Neuropsychiatric symptoms: Risk factor or disease marker? A study of structural imaging biomarkers of Alzheimer's disease and incident cognitive decline.

Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later-life emergent and persistent NPS that may mark early-stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non-MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non-MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta-region of interest (ROI) mean cortical thickness were acquired from T1-weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non-MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later-life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non-MBI NPS.

Interaction of Alzheimer Disease and Traumatic Brain Injury on Cortical Thickness.

INTRODUCTION: Traumatic brain injury (TBI) is associated with an accelerated course of dementia, although biological relationships are incompletely understood. METHODS: The study examined 1124 participants, including 343 with Alzheimer disease (AD), 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. Cortical thickness was quantified from T1-weighted magnetic resonance imaging data. Multiple linear regression was used to determine the interaction between AD and TBI on cortical thickness. RESULTS: Among those with AD, TBI was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls. DISCUSSION: AD with TBI represents a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss. This finding has important implications for the diagnosis and treatment of AD in the presence of TBI and indicates that models of AD, aging, and neural loss should account for TBI history.

The effect of study partner characteristics on the reporting of neuropsychiatric symptoms across the neurocognitive spectrum.

OBJECTIVES: We explored the influence of study partner (SP) characteristics on SP-reported neuropsychiatric symptoms (NPS) presence across the neurocognitive spectrum and on the prognostic utility of mild behavioral impairment (MBI). DESIGN, SETTING, AND PARTICIPANTS: We performed cross-sectional (n = 26,748) and longitudinal (n = 12,794) analyses using participant-SP dyad data from the National Alzheimer's Coordinating Center. Participants were cognitively normal (CN; n = 11,951) or had mild cognitive impairment (MCI; n = 5686) or dementia (n = 9111). MEASUREMENTS: SPs rated NPS using the Neuropsychiatric Inventory Questionnaire. We used multivariable logistic regression to model the association between SP characteristics (age, sex, and relationship to participant [spouse, child, and other]) and NPS status (outcome). Cox regressions assessed SP characteristics as moderators of MBI associations with incident dementia or as predictors of incident dementia in MBI + participants only. RESULTS: Among CN persons, younger, female, and spouse SPs reported NPS more frequently. In MCI, younger SPs and those who were spouses or children of participants reported higher NPS odds. For dementia participants, NPS odds were higher in female and spouse SPs. MBI associations with incident dementia were slightly weaker when SPs were older but did not depend on SP sex or relationship to participant. Among MBI + participants with spouse or child SPs, hazard for dementia was higher when compared to MBI + participants with other SPs. CONCLUSIONS: SP age, sex, and relationship to participant influence NPS reporting across the neurocognitive spectrum, with potential implications for MBI prognosis. Considering SP characteristics may enhance the accuracy of NPS assessments, which may facilitate therapy planning and prognosis.

The mind and motion: exploring the interplay between physical activity and Mild Behavioral Impairment in dementia-free older adults.

Physical inactivity in mid-life is a modifiable risk factor for dementia. Mild behavioral impairment (MBI) is a marker of potential neurodegenerative disease. We investigated the association between physical activity and MBI. Baseline data from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT) were used. Four categories of weekly physical activity (cardiovascular, mind-body, strength training, and physical labour) were derived from the Community Healthy Activities Model Program for Seniors questionnaire. MBI was measured using the MBI-Checklist. Multivariable negative binomial regressions modelled the association between the standardized physical activity duration and MBI severity, adjusted for age, sex, education, marital status, ethno cultural origin, occupation, hypertension, dyslipidemia, mobility, and body mass index. Every 1 SD increase in cardiovascular activity was associated with 8.42% lower MBI severity. In contrast, every 1 SD increase in physical labor duration was associated with 5.64% greater MBI severity. These associations were neither moderated by the frequency engaging in each physical activity nor by sex. Cardiovascular physical activity in older persons may reduce levels of non-cognitive dementia markers like MBI, comparable to effects seen in cognition, potentially modulating dementia risk.

Neuroanatomical correlates of distracted straight driving performance: a driving simulator MRI study across the lifespan.

