Longer time horizons are associated with reduced risk of mortality and disability in older adults.

OBJECTIVES: Longer time horizons are associated with positive health behaviors, but the associations of time horizons with disability and mortality are less understood. This study aims to test the hypothesis that longer time horizons are associated with decreased disability and mortality in older adults. METHOD: Participants were 1052 older adults (mean age = 81 ± 7 years) without dementia. Proportional hazard models adjusted for age, sex, and education were used to examine the associations of time horizons with risk of mortality and disability. RESULTS: During up to 11 years of follow up (mean = 5.7), 317 participants died. In fully adjusted models, longer time horizons were associated with reduced mortality risk (hazard rate [HR] = 0.78, 95% confidence interval [CI] = 0.68-0.89). About 36.7% of participants developed disability in instrumental activities of daily living (ADLs) and 49.3% developed disability in basic ADLs during follow up. Longer time horizons were associated with a reduced risk of disability in basic ADLs (HR = 0.89, 95% CI = 0.79-0.99) but not instrumental ADLs (HR = 0.90, 95% CI = 0.80-1.03). CONCLUSION: Longer time horizons are associated with a reduced risk of all-cause mortality and disability in basic ADLs among community-dwelling older adults, thus highlighting a potentially modifiable psychological risk factor for negative health outcomes in aging.

Sex and Education Modify the Association Between Subjective Cognitive Decline and Amyloid Pathology.

Background: Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer's disease (AD) biomarkers in non-demented older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72±6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD (ß-amyloid 42 (Aß42), Aß42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level , and SCD x education interactions on AD biomarkers. Result: In main effect models, higher SCD was associated with lower Aß42 and Aß42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels ( p- values>0.38). SCD score interacted with sex on Aß42/40 ratio ( p =0.03) but no other biomarkers ( p -values>0.10). In stratified models, higher SCD was associated with lower Aß42/40 ratio in men ( p =0.0003) but not in women ( p =0.48). SCD score interacted with education on Aß42 ( p =0.005) and Aß42/40 ratio ( p =0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values> 0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level. Conclusion: Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.

Clinical and demographic factors modify the association between plasma phosphorylated tau-181 and cognition.

INTRODUCTION: Plasma phosphorylated tau181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and included 1185 adults aged >55 years with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, APOE ε4 carrier status, age, and sex on cognitive outcomes. RESULTS: Higher plasma p-tau181 was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in MCI or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex.

Biomarker disclosure protocols in prodromal Alzheimer's disease clinical trials.

INTRODUCTION: The development of biomarkers for Alzheimer's disease (AD) has allowed researchers to increase sample homogeneity and test candidate treatments earlier in the disease. The integration of biomarker "screening" criteria should be met with a parallel implementation of standardized methods to disclose biomarker testing results to research participants; however, the extent to which protocolized disclosure occurs in trials is unknown. METHODS: We reviewed the literature to identify prodromal AD trials published in the past 10 years. From these, we quantified the frequency of biomarker disclosure reporting and the depth of descriptions provided. RESULTS: Of 30 published trials using positron emission tomography or cerebrospinal fluid-based amyloid positivity as an eligibility criterion, only one mentioned disclosure, with no details on methods. DISCUSSION: Possible reasons for and implications of this information gap are discussed. Recommendations are provided for trialists considering biomarker screening as part of intervention trials focused on prodromal AD. HIGHLIGHTS: Few prodromal Alzheimer's disease (AD) trial papers discuss biomarker disclosure. Disclosure has implications for participants, family members, and trial success. Disclosure must be consistently integrated and reported in prodromal AD trials. Best practice guidelines and training resources for disclosure are needed.

Baseline grey matter volumes and white matter hyperintensities predict decline in functional activities in older adults over a 5-year follow-up period.

