE ε4 dose. In particular, a detrimental effect of elevated pulse pressure on CBF in AD-vulnerable regions was found only among participants with the e4/e4 genotype. Our findings suggest that pulse pressure may play a mechanistic role in neurovascular unit dysregulation for those genetically at greater risk for AD. Given that pulse pressure is just one of many potentially modifiable vascular risk factors for AD, future studies should seek to examine how these other factors (e.g., diabetes, high cholesterol) may interact with APOE genotype to affect cerebrovascular dysfunction.
51 Pupillary Responses During Verbal Fluency Tasks as a Biomarker of Risk for Alzheimer's Disease
- Veronica Gandara, Mark Bondi, Jeremy Elman, William Kremen, David Salmon, Jason Holden, Alexandra Weigand, Seraphina Solders, Peter Link, Eric Granholm
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 258-259
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Objective:
We examined the use of pupillometry as an early risk marker of Alzheimer's disease (AD). Pupil dilation during a cognitive task has been shown to be an index of cognitive effort and may provide a marker of early change in cognition even before performance begins to decline. Individuals who require more effort to successfully perform a task may be closer to decline. We previously found greater compensatory effort to perform the digit span task in individuals with amnestic mild cognitive impairment (aMCI) who may be at greater risk for AD than individuals with non-amnestic MCI (naMCI). Task evoked pupil dilation is linked to increased norepinephrine output from the locus coeruleus (LC), a structure affected early in the AD pathological process. In this study, we measured pupil dilation during verbal fluency tasks in participants with aMCI or naMCI, and cognitively normal (CN) individuals. Based on our findings using the digit span task, we hypothesized that participants with aMCI would show greater compensatory cognitive effort than the other two groups.
Participants and Methods:This study included 101 older adults without dementia recruited from the UC San Diego Shiley-Marcos Alzheimer's Disease Research Center and San Diego community (mean [SD] age = 74.7 [5.8]; education = 16.6 [2.5]; N=58 female; N=92 White); 62 CN, 20 aMCI and 19 naMCI participants. Pupillary responses (change relative to baseline at the start of each trial) were recorded at 30 Hz using a Tobii X2-30 (Tobii, Stockholm, Sweden) during semantic (animals, fruits, vegetables) and phonemic (letters F, A, S) fluency tasks. Participants generated as many words as possible in a category (semantic) or starting with a given letter (phonemic) in 60 seconds.
Results:Repeated measures ANOVA (3 groups X 2 fluency conditions) with age, education and sex as covariates showed a significant main effect of group (F(2,95)=3.64, p=.03), but no group X condition interaction (F<1). Pairwise comparisons showed significantly greater fluency task-evoked dilation for aMCI relative to CN (p=.015) and naMCI (p=.019) participants. When controlling for performance (total letter or category words produced), pupil dilation (cognitive effort) remained significantly greater in aMCI relative to the other two groups in both fluency conditions, suggesting pupil dilation informs risk beyond information provided by task performance.
Conclusions:In a previous sample of community-dwelling men who were an average of 13 years younger than the present sample, we found significantly greater pupil dilation during a digit span task in aMCI relative to naMCI and CN groups. In the present study, we replicated those findings in an older sample using a different cognitive task. Significantly greater pupil dilation was found in individuals with aMCI on verbal fluency tasks, indicating greater compensatory cognitive effort to maintain performance. Pupillometry provides a promising biomarker that might be used as an inexpensive and noninvasive additional screening tool for risk of AD.
17 Education Moderates the Association Between Hippocampal CBF and Memory in Women but Not Men
- Einat K Brenner, Alexandra J Weigand, Lauren C Edwards, Amanda T Calcetas, Maria Bordyug, Sarah J Banks, Erin E Sundermann, Kelsey R Thomas, Mark W Bondi, Katherine J Bangen
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 227-228
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Objective:
Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.
Participants and Methods:Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.
Results:CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.
Conclusions:These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.
1 Associations between social determinants of health and 10-year change in everyday functioning within Black and White older adults from the ACTIVE study
- Alexandra L. Clark, Alexandra J. Weigand, Olivio J. Clay, Michael Marsiske, Joshua Owens, Jacob Fiala, Michael Crowe, Kelsey R. Thomas
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 783-784
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Objective:
Social determinants of health (SDoH) are structural elements of our living and working environments that fundamentally shape health risks and outcomes. The Healthy People 2030 campaign delineated SDoH into five distinct categories that include: economic stability, education access/quality, healthcare access, neighborhood and built environment, and social and community contexts. Recent research has demonstrated that minoritized individuals have greater disadvantage across SDoH domains, which has been linked to poorer cognitive performance in older adulthood. However, the independent effects of SDoH on everyday functioning across and within racial groups remains less clear. The current project explored the association between SDoH factors and 10-year change in everyday functioning in a large sample of community-dwelling Black and White older adults.
