Amnestic Mild Cognitive Impairment Research Articles

Levetiracetam for the treatment of mild cognitive impairment in Parkinson’s disease: a double-blind controlled proof-of-concept trial protocol

BackgroundMild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson’s disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer’s disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance.MethodsTwenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity.ResultsEpisodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes.ConclusionsThis study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD.Trial registrationClinicalTrials.gov, NCT04643327. Registered on 25 November 2020.

Static and dynamic functional connectivity combined with the triple network model in amnestic mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) are characterized by abnormal functional connectivity (FC) of default-mode network (DMN), salience network (SN), and central executive network (CEN). Static FC (sFC) and dynamic FC (dFC) combined with triple network model can better study the dynamic and static changes of brain networks, and improve its potential diagnostic value in the diagnosis of AD spectrum disorders. Differences in sFC values and dFC variability patterns among the three brain networks of the three groups (53 AD patients, 40 aMCI patients, and 40 NCs) were computed by ANOVA using Gaussian Random Field theory (GRF) correction. The correlation between FC values (sFC values and dFC variability) in the three networks and cognitive scores (MMSE and MoCA) in AD and aMCI groups was analyzed separately. Within the DMN network, there were significant differences of sFC values in right/left medial superior frontal gyrus and dFC variability in left opercular part inferior frontal gyrus and right dorsolateral superior frontal gyrus among the three groups. Within the CEN network, there were significant differences of sFC values in left superior parietal gyrus. Within the SN network, there were significant differences of dFC variability in right Cerebelum_7b and left opercular part inferior frontal gyrus. In addition, there was a significant negative correlation between FC values (sFC values of CEN and dFC variability of SN) and MMSE and MoCA scores. It suggests that sFC, dFC combined with triple network model can be considered as potential biomarkers for AD and aMCI.

Divergent brain regional atrophy and associated fiber disruption in amnestic and non-amnestic MCI

BackgroundUnderstanding the pathological characteristics of various mild cognitive impairment (MCI) subtypes is crucial for the differential diagnosis of dementia. The purpose of this study was to feature divergent symptom-deficit profiles in amnestic MCI (aMCI) and non-amnestic MCI (naMCI).MethodsT1 and DTI MRI data from a total of 158 older adults with 50 normal controls, 56 aMCI, and 52 naMCI were included. The voxel-wise gray matter volumes and the number of seed-based white matter fiber bundles were compared among these three groups. Furthermore, correlation and mediation analyses between the neuroimaging indices and cognitive measures were performed.ResultsThe aMCI with specific memory abnormalities was characterized by volumetric atrophy of the left hippocampus but not by damage in the linked white matter fiber bundles. Conversely, naMCI was characterized by both the altered volume of the right inferior frontal gyrus and the significant damage to fiber bundles traversing the region in all three directions, not only affecting fibers around the atrophied area but also distant fibers. Mediation analyses of gray matter-white matter-cognition showed that gray matter atrophy affects the number of fiber bundles and further affects attention and executive function. Meanwhile, fiber bundle damage also affects gray matter volume, which further affects visual processing and language.ConclusionsThe divergent structural damage patterns of the MCI subtypes and cognitive dysfunctions highlight the importance of detailed differential diagnoses in the early stages of pathological neurodegenerative diseases to deepen the understanding of dementia subtypes and inform targeted early clinical interventions.

Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer's disease.

Alzheimer's disease (AD) affects cognition, behavior, and memory of brain. It causes 60-80% of dementia cases. Cross-sectional imaging investigations of AD show that magnetic resonance (MR) with diffusion tensor image (DTI)-detected lesion locations in AD patients are heterogeneous and distributed across the imaging area. This study suggested that Markov model (MM) combined with MR-DTI (MM + MR-DTI) was offered as a method for predicting the onset of AD. In 120 subjects (normal controls [NCs], amnestic mild cognitive impairment [aMCI] patients, and AD patients) from a discovery dataset and 122 subjects (NCs, aMCI, and AD) from a replicated dataset, we used them to evaluate the white matter (WM) integrity and abnormalities. We did this by using automated fiber quantification, which allowed us to identify 20 central WM tracts. Point-wise alterations in WM tracts were shown using discovery and replication datasets. The statistical analysis revealed a substantial correlation between microstructural WM alterations and output in the patient groups and cognitive performance, suggesting that this may be a potential biomarker for AD. The MR-based classifier demonstrated the following performance levels for the basis classifiers, with DTI achieving the lowest performance. The following outcomes were seen in MM + MR-DTI using multimodal techniques when combining two modalities. Finally, a combination of every imaging method produced results with an accuracy of 98%, a specificity of 97%, and a sensitivity of 99%. In summary, DTI performs better when paired with structural MR, despite its relatively weak performance when used alone. These findings support the idea that WM modifications play a significant role in AD.

Chain Mediation Analysis of the Effects of Nutrition and Cognition on the Association of Apolipoprotein E ɛ4 with Neuropsychiatric Symptoms in Alzheimer's Disease.