INTRODUCTION: Functional independence is an essential predictor of quality of life in aging, yet few accessible predictors of functional decline have been identified. This study examined associations between baseline structural neuroimaging markers and longitudinal functional status. METHODS: Linear mixed effects models with follow-up time interaction terms related baseline grey matter volume and white matter hyperintensities (WMHs) to functional trajectory, adjusting for demographic and medical covariates. Subsequent models assessed interactions with cognitive status and apolipoprotein E (APOE) ε4 status. RESULTS: Smaller baseline grey matter volumes, particularly in regions commonly affected by Alzheimer's disease (AD), and greater baseline WMHs were associated with faster functional decline over a mean 5-year follow-up. Effects were stronger in APOE-ε4 carriers on grey matter variables. Cognitive status interacted with most MRI variables. DISCUSSION: Greater atrophy in AD-related regions and higher WMH burden at study entry were associated with faster functional decline, particularly among participants at increased risk of AD.

Utility of empathy informant report in FTD differential diagnosis.

OBJECTIVE: Loss of empathy is a hallmark feature of behavioral variant frontotemporal dementia (bvFTD). Change in socioemotional functioning identified by others is often the primary initial presenting concern in this disorder, in contrast to more subtle early cognitive changes and limited patient insight. The present study examined the predictive utility of an empathy informant-report measure for discriminating clinician-diagnosed bvFTD from other dementia syndromes. METHOD: Data from the National Alzheimer's Coordinating Center (NACC) database were used to study individuals with bvFTD (n = 406) and other dementia syndromes (n = 385). Participants were administered neuropsychological measures and collateral informants completed an informant-report of empathy. RESULTS: Informants reported that patients with bvFTD demonstrated significantly lower levels of empathic concern [F(1, 789) = 120.91, p < .001, η2 = 0.13] and perspective taking [F(1, 789) = 153.08, p < .001, η2 = 0.16] than patients with other dementia syndromes. These differences were not attributable to the level of global cognitive impairment. Empathy scores were not significantly associated with any neurocognitive measure when controlling for age. ROC curve analyses showed fair to good clinical utility of the informant-report empathy measure for distinguishing bvFTD from non-bvFTD, whereas a traditional measure of executive functioning failed to differentiate the groups. CONCLUSIONS: These findings indicate that informant ratings of empathy offer a unique source of clinical information that may be useful in detecting neurobehavioral changes specific to bvFTD before a clear neurocognitive pattern emerges on testing.

Differential Involvement of the Locus Coeruleus in Early- and Late-Onset Alzheimer's Disease: A Potential Mechanism of Clinical Differences?

Sporadic early-onset Alzheimer's disease (sEOAD) is often associated with atypical clinical features, yet the cause of this heterogeneity remains unclear. This study investigated post-mortem atrophy of the locus coeruleus (LC) in sEOAD and late-onset Alzheimer's disease (LOAD). Levels of LC atrophy, as estimated by pathologist-rating of hypopigmentation, were compared between sEOAD (n = 115) and LOAD (n = 672) participants while controlling for other measures of pathological progression. Subsequent analyses compared low vs. high LC atrophy sEOAD subgroups on neuropsychological test performance. Results show nearly 4 times greater likelihood of higher LC atrophy in sEOAD as compared to LOAD (p < .005). sEOAD participants with greater LC atrophy displayed significantly worse performance on various baseline measures of attentional functioning (p < .05), despite similar global cognition (p = .25). These findings suggest the LC is an important potential driver of clinical and pathological heterogeneity in sEOAD.

Cognitive functioning of older adults prior to hematopoietic stem cell transplantation.

Hematopoietic cell transplantation is increasingly used in older adults with hematological malignancies. Younger adult patients who undergo HCT have shown to commonly present with cognitive impairment and depression prior to transplant; however, little research has been done to understand the cognitive and emotional functioning of older adults undergoing HCT. This study aimed to investigate the rate of cognitive impairment in a retrospective sample of older adult HCT candidates prior to transplant using a comprehensive battery. Ninety-three patients over the age of 60 completed a neuropsychology test battery that assessed standard domains of cognitive and emotional functioning. Impairment was defined as z-scores = < -1.5 on at least two tests or a z score = < -2.0 on at least one test. Results indicated that over 68% of patients were impaired with nearly a third of the sample showing impairment in verbal learning and memory and approximately one fifth showing impairments in aspects of executive function, processing speed, and visual learning. Ten percent of the patients endorsed symptoms indicative of a clinical level of depression. Medical comorbidities nor depression predicted cognitive impairment. These findings suggest that older adults candidates for HCT are at risk for cognitive impairment prior to transplant and thus cognition should be a consideration when developing treatment plans.

