Hippocampal connectivity and memory decline in cognitively intact APOE ε4 carriers.

INTRODUCTION: Resting-state functional magnetic resonance imaging (fMRI) graph theory may help detect subtle functional connectivity changes affecting memory prior to impairment. METHODS: Cognitively normal apolipoprotein E (APOE) ε4 carriers/noncarriers underwent longitudinal cognitive assessment and one-time MRI. The relationship of left/right hippocampal connectivity and memory trajectory were compared between carriers/noncarriers. RESULTS: Steepness of verbal memory decline correlated with decreased connectivity in the left hippocampus, only among APOE ε4 carriers. Right hippocampal metrics were not correlated with memory and there were no significant correlations in the noncarriers. Verbal memory decline correlated with left hippocampal volume loss for both carriers and noncarriers, with no other significant volumetric findings. DISCUSSION: Findings support early hippocampal dysfunction in intact carriers, the AD disconnection hypothesis, and left hippocampal dysfunction earlier than the right. Combining lateralized graph theoretical metrics with a sensitive measure of memory trajectory allowed for detection of early-stage changes in APOE ε4 carriers before symptoms of mild cognitive impairment are present. HIGHLIGHTS: Graph theory connectivity detects preclinical hippocampal changes in APOE ε4 carriers. The AD disconnection hypothesis was supported in unimpaired APOE ε4 carriers. Hippocampal dysfunction starts asymmetrically on the left.

The impact of patient and partner personality traits on learning success for a cognitive rehabilitation intervention for patients with MCI.

The Memory Support System (MSS) is the memory compensation tool used in the HABIT Healthy Action to Benefit Independence and Thinking® Program. People diagnosed with mild cognitive impairment (pwMCI; n = 153) participated in this cognitive rehabilitative programme with a partner. We first aimed to determine if prior research on the positive impact of higher baseline cognitive status on successful MSS learning would be replicated in a new sample. We further evaluated the impact of the pwMCI's and partner's personality traits, as measured by the Ten Item Personality Inventory, on successful learning. Better global cognitive status was again shown to increase the odds for MSS learning success. In terms of personality, the highest odds of learning success occurred when the pwMCI was high in Openness to Experience (OR = 5.43), followed by high partner Openness (OR = 2.53) or high Openness in both the pwMCI and partner (OR = 2.31). In sum, when the pwMCI possessed both better cognitive status and openness to new experience they were better able to master a cognitive rehabilitation tool for MCI.

Comparative Effects of Physical Exercise and Other Behavioral Interventions on Functional Status Outcomes in Mild Cognitive Impairment.

OBJECTIVES: Lifestyle modifications for those with mild cognitive impairment (MCI) may promote functional stability, lesson disease severity, and improve well-being outcomes such as quality of life. The current analysis of our larger comparative effectiveness study evaluated which specific combinations of lifestyle modifications offered as part of the Mayo Clinic Healthy Action to Benefit Independence in Thinking (HABIT) program contributed to the least functional decline in people with MCI (pwMCI) over 18 months. METHODS: We undertook to compare evidence-based interventions with one another rather than to a no-treatment control group. The interventions were five behavioral treatments: computerized cognitive training (CCT), yoga, Memory Support System (MSS) training, peer support group (SG), and wellness education (WE), each delivered to both pwMCI and care partners, in a group-based program. To compare interventions, we randomly withheld one of the five HABIT® interventions in each of the group sessions. We conducted 24 group sessions with between 8 and 20 pwMCI-partner dyads in a session. RESULTS: Withholding yoga led to the greatest declines in functional ability as measured by the Functional Activities Questionnaire and Clinical Dementia Rating. In addition, memory compensation (calendar) training and cognitive exercise appeared to have associations (moderate effect sizes) with better functional outcomes. Withholding SG or WE appeared to have little effect on functioning at 18 months. CONCLUSIONS: Overall, these results add to the growing literature that physical exercise can play a significant and lasting role in modifying outcomes in a host of medical conditions, including neurodegenerative diseases.

Psychometric properties of the self-efficacy for managing mild cognitive impairment scale.