Background: Driving is the preferred mode of transportation for adults across the healthy age span. However, motor vehicle crashes are among the leading causes of injury and death, especially for older adults, and under distracted driving conditions. Understanding the neuroanatomical basis of driving may inform interventions that minimize crashes. This exploratory study examined the neuroanatomical correlates of undistracted and distracted simulated straight driving. Methods: One-hundred-and-thirty-eight participants (40.6% female) aged 17-85 years old (mean and SD = 58.1 ± 19.9 years) performed a simulated driving task involving straight driving and turns at intersections in a city environment using a steering wheel and foot pedals. During some straight driving segments, participants responded to auditory questions to simulate distracted driving. Anatomical T1-weighted MRI was used to quantify grey matter volume and cortical thickness for five brain regions: the middle frontal gyrus (MFG), precentral gyrus (PG), superior temporal cortex (STC), posterior parietal cortex (PPC), and cerebellum. Partial correlations controlling for age and sex were used to explore relationships between neuroanatomical measures and straight driving behavior, including speed, acceleration, lane position, heading angle, and time speeding or off-center. Effects of interest were noted at an unadjusted p-value threshold of 0.05. Results: Distracted driving was associated with changes in most measures of straight driving performance. Greater volume and cortical thickness in the PPC and cerebellum were associated with reduced variability in lane position and heading angle during distracted straight driving. Cortical thickness of the MFG, PG, PPC, and STC were associated with speed and acceleration, often in an age-dependent manner. Conclusion: Posterior regions were correlated with lane maintenance whereas anterior and posterior regions were correlated with speed and acceleration, especially during distracted driving. The regions involved and their role in straight driving may change with age, particularly during distracted driving as observed in older adults. Further studies should investigate the relationship between distracted driving and the aging brain to inform driving interventions.

Longitudinal Associations Between Mild Behavioral Impairment, Sleep Disturbance, and Progression to Dementia.

Background: Clinical guidelines recommend incorporating non-cognitive markers like mild behavioral impairment (MBI) and sleep disturbance (SD) into dementia screening to improve detection. Objective: We investigated the longitudinal associations between MBI, SD, and incident dementia. Methods: Participant data were from the National Alzheimer's Coordinating Center in the United States. MBI was derived from the Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. SD was determined using the NPI-Q nighttime behaviors item. Cox proportional hazard regressions with time-dependant variables for MBI, SD, and cognitive diagnosis were used to model associations between baseline 1) MBI and incident SD (n = 11,277); 2) SD and incident MBI (n = 10,535); 3) MBI with concurrent SD and incident dementia (n = 13,544); and 4) MBI without concurrent SD and incident dementia (n = 11,921). Models were adjusted for first-visit age, sex, education, cognitive diagnosis, race, and for multiple comparisons using the Benjamini-Hochberg method. Results: The rate of developing SD was 3.1-fold higher in older adults with MBI at baseline compared to those without MBI (95% CI: 2.8-3.3). The rate of developing MBI was 1.5-fold higher in older adults with baseline SD than those without SD (95% CI: 1.3-1.8). The rate of developing dementia was 2.2-fold greater in older adults with both MBI and SD, as opposed to SD alone (95% CI:1.9-2.6). Conclusions: There is a bidirectional relationship between MBI and SD. Older adults with SD develop dementia at higher rates when co-occurring with MBI. Future studies should explore the mechanisms underlying these relationships, and dementia screening may be improved by assessing for both MBI and SD.

Persistence of neuropsychiatric symptoms and dementia prognostication: A comparison of three operational case definitions of mild behavioral impairment.

INTRODUCTION: We compared three operational case definitions of mild behavioral impairment (MBI) in the context of MBI prevalence estimates and dementia risk modeling. METHODS: Participants were dementia-free older adults (n = 13701) from the National Alzheimer's Coordinating Center. Operational case definitions of MBI were generated based on neuropsychiatric symptoms at one (OV), two-consecutive (TCV), or more than two-thirds (TTV) of dementia-free study visits. Definitions were compared in prevalence and in Cox regressions using MBI to predict incident dementia. RESULTS: OV MBI was the most prevalent (54.4%), followed by TCV (32.3%) and TTV (26.7%) MBI. However, OV MBI had the lowest rate of incident dementia (hazard ratio [HR] = 2.54, 95% confidence interval [CI]: 2.33-2.78) and generated poorer model metrics than TCV MBI (HR = 4.06, 95% CI: 3.74-4.40) and TTV MBI (HR = 5.77, 95% CI: 5.32-6.26). DISCUSSION: Case ascertainment with longer timeframe MBI operational case definitions may more accurately define groups at risk of dementia in datasets lacking tools designed to detect MBI.Highlights: Mild behavioral impairment (MBI) can identify older adults at risk of dementia.Neuropsychiatric symptom (NPS) assessment tools can be proxy measures for MBI.Hazard for dementia was highest for MBI defined by NPS presence at more than two-thirds of visits.

Temporal associations between treated and untreated hearing loss and mild behavioral impairment in older adults without dementia.