Participants and Methods:Data from 2,505 participants without dementia enrolled in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study (age M=73.5; 76% women; 28% Black/African American). Sociodemographic, census, and industry classification data were reduced into five SDoH factors: economic stability, education access and quality, healthcare access and quality, neighborhood and built environment, and social and community contexts. The Observed Tasks of Daily Living, a performance-based measure of everyday functioning with tasks involving medication management, finances, and telephone use, was administered at baseline, 1-, 2-, 3-, 5, and 10-year follow up visits. Mixed-effects models with age as the timescale tested (1) racial group differences in OTDL trajectories, (2) race x SDOH interactions on OTDL trajectories, and (3) associations between SDoH and OTDL trajectories stratified within Black and White older adults. Covariates included sex/gender, vocabulary score, Mini-Mental Status Examination, depressive symptoms, visual acuity, general health, training group status, booster status, testing site, and recruitment wave.
Results:Black older adults had a steeper decline of OTDL performance compared to Whites (linear: b = -.25, quadratic b=-.009, ps < .001). There was a significant race x social and community context interaction on linear OTDL trajectories (b =.06, p=.01), but no other significant race x SDoH interactions were observed (bs =-.007-.05, ps=.73-.11). Stratified analyses revealed lower levels of social and community context were associated with steeper age-related linear declines in OTDL performance in Black (b = .08, p=.001), but not White older adults (b =.004, p=.64). Additionally, lower levels of economic stability were associated with steeper age-related linear declines in OTDL performance in Black (b =.07, p=.04), but not White older adults (b =.01, p=.35). Finally, no significant associations between other SDoH and OTDL trajectories were observed in Black (bs = -.04-.01, ps =.09-.80) or White (bs = -.02-.003, ps=.07-.96) older adults.
Conclusions:SDoH, which measure aspects of structural racism, play an important role in accelerating age-related declines in everyday functioning. Lower levels of economic and community-level social resources are two distinct SDoH domains associated with declines in daily functioning that negatively impact Black, but not White, older adults. It is imperative that future efforts focus on both identifying and acting upon upstream drivers of SDoH-related inequities. Within the United States, this will require addressing more than a century of antiBlack sentiment, White supremacy, and unjust systems of power and policies designed to intentionally disadvantage minoritized groups.
56 TBI Severity Moderates the Association between Subjective and Objective Attention in Older Veterans
- Peter P Rantins, Monica Ly, Alexandra L Clark, Alexandra J Weigand, Kayla S Walker, Victoria C Merritt, Katherine J Bangen, Kelsey R Thomas
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 363-364
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Objective:
Prior work on associations between self-reported cognition and objective cognitive performance in Veterans has yielded mixed findings, with some evidence indicating that mild traumatic brain injury (TBI) may not impact the associations between subjective and objective cognition. However, few studies have examined these relationships in both mild and moderate-to-severe TBI, in older Veterans, and within specific cognitive domains. Therefore, we assessed the moderating effect of TBI severity on subjective and objective cognition across multiple cognitive domains.
Participants and Methods:This study included 246 predominately male Vietnam-Era Veterans (age M=69.61, SD=4.18, Range = 60.87 – 85.16) who completed neuropsychological testing and symptom questionnaires as part of the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI). Participants were classified as having history of no TBI (n=81), mild TBI (n=80), or moderate-tosevere TBI (n=85). Neuropsychological composite scores in the domains of memory, attention/executive functioning, and language were included as the outcome variables. The Everyday Cognition (ECog) measure was used to capture subjective cognition and, specifically, the ECog domain scores of memory, divided attention, and language were chosen as independent variables to mirror the objective cognitive domains. General linear models, adjusting for age, education, apolipoprotein E ε4 carrier status, pulse pressure, depressive symptom severity, and PTSD symptom severity, tested whether TBI severity moderated the associations of domain-specific subjective and objective cognition.