Apolipoprotein E (APOE) is the most recognized risk gene for cognitive decline and clinical progression of late-onset Alzheimer's disease (AD); nonetheless, its association with neuropsychiatric symptoms (NPSs) remains inconclusive. To investigate the association of APOE ɛ4 with NPSs and explore nutritional status and cognition as joint mediators of this association. Between June 2021 and October 2022, patients with amnestic mild cognitive impairment (aMCI) or AD were recruited from the Chinese Imaging, Biomarkers, and Lifestyle Study. NPSs were assessed using the Neuropsychiatric Inventory, while global cognition and nutritional status were evaluated using the Mini-Mental State Examination (MMSE) and Mini-Nutritional Assessment (MNA), respectively. Simple mediation and multiple chain mediation models were developed to examine the mediating effects of the MNA and MMSE scores on the relationship between APOE ɛ4 and specific neuropsychiatric symptom. Among 310 patients, 229 (73.87%) had NPSs, and 110 (35.48%) carried APOE ɛ4. Patients with APOE ɛ4 were more likely to have hallucinations (p = 0.014), apathy (p = 0.008), and aberrant motor activity (p = 0.018). MNA and MMSE scores mediated the association between APOE ɛ4 and hallucinations (17.97% and 37.13%, respectively), APOE ɛ4 and apathy (30.73% and 57.72%, respectively), and APOE ɛ4 and aberrant motor activity (17.82% and 34.24%), respectively. Chain-mediating effects of MNA and MMSE scores on the association of APOE ɛ4 with hallucinations, apathy, and aberrant motor activity after adjusting for confounding factors were 6.84%, 11.54%, and 6.19%, respectively. Nutritional status and cognition jointly mediate the association between APOE ɛ4 and neuropsychiatric symptoms in patients with aMCI or AD.

Cingulate white matter mediates the effects of fecal Ruminococcus on neuropsychiatric symptoms in patients with amyloid-positive amnestic mild cognitive impairment

BackgroundMicrobiota-gut-brain axis interacts with one another to regulate brain functions. However, whether the impacts of gut dysbiosis on limbic white matter (WM) tracts contribute to the neuropsychiatric symptoms (NPS) in patients with amyloid-positive amnestic mild cognitive impairment (aMCI+), have not been explored yet. This study aimed to investigate the mediation effects of limbic WM integrity on the association between gut microbiota and NPS in patients with aMCI+.MethodsTwenty patients with aMCI + and 20 healthy controls (HCs) were enrolled. All subjects underwent neuropsychological assessments and their microbial compositions were characterized using 16S rRNA Miseq sequencing technique. Amyloid deposition inspected by positron emission tomography imaging and limbic WM tracts (i.e., fornix, cingulum, and uncinate fasciculus) detected by diffusion tensor imaging were additionally measured in patients with aMCI+. We employed a regression-based mediation analysis using Hayes’s PROCESS macro in this study.ResultsThe relative abundance of genera Ruminococcus and Lactococcus was significantly decreased in patients with aMCI + versus HCs. The relative abundance of Ruminococcus was negatively correlated with affective symptom cluster in the aMCI + group. Notably, this association was mediated by WM integrity of the left cingulate gyrus.ConclusionsOur findings suggest Ruminococcus as a potential target for the management of affective impairments in patients with aMCI+.

Exploring Circulating Long Non-Coding RNAs in Mild Cognitive Impairment Patients' Blood.

Mild cognitive impairment (MCI) is a transitional clinical stage prior to dementia. Patients with amnestic MCI have a high risk of progression toward Alzheimer's disease. Both amnestic mild cognitive impairment and sporadic Alzheimer's disease are multifactorial disorders consequential from a multifaceted cross-talk among molecular and biological processes. Non-coding RNAs play an important role in the regulation of gene expression, mainly long non-coding RNAs (lncRNAs), that regulate other RNA transcripts through binding microRNAs. Cross-talk between RNAs, including coding RNAs and non-coding RNAs, produces a significant regulatory network all through the transcriptome. The relationship of genes and non-coding RNAs could improve the knowledge of the genetic factors contributing to the predisposition and pathophysiology of MCI. The objective of this study was to identify the expression patterns and relevant lncRNA-associated miRNA regulatory axes in the blood of MCI patients, which includes lncRNA-SNHG16, lncRNA-H19, and lncRNA-NEAT1. Microarray investigations have demonstrated modifications in the expression of long non-coding RNAs (lncRNA) in the blood of patients with MCI compared with control samples. This is the first study to explore lncRNA profiles in mild cognitive impairment blood. Our study proposes RNAs targets involved in molecular pathways connected to the pathogenesis of MCI.

1 Associations of Locus of Control and Memory Self-Awareness in Older Adults with and without MCI

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.

Prevalence and localization of nocturnal epileptiform discharges in mild cognitive impairment.