INTRODUCTION: Hearing loss (HL) and mild behavioral impairment (MBI) are non-cognitive markers of dementia. This study investigated the relationship between hearing and MBI and explored the influence of hearing aid use on the treatment of hearing loss, both cross-sectionally and longitudinally. METHODS: Data were analyzed from National Alzheimer's Coordinating Center participants, age ≥50, dementia-free at baseline, collected between 2005 and 2022. Three self-report questions were used to generate a three-level categorical hearing variable: No-HL, Untreated-HL, and Treated-HL. MBI status was derived from the informant-rated Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. At baseline (n = 7080), logistic regression was used to examine the association between hearing status (predictor) and the presence of global and domain-specific MBI (outcome), adjusting for age, sex, cognitive diagnosis, and apolipoprotein E4 (APOE4). Cox proportional hazard models with time-dependent covariates were used to examine the effect of (1) hearing status as exposure on the rate of incident MBI (n = 5889); and (2) MBI as exposure on the rate of incident HL in those with no HL at baseline (n = 6252). RESULTS: Cross-sectionally, participants with Untreated-HL were more likely to exhibit global MBI (adjusted odds ratio (aOR) = 1.66, 95% CI: 1.24-2.21) and individual MBI domains of social inappropriateness (aOR = 1.95, 95% CI: 1.06-3.39), affective dysregulation (aOR = 1.71, 95% CI: 1.21-2.38), and impulse dyscontrol (aOR = 1.71, 95% CI: 1.21-2.38), compared to those with No-HL. Participants with Treated-HL (i.e., hearing aid use) did not differ from No-HL for odds of global or most MBI domains, except for impulse dyscontrol (aOR = 1.38, 95% CI: 1.05-1.81). Longitudinally, we found relationships between Treated-HL and incident MBI (adjusted hazard ratio (aHR) = 1.29, 95% CI: 1.01-1.63) and between MBI and incident Untreated-HL (aHR = 1.51, 95% CI: 1.19-1.94). DISCUSSION: Our cross-sectional results support that hearing aid use is associated with lower odds of concurrent global MBI in dementia-free participants. Longitudinally, relationships were found between MBI and HL. The severity of HL was not assessed, however, and may require further exploration. Highlights: Hearing Loss (HL) and mild behavioral impairment (MBI) are markers of dementiaCross-sectionally: Untreated-HL was associated with global MBI burden, butHL treated with hearing aids was notWe found associations between MBI and incident Untreated-HL.

Dual-task gait and mild behavioral impairment: The interface between non-cognitive dementia markers.

BACKGROUND: Mild behavioral impairment (MBI) and dual-task gait cost (DTGC) are two non-cognitive markers of dementia that capture behavioral and motor symptoms. We investigated the relationship between MBI and DTGC in a sample of non-demented older adults. METHODS: This was a cross-sectional observational study of 193 participants (10 cognitively normal, 48 subjective cognitive decline (SCD), 135 mild cognitive impairment (MCI); 52.8% female) from 13 Canadian sites from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. The Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to define MBI severity using a published algorithm. DTGC, the percentage difference between dual-task and preferred walking speeds, was assessed under three cognitive tasks: animal naming, counting backwards, and serial seven subtractions. Associations were tested in the entire cohort and in the MCI subgroup using multivariable linear regression adjusted for age, sex, education, and diagnosis. The role of global cognition, executive function, verbal and working memory in the association were investigated using tests of mediation and moderation. RESULTS: MBI symptoms were present in 46.6% of participants (mean age = 72.4 years). Greater overall MBI burden was associated with lower gait speed across all conditions. Furthermore, a one-point increase in global MBI symptom severity was associated with a 0.8% increase in DTGC in the animal fluency condition, a 0.9% increase in the counting backwards condition and a 1.1% increase in the serial sevens condition. These associations were strongest in the subgroup of MCI participants. Executive function but not global cognition or verbal and working memory mediated the association between MBI and DTGC in all three conditions. CONCLUSIONS: MBI is associated with gait speed and DTGC in this group of non-demented individuals, independent of the presence or absence of MCI. These findings provide evidence of the relationship between these non-cognitive dementia markers of behavior and gait beyond cognitive impairment.

The Relationship Between Hearing and Mild Behavioral Impairment and the Influence of Sex: A Study of Older Adults Without Dementia from the COMPASS-ND Study.

Background: Hearing loss and mild behavioral impairment (MBI), both non-cognitive markers of dementia, can be early warning signs of incident cognitive decline. Objective: We investigated the relationship between these markers and reported the influence of sex, using non-dementia participants (n = 219; 107 females) from the Canadian Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND). Methods: Hearing was assessed with the 10-item Hearing Handicap for the Elderly-Screening (HHIE-S) questionnaire, a speech-in-noise test, screening audiometry, and hearing aid use. MBI symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Multivariable linear regressions examined the association between hearing and MBI symptom severity and multiple logistic regressions examined the association between hearing and MBI domains. Results: HHIE-S score was significantly associated with greater global MBI symptom burden, and symptoms in the apathy and affective dysregulation domains. Objective measures of audiometric hearing loss and speech-in-noise testing as well as hearing aid use were not associated with global MBI symptom severity or the presence of MBI domain-specific symptoms. Males were older, had more audiometric and speech-in-noise hearing loss, higher rates of hearing-aid use, and showed more MBI symptoms than females, especially apathy. Conclusion: The HHIE-S, a subjective self-report measure that captures emotional and social aspects of hearing disability, was associated with informant-reported global MBI symptom burden, and more specifically the domains of affective dysregulation and apathy. These domains can be potential drivers of depression and social isolation. Hearing and behavior change can be assessed with non-invasive measures, adding value to a comprehensive dementia risk assessment.