Results:Across the sample, subjective memory was associated with objective memory (β=-.205, 95% CI [-.332, -.078], p=.002) and subjective language was associated with objective language (β=-.267, 95% CI [-.399, -.134], p<.001). However, the main effect of subjective divided attention was not associated with objective attention/executive functioning (p=.124). The main effect of TBI severity was not associated with any of the objective cognitive domain scores after adjusting for the other variables in the model. The TBI severity x subjective cognition interaction was significant for attention/executive functioning [F(2,234)=5.18, p=.006]. Specifically, relative to Veterans without a TBI, participants with mild TBI (β=-.311, 95% CI [-.620, -.002], p=.048) and moderate-to-severe TBI (β=-.499, 95% CI [-.806, -.193], p=.002) showed stronger negative associations between subjective divided attention and objective attention/executive functioning. TBI severity did not moderate the associations between subjective and objective cognition for memory or language domains. The pattern of results did not change when the total number of TBIs was included in the models.
Conclusions:In this DoD-ADNI sample, stronger associations between subjective and objective attention were evident among individuals with mild and moderate-to-severe TBI compared to Veterans without a TBI history. Attention/executive functioning measures (Trails A and B) may be particularly sensitive to detecting subtle cognitive difficulties related to TBI and/or comorbid psychiatric symptoms, which may contribute to these attention-specific findings. The strongest associations were among those with moderate-to-severe TBI, potentially because the extent to which their attention difficulties are affecting their daily lives are more apparent despite no significant differences in objective attention performance by TBI group. This study highlights the importance of assessing both subjective and objective cognition in older Veterans and the particular relevance of the attention domain within the context of TBI.
10 Pupil Dilation During the Stroop Task Offers a Sensitive and Scalable Biomarker of Locus Coeruleus Integrity
- Alexandra J Weigand, Jeremy A Elman, Seraphina K Solders, Alyssa J Macomber, Lawrence R Frank, Eric L Granholm, Mark W Bondi
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 802-803
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Objective:
Neuronal dysfunction of the locus coeruleus (LC), the primary producer of norepinephrine, has been identified as a biomarker of early Alzheimer's disease (AD) pathophysiology. Norepinephrine has been implicated in attentional control, and its reduced cortical circulation in AD may be associated with selective attentional difficulties. Additionally, greater pupil dilation indicates greater effort needed to perform a cognitive task, and greater compensatory effort to perform the digit span task has been found in individuals at risk for AD. In this study, we examined associations between a neuroimaging biomarker of the LC and pupil dilation during the Stroop task as a sensitive measure of attentional control.
Participants and Methods:64 older adults without dementia were recruited from the San Diego community (mean [SD] age = 74.3 [6.3]; 39 cognitively unimpaired and 25 with mild cognitive impairment). All participants underwent magnetic resonance imaging of the LC and generated behavioral data from a computerized Stroop task that included 36 incongruent trials (e.g., GREEN presented in red ink), 36 congruent trials (e.g., GREEN presented in green ink), and 32 neutral trials (e.g., LEGAL presented in green ink) in a randomized presentation. Mean pupil dilation for each trial (change relative to baseline at the start of each trial) was measured at 30 Hz using the Tobii X2-30 system (Tobii, Stockholm, Sweden) and averaged within each Stroop condition. Paired t-tests assessed for differences in mean pupil dilation across incongruent and congruent Stroop conditions. Iterative re-weighted least squares regression was used to assess the association between a rostral LC contrast ratio measure derived from manually marked ROIs and mean pupil dilation during incongruent trials divided by congruent trials, adjusting for age, sex, and education. Follow-up analyses also assessed the association of these variables with mean reaction time (RT) for incongruent trials divided by congruent trials.
Results:Mean pupil dilation significantly differed across conditions (t = 3.74, mean difference = .13, 95% CI [.06, .20]) such that dilation was higher during the incongruent condition (mean [SD] dilation = .18 [.38] mm) relative to the congruent condition (mean [SD] dilation = .05 [.35] mm). A significant association was observed between pupil dilation and LC contrast ratio, such that increased levels of mean dilation during incongruent trials relative to congruent trials were observed at lower levels of LC contrast ratio (i.e., lower LC integrity; r = -.37, 95% CI [-.55, -.13]). This association was not observed for mean dilation during only congruent trials (r = -.08, 95% CI [-.31, .18]). Additionally, neither LC contrast ratio [r = .24, 95% CI [-.02, .46]) nor mean incongruent/congruent pupil dilation (r = .14, 95% CI [-.13, .37]) were associated with incongruent/congruent RT.
Conclusions:Findings suggest that increased pupil dilation during a demanding attentional task is indicative of increased compensatory effort needed to achieve the same level of performance for individuals with reduced LC biomarker integrity. Pupillometry assessment offers a low-cost, non-invasive, and scalable biomarker of LC dysfunction that may be indicative of preclinical AD.