Recent evidence shows that identifying and treating epileptiform abnormalities in patients with Alzheimer's disease could represent a potential avenue to improve clinical outcome. Specifically, animal and human studies have revealed that in the early phase of Alzheimer's disease, there is an increased risk of seizures. It has also been demonstrated that the administration of anti-seizure medications can slow the functional progression of the disease only in patients with EEG signs of cortical hyperexcitability. In addition, although it is not known at what disease stage hyperexcitability emerges, there remains no consensus regarding the imaging and diagnostic methods best able to detect interictal events to further distinguish different phenotypes of Alzheimer's disease. In this exploratory work, we studied 13 subjects with amnestic mild cognitive impairment and 20 healthy controls using overnight high-density EEG with 256 channels. All participants also underwent MRI and neuropsychological assessment. Electronic source reconstruction was also used to better select and localize spikes. We found spikes in six of 13 (46%) amnestic mild cognitive impairment compared with two of 20 (10%) healthy control participants (P = 0.035), representing a spike prevalence similar to that detected in previous studies of patients with early-stage Alzheimer's disease. The interictal events were low-amplitude temporal spikes more prevalent during non-rapid eye movement sleep. No statistically significant differences were found in cognitive performance between amnestic mild cognitive impairment patients with and without spikes, but a trend in immediate and delayed memory was observed. Moreover, no imaging findings of cortical and subcortical atrophy were found between amnestic mild cognitive impairment participants with and without epileptiform spikes. In summary, our exploratory study shows that patients with amnestic mild cognitive impairment reveal EEG signs of hyperexcitability early in the disease course, while no other significant differences in neuropsychological or imaging features were observed among the subgroups. If confirmed with longitudinal data, these exploratory findings could represent one of the first signatures of a preclinical epileptiform phenotype of amnestic mild cognitive impairment and its progression.

Error monitoring in amnestic mild cognitive impairment: Cognitive correlates and relationship to measures of everyday function.

Accurate error monitoring is important for successful completion of everyday tasks and compensatory strategy use. This study examined how error awareness is impacted in amnestic mild cognitive impairment (aMCI) compared to cognitively healthy older adults (HOA). Cognitive correlates of error monitoring and relation to objective and self-reported measurement of everyday function were also evaluated. Twenty-four individuals with aMCI and 24 cognitively HOAs completed standardized cognitive measures (domains: attention, working memory, executive functioning, memory, language, visuospatial abilities); a computerized go-no-go paradigm task that evaluated error monitoring; a naturalistic, performance-based measure of everyday functioning (day-out-task; DOT); and self- and informant-report measures of everyday dysexecutive difficulties (DEX). Participants with aMCI demonstrated significantly poorer error monitoring as compared to the HOA group (Cohen's d = 1.02). Working memory and executive functioning were significantly related to error monitoring for both groups. After accounting for age and global cognitive status, hierarchical regressions revealed error monitoring significantly predicted DOT total time (but not accuracy) as well as both self- and informant-report DEX scores. Compared to HOAs, individuals with aMCI exhibited poorer conscious error awareness. Better error monitoring was associated with higher working memory and executive functioning abilities and predicted better everyday functioning. If individuals with aMCI experience difficulties recognizing performance inaccuracies, they will be unable to correct their errors, leading to mistakes in everyday task completion and difficulty implementing appropriate compensatory strategies. Findings suggest that error monitoring may be a potential target for intervention with individuals with aMCI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

77 Differentiating Amnestic Versus Non-Amnestic Mild Cognitive Impairment Using the NIH Toolbox Cognition Battery

Objective:In research, and particularly clinical trials, it is important to identify persons at high risk for developing Alzheimer’s Disease (AD), such as those with Mild Cognitive Impairment (MCI). However, not all persons with this diagnosis have a high risk of AD as MCI can be broken down further into amnestic MCI (aMCI), who have a high risk specifically for AD, and non-amnestic MCI (naMCI), who are predominantly at risk for other dementias. People with aMCI largely differ from healthy controls and naMCI on memory tasks as it is the hallmark criteria for an amnestic diagnosis. Given the growing use of the NIH Toolbox Cognition battery in research trials, this project investigated which Toolbox Cognition measures best differentiated aMCI from naMCI and in comparison to persons with normal cognition.Participants and Methods:A retrospective data analysis was conducted investigating performance on NIH Toolbox Cognition tasks among 199 participants enrolled in the Michigan Alzheimer’s Disease Research Center. All participants were over age 50 (51-89 years, M=70.64) and had a diagnosis of aMCI (N=74), naMCI (N=24), or Normal Cognition (N=101). Potential demographic differences were investigated using chi-square and ANOVAs. Repeated measure general linear model was used to look at potential group differences in Toolbox Cognition performance, covarying for age which was statistically different in aMCI versus Normal participants. Linear regression was used to determine which cognitive abilities, as measured by the Uniform Data Set-3 (UDS3), might contribute to Toolbox differences noted in naMCI versus aMCI groups.Results:As expected, aMCI had lower Toolbox memory scores compared to naMCI (p=0.007) and Normals (p<0.001). Interestingly, naMCI had lower Oral Reading scores than both aMCI (p=0.008) and Normals (p<0.001). There were no other Toolbox performance differences between the MCI groups. 19.4% of the variance in Oral Reading scores was explained by performance on the following UDS3 measures: Benson delayed recall (inverse relationship) and backward digit span and phonemic fluency (positive relationship).Conclusions:In this study, Toolbox Picture Sequence Memory and Oral Reading scores differentiated aMCI and naMCI groups. While the difference in memory was expected, it was surprising that the naMCI group performed worse than the aMCI and normal groups on the Toolbox Oral Reading task, a task presumed to reflect Crystalized abilities resistive to cognitive decline. Results suggest that Oral Reading is primarily positively associated with working memory and executive tasks from the UDS3, but negatively associated with visual memory. It is possible that the Oral Reading subtest is sensitive to domains of deficit aside from memory that can best distinguish aMCI from naMCI. A better understanding of the underlying features in the Oral Reading task will assist in better characterizing deficit patterns seen in naMCI, making selection of aMCI participants more effective in clinical trials.