OBJECTIVES: We adapted a self-efficacy measure for managing chronic illness to be specific to persons with mild cognitive impairment (pwMCI). The aim of this study was to investigate the psychometric properties of the scale, the self-efficacy for managing MCI scale, for use in research. METHODS: Analyses involved data from pwMCI enrolled in a behavioral intervention study that completed the measure five times from intervention enrollment to 18-month post-intervention. Factor structure, construct validity, internal consistency, and test-retest reliability were analyzed. RESULTS: Factor analysis identified two factors, related to self-efficacy for daily activities and managing MCI, which corresponded with domains from the original chronic illness self-efficacy scale. Consistent with prior research, construct validity analysis suggested an association between memory-loss self-efficacy and psychosocial distress, but not cognitive or functional ability. Further analyses supported the scale's internal and test-retest reliability. CONCLUSIONS: Currently, no "gold standard" scale of memory-loss self-efficacy for pwMCI exists, despite the positive impact self-efficacy may have on modifiable health behaviors. Overall, results supported the notion that the scale is a valid and reliable measure of memory-loss self-efficacy for pwMCI.

Memory Support System training in mild cognitive impairment: Predictors of learning and adherence.

This study aimed to identify predictors of learning and adherence to a previously validated compensatory calendar and note-taking system (Memory Support System; MSS) in persons with amnestic mild cognitive impairment (aMCI). Age, education, global cognition, depression, and memory-related self-efficacy were studied as predictors of individuals' ability to learn the use of the MSS during the two-week training and of their adherence to the MSS 6, 12, and 18 months after training. How well an individual was able to learn the use of the MSS was itself examined as a predictor of adherence. Two-hundred-and-fifteen older adults with aMCI and their study partners (e.g., spouse, adult child) received MSS training one-hour daily for 10 days. Ordinal logistic regression analyses indicated that (1) global cognition predicted MSS learning at end of training, and (2) MSS learning at end of trainng predicted MSS adherence at 6, 12, and 18 months post-training. The current study suggests that offering compensatory strategies as early as possible for those with MCI might be of most benefit, and might have implications for long-term adherence.

Neuropsychological decline up to 20 years before incident mild cognitive impairment.

INTRODUCTION: Some Alzheimer's disease biomarker studies found amyloid changes 20 years or more in advance of expected symptoms, while cognitive changes lagged for more than a decade, but this apparent lag might reflect the sensitivities of the biomarker and cognitive assays used. How far in advance of incident amnestic mild cognitive impairment (MCI) does cognition begin to decline? METHODS: Longitudinal neuropsychological study of an apolipoprotein E e4 enriched cohort of cognitively normal individuals at entry. Linear mixed models for MCI converters (n = 65) and nonconverters (n = 719) fitted for each neuropsychological measure; annual changes compared between groups before and after linear model intersections (inflection points). RESULTS: 34 of 35 cognitive measures and 9 of 18 behavioral measures declined faster post-inflection in the MCI converters; the earliest cognitive inflection point was nearly 20 years in advance of MCI diagnosis. DISCUSSION: The preclinical duration of cognitive and behavioral changes approaches the earliest reported biomarker changes.

Subjective Cognitive Impairment and the Broad Autism Phenotype.

INTRODUCTION: Roughly 4% to 23% of the population embody stress prone personality and other traits characterizing a subclinical "broad autism phenotype" (BAP). Subjective cognitive impairment (SCI) among healthy elderly is associated with psychological distress leading us to predict BAP would be associated with SCI. METHODS: The Autism Spectrum Quotient, a self-administered 50 item questionnaire, was completed by 419 consecutive members of the Arizona APOE Cohort who underwent neuropsychological testing every 2 years. SCI was assessed with self and informant versions of the Multidimensional Assessment of Neurodegenerative Symptoms (MANS) Questionnaire. RESULTS: A total of 45 individuals scored in the BAP range, designated BAP+, and the rest were BAP-. At entry, both Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire Self and Informant scores were higher in the BAP+ group (P<0.0001). After age 60, the BAP+ group had greater annual increases in Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire Self scores (0.05 vs. 0.02; difference=0.03; 95% confidence interval, 0.004-0.05; P=0.02) yet there was no difference between groups in memory decline. Over ~10 years 33 individuals developed mild cognitive impairment: 4 in the BAP+ group (8.9%) and 29 in the BAP- group (7.8%), P=0.77. DISCUSSION: Individuals who meet criteria for the BAP have escalating SCI with age, but no greater rate of memory decline or clinical progression to mild cognitive impairment.