1 Associations of Locus of Control and Memory Self-Awareness in Older Adults with and without MCI
- Mary E Garcia, Jeanine M Parisi, Sarah Cook, Ian McDonough, Alexandra J Weigand, Alexandra L Clark, Michael Marsiske, Kelsey R Thomas
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 676-677
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Objective:
While loss of insight into one’s cognitive impairment (anosognosia) is a feature in Alzheimer’s disease dementia, less is known about memory self-awareness in cognitively unimpaired (CU) older adults or mild cognitive impairment (MCI) or factors that may impact self-awareness. Locus of control, specifically external locus of control, has been linked to worse cognitive/health outcomes, though little work has examined locus of control as it relates to self-awareness of memory functioning or across cognitive impairment status. Therefore, we examined associations between locus of control and memory self-awareness and whether MCI status impacted these associations.
Participants and Methods:Participants from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study (mean age=73.51; 76% women; 26% Black/African American) were classified as CU (n=2177) or MCI (amnestic n=313; non-amnestic n=170) using Neuropsychological Criteria. A memory composite score measured objective memory performance and the Memory Functioning Questionnaire measured subjective memory. Memory self-awareness was defined as objective memory minus subjective memory, with positive values indicating overreporting of memory difficulties relative to actual performance (hypernosognosia) and negative values indicating underreporting (hyponosognosia). Internal (i.e., personal skills/attributes dictate life events) and external (i.e., environment/others dictate life events) locus of control scores came from the Personality in Intellectual Aging Contexts Inventory. General linear models, adjusting for age, education, sex/gender, depressive symptoms, general health, and vocabulary examined the effects of internal and external locus of control on memory self-awareness and whether MCI status moderated these associations.
Results:Amnestic and non-amnestic MCI participants reported lower internal and higher external locus of control than CU participants. There was a main effect of MCI status on memory self-awareness such that amnestic MCI participants showed the greatest degree of hyponosognosia/underreporting, followed by non-amnestic MCI, and CU participants slightly overreported their memory difficulties. While, on average, participants were fairly accurate at reporting their degree of memory difficulty, internal locus of control was negatively associated with self-awareness such that higher internal locus of control was associated with greater underreporting (ß=-.127, 95% CI [-.164, -.089], p<.001). MCI status did not moderate this association. External locus of control was positively associated with self-awareness such that higher external locus of control was associated with greater hypernosonosia/overreporting (ß=.259, 95% CI [.218, .300], p<.001). Relative to CU, amnestic, but not non-amnestic, MCI showed a stronger association between external locus of control and memory self-awareness. Specifically, higher external locus of control was associated with less underreporting of cognitive difficulties in amnestic MCI (ß=.107, 95% CI [.006, .208], p=.038).
Conclusions:In CU participants, higher external locus of control was associated with greater hypernosognosia/overreporting. In amnestic MCI, the lower external locus of control associations with greater underreporting of objective cognitive difficulties suggests that perhaps reduced insight in some people with MCI may result in not realizing the need for external supports, and therefore not asking for help from others. Alternatively, in amnestic participants with greater external locus of control, perhaps the environmental cues/feedback translate to greater accuracy in their memory self-perceptions. Longitudinal analyses are needed to determine how memory self-awareness is related to future cognitive declines.
49 Locus Coeruleus MR Signal Interacts with CSF p-tau/AB42 to Predict Attention, Executive Function, and Verbal Memory
- Seraphina K Solders, Tamara R Shabi, Alexandra J Weigand, Jeremy A Elman, Eric L Granholm, Lawrence R Frank, Mark W Bondi
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 921-922
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Objective:
The locus coeruleus (LC) plays a key role in cognitive processes such as attention, executive function, and memory. The LC has been identified as an early site of tau accumulation in Alzheimer’s disease (AD). LC neurons are thought to survive, albeit with limited functionality, until later stages of the disease, though how exactly this limited functionality impacts cognition through the course of AD is still poorly understood. We investigated the interactive effects of an imaging biomarker of the LC and AD-related cerebrospinal fluid (CSF) biomarkers on attention, executive function, and memory.