74 Adherence to Behavioral Interventions is Associated with a Change in Participant Adjustment in a Sample of aMCI Patients

Objective:Behavioral interventions are a non-pharmacological treatment that shows improvement in the everyday functioning of people with Mild Cognitive Impairment (MCI). Multiple studies have focused on examining factors that can reduce or enhance adherence to behavioral interventions. However, few studies use adherence as a predictor of functional changes. The goal of this study was to analyze the association between adherence, age, and education in factor score changes of participant impairment, participant adjustment, and partner adjustment in a sample of participants with amnestic MCI (aMCI) and their study partners.Participants and Methods:We included fifty-two dyads of a person with aMCI and their study partner with intervention data at baseline and 24-week follow-up from the Physical Exercise and Cognitive Engagement Outcomes for Mild Neurocognitive Disorder (PEACEOFMND) study. At baseline, participants were randomized to one of three behavioral interventions: computerized cognitive training (BrainHQ; n=19), yoga (n=15), or wellness education (n=18). Factors were established from a larger clinical sample that used the same measures as PEACEOFMND. The three-factor latent structure was constructed as the following: 1) participant adjustment combined scores of the Center for Epidemiologic Studies Depression Scale (CES-D), Quality of Life in Alzheimer’s Disease (QoL-AD), and Self-Efficacy for managing MCI scales; 2) partner adjustment included study partner’s scores in CES-D, QoLAD and Caregiving Competence and Mastery Components (CCMC) of the Pearlin scales; 3) participant impairment included participant’s scores in E-Cog memory domain, and study partner’s scores in the Functional Activity Questionnaire (FAQ) and Zarit Burden Interview. We calculated factor changes by obtaining the difference between factor scores at follow-up and baseline. Bayesian correlation analysis was performed to investigate the association between age, education, adherence to the combined behavioral interventions, participant adjustment, participant impairment, and partner adjustment.Results:The Bayesian correlation results showed moderate evidence (BF10=6.8, Pearson’s r=0.38) supporting a positive correlation between adherence and change in participant adjustment. Additionally, there was moderate evidence (BF10=2.18, Pearson’s r=0.32) supporting a positive correlation between change in participant impairment and participant level of education as well as participant age and change in partner adjustment (BF10=2.8, Pearson’s r=0.33).Conclusions:Bayesian correlations replicated results from previous analysis using a traditional method, showing that increased adherence to combined behavioral interventions is associated with an increase in participant’s quality of life, self-efficacy, and better mood. Thus, commitment to behavioral intervention completion in aMCI participants is related to overall participant adjustment.