Diagnostic utility of the Minnesota Multiphasic Personality Inventory-2 Restructured Form in the epilepsy monitoring unit: Considering sex differences.

Psychological assessment measures are frequently used to evaluate patients in epilepsy monitoring units. One goal of that assessment is to contribute information that may help with differential diagnosis between epilepsy and psychogenic nonepileptic seizures (PNES). The Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) is one such measure. Del Bene et al. (2017) recently published an analysis that was the first to compare MMPI-2-RF scale elevations between diagnostic groups stratified by sex. The purpose of the present study was to replicate that analysis in a larger sample. Similar to previous work, we found that both men and women with PNES were more likely than men and women with epilepsy to report high levels of somatic complaints (2 to 5 times greater odds of somatic symptom reporting) and a variety of types of complaints. Mood disturbance scales were not significantly elevated in our PNES sample. Results contribute to the small body of research on sex differences in patients with PNES and suggest that somatization is a key characterization across sexes.

Lorazepam Challenge for Individuals at Varying Genetic Risk for Alzheimer Disease.

INTRODUCTION: This study set out to clarify the differential acute cognitive impact of lorazepam based on varying genetic risk for Alzheimer disease. METHODS: Fifty-seven cognitively unimpaired individuals aged 51 to 88, genotyped according to apolipoprotein E (APOE) and translocase of outer mitochondrial membrane (40 homolog) poly-T lengths, completed cognitive testing before, 2.5 and 5 hours after receiving a 1 mg dose of lorazepam. RESULTS: Post-lorazepam, there were significant (P<0.05) declines from baseline in memory, psychomotor processing speed, and executive function. At 2.5 hours, the magnitude of this lorazepam-induced cognitive change was significantly greater in the APOE3/4 group than in the APOE3/3 group for tests of working memory and visuospatial memory/executive function. At 5 hours postchallenge, verbal memory and working memory deficits persisted in the APOE3/4 group compared with the APOE3/3 group. At 5 hours after lorazepam challenge, as compared with the very long/very long group, the short/short group performed slightly worse on a test of working memory (P<0.05), but no other differences were observed among translocase of the outer mitochondrial membrane 40 homolog poly-T variant groups. DISCUSSION: The lorazepam challenge may be unmasking presymptomatic cognitive dysfunction associated with APOE4 carriage.

A pilot randomized trial of two cognitive rehabilitation interventions for mild cognitive impairment: caregiver outcomes.

OBJECTIVE: This study aims to provide effect size estimates of the impact of two cognitive rehabilitation interventions provided to patients with mild cognitive impairment: computerized brain fitness exercise and memory support system on support partners' outcomes of depression, anxiety, quality of life, and partner burden. METHODS: A randomized controlled pilot trial was performed. RESULTS: At 6 months, the partners from both treatment groups showed stable to improved depression scores, while partners in an untreated control group showed worsening depression over 6 months. There were no statistically significant differences on anxiety, quality of life, or burden outcomes in this small pilot trial; however, effect sizes were moderate, suggesting that the sample sizes in this pilot study were not adequate to detect statistical significance. CONCLUSION: Either form of cognitive rehabilitation may help partners' mood, compared with providing no treatment. However, effect size estimates related to other partner outcomes (i.e., burden, quality of life, and anxiety) suggest that follow-up efficacy trials will need sample sizes of at least 30-100 people per group to accurately determine significance. Copyright © 2017 John Wiley & Sons, Ltd.

Impact of Personality on Cognitive Aging: A Prospective Cohort Study.