Participants and Methods:We recruited 67 older adults from the San Diego community (mean age=74.52 years; 38 cognitively normal, 23 with mild cognitive impairment, and 6 with probable AD). Participants had LC-sensitive magnetic resonance imaging (MRI) used to obtain a measure of LC signal relative to surrounding tissue, with lower LC signal possibly indicating limited functionality. Participants also underwent a lumbar puncture to obtain CSF measurements of amyloid-beta 42 (Ab42) and phosphorylated tau (p-tau). We calculated the p-tau/Ab42 ratio, which is positively correlated with AD progression. Finally, participants were administered a comprehensive neuropsychological battery, and cognitive composites were created for attention (Digit Symbol, Digit Span Forward, Trails A), executive function (Digit Span Backward, Trails B, Color-Word Inhibition Switching), and two measures of verbal memory [learning (CVLT List A 1-5, Logical Memory Immediate Recall) and delay (CVLT Long Free Recall, Logical Memory Delayed Recall)]. Four multiple linear regressions modeled the relationship between each composite with age, gender, education, p-tau/Ab42, average LC contrast, and interactions between average LC contrast and p-tau/Ab42. For models that were statistically significant, additional regressions were assessed to determine which segment of the LC (caudal, middle, rostral) contributed to the relationship.
Results:Our model predicted attention (p=.001, R2=.298) with main effects of average LC signal, p-tau/Ab42, and LC by p-tau/Ab42 interaction. Follow-up regressions revealed that each LC segment contributes to this relationship. Our model predicted executive function (p=.006, R2=.262) with a main effect of average LC signal and LC by p-tau/Ab42 interaction. Follow-up regressions revealed that this relationship was limited to the caudal and middle LC. Our models predicted both verbal learning (p<.001, R2=.512) and delayed memory (p<.001, R2=.364); both with main effects of gender and education. Follow-up regressions revealed that the rostral LC signal interacts with p-tau/Ab42 to predict both verbal learning and delayed memory. For all interactions, those with low p-tau/Ab42 exhibited a positive relationship between LC signal and cognition, whereas those with higher p-tau/Ab42 showed a negative relationship.
Conclusions:MR-assessed LC signal relates to attention, executive function, and verbal learning and memory in a manner that depends on CSF levels of p-tau and Ab42. The relationship between LC signal and cognition is positive at low levels and negative at higher levels of p-tau/Ab42. If lower LC signal indicates reduced integrity, these findings imply that MR-assessed LC signal may be a more meaningful marker of AD progression in earlier stages of the disease. Alternatively, this measure may capture a different underlying mechanism depending on tau and amyloid biomarker status.
Increasing Inaccuracy of Self-Reported Subjective Cognitive Complaints Over 24 Months in Empirically Derived Subtypes of Mild Cognitive Impairment
- Emily C. Edmonds, Alexandra J. Weigand, Kelsey R. Thomas, Joel Eppig, Lisa Delano-Wood, Douglas R. Galasko, David P. Salmon, Mark W. Bondi
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- Journal:
- Journal of the International Neuropsychological Society / Volume 24 / Issue 8 / September 2018
- Published online by Cambridge University Press:
- 02 October 2018, pp. 842-853
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- Article
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Objectives: Although subjective cognitive complaints (SCC) are an integral component of the diagnostic criteria for mild cognitive impairment (MCI), previous findings indicate they may not accurately reflect cognitive ability. Within the Alzheimer’s Disease Neuroimaging Initiative, we investigated longitudinal change in the discrepancy between self- and informant-reported SCC across empirically derived subtypes of MCI and normal control (NC) participants. Methods: Data were obtained for 353 MCI participants and 122 “robust” NC participants. Participants were classified into three subtypes at baseline via cluster analysis: amnestic MCI, mixed MCI, and cluster-derived normal (CDN), a presumptive false-positive group who performed within normal limits on neuropsychological testing. SCC at baseline and two annual follow-up visits were assessed via the Everyday Cognition Questionnaire (ECog), and discrepancy scores between self- and informant-report were calculated. Analysis of change was conducted using analysis of covariance. Results: The amnestic and mixed MCI subtypes demonstrated increasing ECog discrepancy scores over time. This was driven by an increase in informant-reported SCC, which corresponded to participants’ objective cognitive decline, despite stable self-reported SCC. Increasing unawareness was associated with cerebrospinal fluid Alzheimer’s disease biomarker positivity and progression to Alzheimer’s disease. In contrast, CDN and NC groups over-reported cognitive difficulty and demonstrated normal cognition at all time points. Conclusions: MCI participants’ discrepancy scores indicate progressive underappreciation of their evolving cognitive deficits. Consistent over-reporting in the CDN and NC groups despite normal objective cognition suggests that self-reported SCC do not predict impending cognitive decline. Results demonstrate that self-reported SCC become increasingly misleading as objective cognitive impairment becomes more pronounced. (JINS, 2018, 24, 842–853)