2 Water-Based Exercise Improves Cognition and Reduces Neurological-Related Plasma Proteins in Older Adults.

Objective:In the United States, Alzheimer’s disease (AD) is the most common cause of dementia and the seventh leading cause of death. Exercise has demonstrated health benefits in older adults and reduces the risk of developing AD. Exploring underlying biological mechanisms of exercise could aid in identifying therapeutic targets to prevent AD progression, especially for high-risk individuals such as those with Mild Cognitive Impairment (MCI). Many studies of dementia focus on memory; however, executive function and processing speed are also vulnerable to the neuropathology that causes AD. This exploratory study aimed to identify potential mechanisms by which physical activity can facilitate change in cognitive functioning in older adults. This was accomplished by investigating correlations between changes in neurology-related plasma proteins and changes in measures of executive function and processing speed after participation in a water-based exercise intervention.Participants and Methods:The sample included 20 older adults with amnestic MCI, ages 55-82 years (mean 68.15 ±7.75). Participants were predominately male (90%), White (70%), and non-Hispanic (85%), with more than high school education (95%). Participants engaged in supervised high-intensity water-based exercise three times per week for six months. Neuropsychological assessments and blood samples were assessed at baseline and after completion of the exercise intervention. Cognitive measures included: the Digit Span subtests from the Wechsler Adult Intelligence Scale, 4th Edition, Trail-Making Test (TMT), Stroop Color Word Test (SCWT), and the Symbol Digit Modalities Test (SDMT). Plasma protein levels were analyzed using the Olink Target 96 Neurology assay (Uppsala, Sweden), selected a priori for the established markers linked to neurobiological processes and diseases. Changes in cognitive measures and protein levels were assessed using paired-sample t-tests, and Pearson’s correlations were calculated for significant findings.Results:Participants’ cognitive performance significantly improved on the SCWT color trial (t = -2.19, p = 0.042) and SDMT (t = -2.17, p = .043). Significant decreases in plasma proteins levels were found for GDNF family receptor alpha-1 ([GFRA1]: t =2.05, p = 0.055), neuroblastoma suppressor tumorigenicity-1 ([NBL1]: t = 2.13, p= .046), and neuropilin-2 ([NRP2]: t = 2.61 p= 0.017). Correlational analyses showed reductions in NBL1 were significantly associated with changes in both SDMT (r = -.61, p = 0.006) and the color trial of SCWT (r = .48, p = .038), and NRP2 was significantly associated with improvement on the SDMT (r = -.46, p = 0.045). GFRA1 was not significantly associated with change on any cognitive measure.Conclusions:In a sample of older adults with MCI, participation in high-intensity water-based exercise led to significant improvements in cognitive function as well as changes in neurological plasma proteome. Improved outcomes in processing speed, attention, visuospatial scanning, and working memory were associated with changes in specific plasma protein concentrations. This highlights potential activity-dependent neurobiological mechanisms that may underlie the cognitive benefits derived from physical activity. Future studies should explore these findings in Randomized Control Trials with a comparative condition and larger sample size.

89 The Effect of Personality Traits on the Development of Predementia Cognitive States: Results from the Einstein Aging Study

Objective:Recent research has found associations between the Five Factor Model (FFM) personality traits (Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism) and risk of developing subjective cognitive decline (SCD), mild cognitive impairment (MCI), and/or dementia. It has therefore been proposed that personality should be incorporated into conceptual models of dementia risk, as personality assessments have utility as readily available, low-cost measures to predict who is at greater risk for developing pathological cognitive decline. The objective of the present study was to explore the relationship between FFM personality traits and predementia cognitive syndromes including SCD, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The first aim was to compare baseline personality traits between participants who transitioned from healthy cognition or SCD to aMCI vs. naMCI. The second aim was to determine the relationship between FFM personality traits and risk of transition between predementia cognitive states. The third aim was to explore relationships between levels of FFM personality traits and performance on a comprehensive cognitive battery.Participants and Methods:The participants for this study were 562 (Aim 3; Mean Age = 78.90) older adults from the Einstein Aging Study, 378 of which had at least one follow-up assessment (Aims 1 & 2; Mean Age = 78.60). Baseline levels of FFM personality traits were measured in the EAS using the 50-item International Personality Item Pool (IPIP) version of the NEO-Personality Inventory. Baseline levels of anxiety and depressive symptoms, medical history, performance on a cognitive battery and age sex, and years of education were also collected. A multistate Markov approach was used to model the risk of transition across the four predementia states (cognitively healthy, SCD, aMCI, and naMCI) with each FFM personality trait as covariates.Results:Regarding Aim 1, Mann-Whitney U tests revealed no differences in levels of FFM personality traits between participants who developed aMCI compared to those who developed naMCI. Regarding Aim 2, the multistate Markov model revealed that higher levels of conscientiousness were protective against developing SCD while higher levels of neuroticism resulted in an increased risk of developing SCD. Further, the model revealed that higher levels of extraversion were protective against developing naMCI. Finally, regarding Aim 3, exploratory correlations revealed many positive associations between levels of openness to experience and performance on neuropsychological tests. Few associations were found for the other FFM personality traits.Conclusions:Results from this study suggest that premorbid personality traits may play a predictive role in the risk for or protection against specific predementia syndromes. Thus, FFM personality traits may be useful in improving predictions of who is at greatest risk for developing specific predementia syndromes. These personality measures could be used (in addition to other established risk factors for cognitive decline) to enrich clinical trials by targeting individuals who are at greatest risk for developing specific forms of cognitive decline. Such measures may also be useful in diagnostic prediction models for predementia syndromes. These results should be replicated in future studies with larger sample sizes and younger participants.