Post-traumatic Stress Disorder Following Acute Delirium.

Delirium is a significant medical condition that is common in hospitalized patients. Beyond the increased risk of mortality, patients who experience an episode of delirium often go on to develop long-term psychiatric disturbance, including symptoms of post-traumatic stress disorder (PTSD). While there is a growing interest in understanding the complex relationship between delirium and PTSD, the existing literature is sparse and lacking harmony. Thus, this review seeks to develop a unified and thorough description of the cognitive and psychiatric underpinnings of post-delirium PTSD with the aims of promoting awareness of this condition amongst clinicians in medical settings, improving patient care, and sparking further research on this topic. While specific underlying mechanisms are yet unclear, PTSD was found to be associated with delirium in that delirious patients may have decreased factual recall of hospital events and increased hallucinations/delusions of a traumatic nature. Several potential interventions were identified, as well as suggestions for future research and clinical practice.

Differential Involvement of the Locus Coeruleus in Early- and Late-Onset Alzheimer's Disease: A Potential Mechanism of Clinical Differences?

Early-onset Alzheimer's disease (EOAD) has been associated with an increased likelihood of atypical clinical manifestations such as attentional impairment, yet the cause of this heterogeneity remains unclear. The locus coeruleus (LC) is implicated early in Alzheimer's disease pathology and is associated with attentional functioning. This study investigated post-mortem atrophy of the LC in EOAD and late-onset Alzheimer's disease (LOAD) in a large, well-characterized sample. Results show nearly four times greater likelihood of higher LC atrophy in EOAD as compared to LOAD after controlling for other measures of pathological progression ( p < .005). Follow-up analyses within the EOAD group revealed that compared to those who displayed mild or no LC atrophy at autopsy, those with moderate-severe atrophy of the LC displayed significantly worse performance on various baseline measures of attentional functioning ( p < .05), despite similar overall cognition ( p = .25). These findings suggest the LC is an important potential driver of clinical and pathological heterogeneity in EOAD.

Comparison of cognitive profiles in spinocerebellar ataxia subtypes: a case series.

BACKGROUND: The spinocerebellar ataxias (SCA) are a heterogeneous group of progressive neurodegenerative disorders that are associated with diffuse cerebellar atrophy. While the physical symptoms of this condition have long been studied, more attention has been given to cognitive changes in recent years. We describe a case series of four adults with various genetically-confirmed subtypes of SCA. CASE PRESENTATION: Patients with SCA types 2, 3, and 6 presented with impaired cognitive profiles consistent with the existing literature while the reported patient with SCA-14 showed notable impairment inconsistent with the only published case controlled study. CONCLUSIONS: Comparisons were made between the four patients with a common pattern of slowed processing speed, poor memory retrieval, and reduced mental flexibility. Confrontation naming and consolidation-based memory were intact across all patients. These findings are discussed in light of the relevant literature on cerebellar cognitive affective syndrome.

Neurocognitive Functioning in Unoperated Adults with Chiari Malformation Type I.

OBJECTIVE: Adults with Chiari malformation type 1 (CM1) often report cognitive impairment. This cross-sectional study investigates the cognitive and emotional functioning of a sample of adults with CM1 who presented for neurosurgical evaluation prior to intervention. METHODS: A total of 36 participants (18 patients with CM1 and 18 healthy control subjects) completed a comprehensive neurocognitive battery of tests. RESULTS: Demographic variables (sex, age, handedness, and education) were not statistically significant between the groups. Measures of gross cognition (Mini-Mental State Examination and Repeatable Battery for the Assessment of Neuropsychological Status) were statistically significant between the groups. On a more focused assessment of neurocognitive abilities, the CM1 group performed significantly worse on measures of learning, memory, fluency, and figural copy. A high rate of clinical depression was seen in the CM1 group; however, this did not correlate with cognitive performance. CONCLUSIONS: The CM1 group displayed subtle learning, semantic fluency, and complex construction difficulties compared with healthy control subjects. Although not correlated with cognition, adults with CM1 are at high risk for clinical depression.