OBJECTIVES: The aim of this study was to assess the association between personality factors and age-related longitudinal cognitive performance, and explore interactions of stress-proneness with apolipoprotein E (APOE) ɛ4, a prevalent risk factor for Alzheimer's disease (AD). METHODS: A total of 510 neuropsychiatrically healthy residents of Maricopa County recruited through media ads (mean age 57.6±10.6 years; 70% women; mean education 15.8±2.4 years; 213 APOE ɛ4 carriers) had neuropsychological testing every 2 years (mean duration follow-up 9.1±4.4 years), and the complete Neuroticism Extraversion Openness Personality Inventory-Revised. Several tests were administered within each of the following cognitive domains: memory, executive skills, language, visuospatial skills, and general cognition. Primary effects on cognitive trajectories and APOE ɛ4 interactions were ascertained with quadratic models. RESULTS: With personality factors treated as continuous variables, Neuroticism was associated with greater decline, and Conscientiousness associated with reduced decline consistently across tests in memory and executive domains. With personality factors trichotomized, the associations of Neuroticism and Conscientiousness were again highly consistent across tests within memory and to a lesser degree executive domains. While age-related memory decline was greater in APOE ɛ4 carriers as a group than ɛ4 noncarriers, verbal memory decline was mitigated in ɛ4 carriers with higher Conscientiousness, and visuospatial perception and memory decline was mitigated in ɛ4 carriers with higher Openness. CONCLUSIONS: Neuroticism and Conscientiousness were associated with changes in longitudinal performances on tests sensitive to memory and executive skills. APOE interactions were less consistent. Our findings are consistent with previous studies that have suggested that personality factors, particularly Neuroticism and Conscientiousness are associated with cognitive aging patterns. (JINS, 2016, 22, 765-776).

Sex-based memory advantages and cognitive aging: a challenge to the cognitive reserve construct?

Education and related proxies for cognitive reserve (CR) are confounded by associations with environmental factors that correlate with cerebrovascular disease possibly explaining discrepancies between studies examining their relationships to cognitive aging and dementia. In contrast, sex-related memory differences may be a better proxy. Since they arise developmentally, they are less likely to reflect environmental confounds. Women outperform men on verbal and men generally outperform women on visuospatial memory tasks. Furthermore, memory declines during the preclinical stage of AD, when it is clinically indistinguishable from normal aging. To determine whether CR mitigates age-related memory decline, we examined the effects of gender and APOE genotype on longitudinal memory performances. Memory decline was assessed in a cohort of healthy men and women enriched for APOE ɛ4 who completed two verbal [Rey Auditory Verbal Learning Test (AVLT), Buschke Selective Reminding Test (SRT)] and two visuospatial [Rey-Osterrieth Complex Figure Test (CFT), and Benton Visual Retention Test (VRT)] memory tests, as well as in a separate larger and older cohort [National Alzheimer's Coordinating Center (NACC)] who completed a verbal memory test (Logical Memory). Age-related memory decline was accelerated in APOE ɛ4 carriers on all verbal memory measures (AVLT, p=.03; SRT p<.001; logical memory p<.001) and on the VRT p=.006. Baseline sex associated differences were retained over time, but no sex differences in rate of decline were found for any measure in either cohort. Sex-based memory advantage does not mitigate age-related memory decline in either APOE ɛ4 carriers or non-carriers.

APOE ε4 Genotype and the Risk for Subjective Cognitive Impairment in Elderly Persons.

The authors compared the risk for subjective cognitive impairment (SCI) between carriers of the apolipoprotein E ε4 (APOE ε4) allele (cases) and APOE ε4 noncarriers (controls). SCI was assessed by a validated self-reported questionnaire. The authors used multivariable logistic regression analyses to compute odds ratios and 95% confidence intervals adjusted for age, sex, education, and marital status. Data were available on 114 participants (83 women; 47 APOE ε4 carriers; mean age, 69 years). The risk for SCI was significantly higher among cases than controls, particularly for those 70 years of age and older. These findings should be considered preliminary until confirmed by a prospective cohort study.

Quality of life in psychogenic nonepileptic seizures and epilepsy: the role of somatization and alexithymia.

It is clear that many individuals with psychogenic nonepileptic seizures (PNESs) often present with poorer quality of life compared with those with epileptic seizures (ESs). However, the mechanisms linking seizure diagnosis to quality-of-life outcomes are much less clear. Alexithymia and somatization are emotional markers of psychological functioning that may explain these differences in quality of life. In the current study, patients from an epilepsy monitoring unit with vEEG-confirmed diagnosis of PNESs or ESs were compared on measures of alexithymia, somatization, quality of life, and a variety of demographic and medical variables. Two models using alexithymia and somatization individually as mediators of the relations between diagnosis and quality of life were tested. Results indicated that patients with PNESs had significantly poorer quality of life compared with those with ESs. Alexithymia was associated with poor quality of life in both groups but did not differentiate between diagnostic groups. Further, alexithymia did not mediate the relationship between diagnosis and quality of life. Somatization was associated with poor quality of life, and patients with PNESs reported greater somatization compared with patients with ESs. Somatization also significantly mediated the relationship between diagnosis and quality of life. In conclusion, somatization may be one mechanism affecting poor quality of life among patients with PNESs compared with ESs and should be a target of comprehensive treatments for PNESs. Alexithymia proved to be an important factor impacting quality of life in both groups and should also be targeted in treatment for patients with PNESs and patients with ESs.