7 The MOCA Versus Neuropsychological Testing in Assessing Presence of Memory Impairment and MCI

Objective:The Montreal Cognitive Assessment (MOCA) is a brief cognitive screener, widely used by providers to detect mild cognitive impairment (MCI). It encompasses 30 questions, assessing executive functioning, visuospatial skills, language, memory, attention, and orientation. Although the MOCA has been shown to have high sensitivity (90%) and specificity (87%) for detecting MCI, existing studies have primarily included participants who were already diagnosed with amnestic MCI via neuropsychological testing. Since several factors beyond the presence of MCI can contribute to low performance on the MOCA (e.g., premorbid IQ, fatigue, mood symptoms), over-reliance on the MOCA runs the risk of falsely identifying individuals as having cognitive impairment. The MOCA’s memory subtest raises particular concern as there are several language-based tasks between the learning and delay trials, introducing the potential for interference effects. Thus, the MOCA’s ability to accurately identify those at risk for MCI in the community remains unclear. The objective of the present study was to evaluate: (1) the MOCA’s association with neuropsychological memory measures; and (2) its ability to distinguish between neurocognitive groups (intact vs. MCI vs. dementia).Participants and Methods:This study involved a retrospective analysis of fifty-one patients (M age=72.58 [7.90]; M education= 16.37 [16.37]) who underwent neuropsychological evaluation. Standardized scores for total list-learning (HVLT; CVLT-bf) were used to capture memory encoding; retention % scores were used to capture memory storage. MOCA scores included Total MOCA, MOCA-Orientation, and the MOCA Memory Index (MOCA-MEM). MOCA-MEM was calculated based on Julayanont et al., 2014— (Free-Delayed Recall*3) + (Category-Cued Recall*2) + Multiple Choice-Cued Recall. Bivariate correlations were conducted for the MOCA and neuropsychological test scores. Participants were divided into three diagnostic groups, classified by the neuropsychologist: (1) Cognitive Intact (CI; n=13); (2) MCI (n=26); and (3) Major Neurocognitive Disorder/Dementia (MNCD; n=11). Analysis of covariance was used to analyze differences between the cognitive groups on Total MOCA, MOCA-Orientation, and MOCA-MEM.Results:Total MOCA correlated with word-list learning (r=.434, p=.004) and retention% (r=.306, p=.049). MOCA-MEM was correlated with word-list learning (r=.367, p=.042); it did not significantly correlate with retention%. MOCA-Orientation had the strongest correlation with retention0/) (r=.406, p=.009). Means of Total MOCA significantly differed between CI (25.31[2.56]), MCI (22.04[4.14]), and MNCD (15.44[4.13]). MOCA-MEM only differentiated CI (10[3.66]) and MNCD (5.71[2.14]); it did not differentiate MCI (6.94[3.13]) from either CI or MNCD.Conclusions:Our findings suggest that the MOCA has limitations in accurately classifying memory deficits in older adults. First, our study suggests that the MOCA-MEM reflects encoding rather than memory storage. Given that deficiency in encoding may be secondary to other cognitive deficits, such as attention and executive dysfunction, performance on MOCA-MEM cannot readily delineate the presence of an amnestic process. Second, the findings show that MOCA-MEM does not differentiate between patient groups with intact cognition versus MCI, nor those with MCI versus MNCD. These findings argue the importance of neuropsychological evaluation in deciphering patterns of memory performance and the presence of an amnestic process.

57 CSF Markers of AD-Related Pathology Relate to aMCI among People with HIV

Objective:Older people with HIV (PWH) are at-risk for Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Identifying aMCI among PWH is challenging because memory impairment is also common in HIV-associated neurocognitive disorders (HAND). The neuropathological hallmarks of aMCI/AD are amyloid-ß42 (Aß42) plaque and phosphorylated tau (p-tau) accumulation. Neurofilament light chain protein (NfL) is a marker of neuronal injury in AD and other neurodegenerative diseases. In this study, we assessed the prognostic value of the CSF AD pathology markers of lower Aß42, and higher p-tau, p-tau/Aß42 ratio, and NfL levels to identify an aMCI-like profile among older PWH and differentiating it from HAND. We assessed the relationship between aMCI and HAND diagnosis and AD biomarker levelsParticipants and Methods:Participants included 74 PWH (Mean age=48 [SD=8.5]; 87.4% male, 56.5% White) from the National NeuroAIDS Tissue Consortium (NNTC). CSF Aß42, Aß40, p-tau and NfL were measured by commercial immunoassay. Participants completed a neurocognitive evaluation assessing the domains of learning, recall, executive function, speed of information processing, working memory, verbal fluency, and motor. Memory domains were assessed with the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised, and aMCI was defined as impairment (<1.0 SD below normative mean) on two or more memory outcomes among HVLT-R and BVMT-R learning, delayed recall and recognition with at-least one recognition impairment required. HAND was defined as impairment (<1.0 SD below normative mean) in 2 or more cognitive domains. A series of separate linear regression models were used to examine how the levels of CSF p-tau, Aß42, p-tau/Aß42 ratio, and NfL relate to aMCI and HAND status while controlling for demographic variables (age, gender, race and education). Covariates were excluded from the model if they did not reach statistical significance.Results:58% percent of participants were diagnosed with HAND, 50.5% were diagnosed with aMCI. PWH with aMCI had higher levels of CSF p-tau/Aß42 ratio compared to PWH without aMCI (ß=.222, SE=.001, p=.043) while controlling for age (ß=.363, p=.001). No other AD biomarker significantly differed by aMCI or HAND status.Conclusions:Our results indicate that the CSF p-tau/Aß42 ratio relates specifically to an aMCI-like profile among PWH with high rates of cognitive impairment across multiple domains in this advanced HIV disease cohort. Thus, the p-tau/Aß42 ratio may have utility in disentangling aMCI from HAND and informing the need for further diagnostic procedures and intervention. Further research is needed to fully identify, among a broader group of PWH, who is at greatest risk for aMCI/AD and whether there is increased risk for aMCI/AD among PWH as compared to those without HIV.

74 A Phase I Trial of Accelerated, HighDose Repetitive Transcranial Magnetic Stimulation to Improve Cognition in Amnestic MCI

Objective:Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation therapy most widely used in depression, has shown evidence of secondary benefits for cognition in both neurologic and neuropsychiatric conditions. The recent development of more efficient stimulation protocols, such as accelerated high-dose intermittent theta burst (iTBS)-rTMS, has substantially reduced treatment burden by shortening the treatment course by >50%. This study aimed to establish the safety, feasibility, acceptability, and preliminary efficacy of iTBS-rTMS as a tool for bolstering cognition in individuals with amnestic mild cognitive impairment (aMCI).Participants and Methods:Twenty-four patients with aMCI were enrolled in an open-label phase I trial of iTBS-rTMS; 2 withdrew prior to initiating treatment due to personal circumstances. All participants had received a diagnosis of MCI due to possible AD from a healthcare provider (i.e., neurologist or neuropsychologist) and met actuarial neuropsychological criteria for aMCI. This sample of older adults (range: 61.5-85.2 years, M = 74.1, SD = 5.71) was predominantly White/non-Hispanic (n = 23; Black/non-Hispanic: n = 1), roughly half female (n = 13), with a college education (range: 12-20 years, M = 15.9, SD = 2.5). Participants received 24 sessions of iTBS-rTMS to the left dorsolateral prefrontal cortex over 3 days (8 sessions each, lasting roughly 2 hours per day). Participants rated their perceptions and experience of common side effects during and after each treatment session as well as retrospectively at post-treatment and 4-week follow-up. They completed structural and functional brain MRI, neuropsychiatric evaluations, and neuropsychological assessments before and after treatment and were administered a subset of these measures at 4-week follow-up. MoCA scores were used to monitor for adverse neurocognitive effects, and the fluid cognition composite score from the NIH Toolbox Cognition Battery was used to test preliminary efficacy.Results:We achieved a high retention rate (95%), with 21 of the 22 participants completing all study procedures. There were no clinically significant adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participant reports indicated high tolerability and acceptability, with a modal rating of 0 (on a scale from 0=not at all to 10=extremely) for six common side effects (i.e., headache, pain, scalp irritation, facial twitching, fatigue, fear/anxiety), assessed both during and after each treatment session. They reported very low desire to quit despite some participants rating the treatment as moderately tiring. We observed significant, large effect-size (d = 0.98) improvements in fluid cognition from pre- to post-treatment.Conclusions:Our findings support the safety, feasibility, and acceptability of iTBS-rTMS treatment in patients with aMCI. Further, although not explicitly dosed for efficacy, we provide preliminary evidence of improved fluid cognition as a function of treatment, highlighting the potential of this treatment for improving trans-domain cognitive impairment. These promising results can directly inform future trials aimed at optimizing treatment parameters, broadening the indication to other MCI subtypes, and testing the augmentation of established cognitive rehabilitation interventions when combined with rTMS.

But will they use it? Predictors of adoption of an electronic memory aid in individuals with amnestic mild cognitive impairment.

Electronic memory aids are being researched and developed widely to assist the everyday functioning of individuals experiencing cognitive decline. Although development studies show promise in the initial use of electronic memory aids, little is known about the factors that influence adoption of these aids after training ends. We analyzed the baseline characteristics (e.g., demographics, cognitive performance) and training usage (e.g., frequency and pattern of use) of 32 older adults experiencing amnestic mild cognitive impairment who participated in a pilot clinical trial with an electronic memory and management aid (EMMA) tablet application. Sixteen participants who were still using EMMA at 3-months posttraining were defined as "adopters," whereas the 16 participants who were not using EMMA at 3-months posttraining were defined as "nonadopters." Adopters scored higher on baseline delayed memory (Cohen's d = .87) and language (Cohen's d = .82) index scores than nonadopters. Adopters also interacted with EMMA more frequently (Cohen's d = 1.34) and in greater quantities (Cohen's d > .87) than nonadopters by Week 2 of training. Stepwise logistic regression revealed that higher baseline language score and increased frequency of use during training significantly predicted classification of adopters at 3-months posttraining. Adoption of this electronic memory aid was enhanced by teaching the aid to individuals who demonstrated average-level language abilities and who used the aid on average eight times per day during training. Encouraging individuals to use the aid early and often during training can increase adoption of electronic memory aids. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

59 Investigating the Relationship Between Neuropsychological Test Performance and Electrophysiological Measures of Semantic Functioning in Alzheimer's Disease.