Role of theory of mind in emotional awareness and alexithymia: Implications for conceptualization and measurement.

The goal of this study was to determine whether alexithymia, which is characterized by difficulty in recognizing and describing emotions, is associated with impairments in the ability to mentally represent emotional states. We studied 89 outpatients including 29 conversion disorder patients, 30 functional somatic syndrome [e.g. fibromyalgia] patients and 30 medical controls. Groups did not differ on affective or cognitive Theory of Mind (ToM) measures, the Levels of Emotional Awareness Scale (LEAS) or the Twenty-Item Toronto Alexithymia Scale (TAS-20) after adjusting for Positive and Negative Affect Scale (PANAS) variables. Across all patients, LEAS but not TAS-20 correlated positively with affective and cognitive ToM measures after adjusting for PANAS scores. Impairments in ToM functioning influence LEAS performance but not TAS-20 scores. These findings support the distinction between a milder "anomia" form of alexithymia associated with impaired emotion naming and a more severe "agnosia" form associated with impaired mental representation of emotion.

Subjective cognitive decline: self and informant comparisons.

BACKGROUND: It is unclear whether self- or informant-based subjective cognition better distinguishes emotional factors from early-stage Alzheimer's disease (AD). METHODS: Healthy members (n = 447) of the Arizona apolipoprotein E (APOE) cohort and their informants completed the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS). RESULTS: Decline on the MANS was endorsed by 30.6% of members and 26.2% of informants. Self- and informant-based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8 [7.0] vs 58.8 [7.3] years, P = .003), 85% were APOE ε4 carriers (P < .0001), and they self-endorsed decline earlier than informants (58.9 [39.2] vs 28.0 [40.4] months before MCI; P = .002). CONCLUSIONS: Self- and informant-based subjective decline correlated with greater psychological distress and slightly lower cognitive performance. Those with incident MCI generally self-endorsed decline earlier than informants.

The neuropsychology of normal aging and preclinical Alzheimer's disease.

OBJECTIVE: A National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. METHODS: Seventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups. RESULTS: There was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups. CONCLUSIONS: Although cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design.

Fibrillar amyloid correlates of preclinical cognitive decline.

BACKGROUND: It is not known whether preclinical cognitive decline is associated with fibrillar ß-amyloid (Aß) deposition irrespective of apolipoprotein E (APOE) ε4 status. METHODS: From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aß burden. RESULTS: At P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners. CONCLUSIONS: Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

Cognition Before and After COVID-19 Disease in Older Adults: An Exploratory Study.

BACKGROUND: Older age is a major risk factor for severe COVID-19 disease which has been associated with a variety of neurologic complications, both acutely and chronically. OBJECTIVE: We sought to determine whether milder COVID-19 disease in older vulnerable individuals is also associated with cognitive and behavioral sequelae. METHODS: Neuropsychological, behavioral, and clinical outcomes before and after contracting COVID-19 disease, were compared in members of two ongoing longitudinal studies, the Arizona APOE Cohort and the national Alzheimer's Disease Research Center (ADRC). RESULTS: 152 APOE and 852 ADRC cohort members, mean age overall roughly 70 years, responded to a survey that indicated 21 APOE and 57 ADRC members had contracted COVID-19 before their ensuing (post-COVID) study visit. The mean interval between test sessions that preceded and followed COVID was 2.2 years and 1.2 years respectively for the APOE and ADRC cohorts. The magnitude of change between the pre and post COVID test sessions did not differ on any neuropsychological measure in either cohort. There was, however, a greater increase in informant (but not self) reported cognitive change in the APOE cohort (p = 0.018), but this became nonsignificant after correcting for multiple comparisons. CONCLUSION: Overall members of both cohorts recovered well despite their greater age-related vulnerability to more severe disease.

Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect.

BACKGROUND: The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. CONCLUSIONS: Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.