Objective:Improving the timeline for intervention in Alzheimer's disease (AD) has considerable potential to delay and mitigate disability and suffering. Neuropsychological assessment is useful for distinguishing AD from normal aging and other dementias but is less useful in preclinical detection due to its limited sensitivity. The N400 (N4), a language-based EEG event-related potential (ERP) related to semantic functioning, is a promising candidate marker of AD with potential to improve early detection and monitoring of AD. For example, studies have shown that individuals with AD show a reduced N4 "effect"—a smaller difference in the size of the N4 to semantically congruent vs. incongruent word-pairs. The goal of this study is to assess the presence of the N4 effect in healthy seniors, and those with amnestic mild cognitive impairment (MCI) or mild AD, and to evaluate associations between performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the N4 across these samples.Participants and Methods:Fifty older adults (intact=27, combined MCI/mild AD group=23; "impaired") completed neuropsychological testing, including the RBANS, as part of a larger study. Participants were re-contacted and returned for EEG assessment between several weeks to one year later. During EEG recording, participants completed a word-pair judgement paradigm, which involved distinguishing between semantically congruent and incongruent word-pairs. Data was collected and analyzed according to customized N4 analysis scripts provided as part of ERPCORE, an online resource for acquiring and analyzing common ERP components (Kappenman et al., 2021; https://osf.io/thsqg/). The change in N4 amplitude between congruent and incongruent trials (the N4 effect) was used as an index of participants' semantic functioning. Participants' N4 effect was quantified using the mean amplitude from 300-550 milliseconds poststimulus at electrode Cz.Results:Repeated measures ANOVAs indicated a significant effect of trial type on the N400 amplitude in the intact individuals (F(1, 26)=77.66, p<.001), which remained significant in the sample as a whole (F(1, 48)=65.18, p<.001). Although intact participants numerically showed a larger N4 effect (intact: M=-4.02, SD=2.37; impaired: M=-2.60, SD=3.40), the expected group-by-trial interaction was not significant (F(1, 48)=3.01, p=.089). Correlational analyses revealed no significant associations between the N4 effect and the RBANS Total Scale scores (r=-.14, p=.32), nor for the Immediate Memory (r=-.002, p=.99), Visuospatial/Constructional (r=-.069, p=.63), Language (r=-.15, p=.30) Attention (r=-.21, p=.14), or Delayed Memory (r=-.18 p=.58) indexes.Conclusions:Results confirmed the presence of the N4 effect in intact participants and in the sample as a whole. Although the N4 effect was numerically smaller in the impaired group as expected, this difference was not significant in the present sample. Likewise, we observed no evidence for associations between the size of N4 effect and performance on RBANS indexes. Overall, the present study provides mixed evidence for the utility of the N4 as a biomarker in mild AD. Factors that may have contributed to the lack of associations between the N4 effect and the RBANS include the limited sample size and variable lengths of time between participants' initial cognitive assessments and EEG testing.

21 Assessment of Semantic Memory Decline in aMCI : Naming and Semantic Knowledge of Unique and Non-Unique Entities

Objective:Semantic memory deficits have been reported in both Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). However, the nature of this decline is still a matter of debate. The aim of this study was to explore the patterns of semantic memory impairment in aMCI by examining performance on naming tasks, and on tests assessing both general and specific semantic knowledge.Participants and Methods:Participants were divided in two groups matched for age and education, one comprising 33 aMCI individuals and the other 39 healthy controls. Three experimental tests assessing naming and semantic knowledge of unique items of famous persons (FACE) and places (PLACE), logos recognition (LOGO: brands and pictograms), and non-unique entities (Boston Naming Test: BNT) were administered, and the performance of the two groups was compared.Results:Lower scores were observed on all naming tests (PLACE, FACE, LOGO and BNT) in the aMCI group compared to controls. On the PLACE test, the general knowledge mean score (M=84.5, SD=12.9) was significantly higher than the specific knowledge mean score (M=54.2, SD=18.5) in aMCI participants (t(31)=11.9, p<.001), but not in controls (general: M=92.2, SD=11.1; specific: M=73.7, SD=15.8), and there was a significant Group X Type of knowledge interaction (F(1,1)=15.13, p <.001, n2 = 18). On the FACE test, in addition to significant group and condition (naming, semantic questions) main effects, a significant interaction was found (F(1,1)=7.19, p = .009, n2 = .09). On the LOGO task, controls were significantly better on brand items (M= 94.4, SD=10.5) than on pictograms (M=83.3, SD=12.2), while no significant difference was noted in aMCI (brands: M=81.5, SD=22.6; pictograms: M=77.5, SD=14.1). Lastly, on the BNT, aMCI participants benefited more from phonemic cues than controls (F(1,1)=16.56, p<.001, n2=19), suggesting a lexical access deficit, in addition to their semantic memory impairment.Conclusions:This study adds to the growing evidence confirming the presence of semantic memory deficits in aMCI. Specific semantic knowledge seems to be more affected than general semantic knowledge, a finding reported in previous studies. Lexical access deficits, in addition to semantic decline, were also observed in the aMCI group. These results allow for a better understanding of the pattern of semantic memory deficits in the prodromal stage of AD and could potentially facilitate diagnosis of aMCI.