Objective:Mild cognitive impairment (MCI) is an at-risk state for dementia, however not all individuals with MCI transition to dementia, and some revert to normal cognition. Here, we investigate whether mild behavioral impairment (MBI), the late-life onset of persistent neuropsychiatric symptoms (NPS), improves the prognostic specificity of MCI.Methods:Participants with MCI from the National Alzheimer's Coordinating Center Uniform Data Set were included. Neuropsychiatric symptoms were operationalized with the neuropsychiatric inventory questionnaire (NPI-Q) to identify participants without NPS and those with MBI (persistent, late-onset NPS). Individuals with late-onset NPS not meeting the MBI persistence criterion (NPS_NOT_MBI) were retained for secondary analyses. Progression to dementia, stable MCI, and reversion to NC after 3 years of follow-up were defined as per NIA-AA and Petersen criteria.Results:The primary sample consisted of 739 participants (NPS- n=409 and MBI+ n=330; 75.16±8.6 years old, 40.5% female). After 3 years, 238 participants (33.6%) progressed to dementia and 90 (12.2%) reverted to NC. Compared to participants without NPS, participants with MBI were significantly more likely to progress to dementia (Adjusted Odds Ratio [AOR]=2.13, 95%CI 1.52-2.99), with an annual progression rate of 14.7% (vs 8.3% for MCI participants without NPS). Compared to participants without NPS, MBI participants were less likely to revert to NC (AOR=0.48, 95%CI 0.28-0.83, 2.5% vs 5.3% annual reversion rate). The NPS_NOT_MBI group (n=331, 76.5±8.6 years old 45.9% female), were more likely to progress to dementia (AOR=2.18, 95%CI 1.56-3.03, 14.3% annual progression rate) but not less likely to revert to NC than those without NPS. Accordingly, both NPS_NOT_MBI and MBI+ participants had lower MMSE scores than NPS- participants after 3 years.Discussion:Late-onset NPS improve the specificity of MCI as an at-risk state for progression to dementia. However, only persistent late-onset NPS are associated with a lower likelihood of reversion to NC, with transient NPS (i.e., NPS_NOT_MBI) not differing from the NPS- group. Clinical prognostication can be improved by incorporating late-onset NPS, especially those that persist (i.e., MBI), into risk assessments. Clinical trials may benefit from enrichment with these higher-risk MCI participants.

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Background Mild behavioral impairment (MBI) is a syndrome that uses later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a group at high risk for incident dementia. MBI is associated with neurodegenerative disease markers in advance of syndromic dementia. Functional connectivity (FC) correlates of MBI are understudied and could provide further insights into mechanisms early in the disease course. We used resting‐state functional magnetic resonance imaging (rs‐fMRI) to test the hypothesis that FC within the default mode network (DMN) and salience network (SN) of persons with MBI (MBI+) is reduced, relative to those without (MBI–). Methods From two harmonized dementia‐free cohort studies, using a score of ≥6 on the MBI Checklist to define MBI status, 32 MBI+ and 63 MBI– individuals were identified (mean age: 71.7 years; 54.7% female). Seed‐based connectivity analysis was implemented in each MBI group using the CONN fMRI toolbox (v20.b), with the posterior cingulate cortex (PCC) as the seed region within the DMN and anterior cingulate cortex (ACC) as the seed within the SN. The average time series from the PCC and ACC were used to determine FC with other regions within the DMN (medial prefrontal cortex, lateral inferior parietal cortex) and SN (anterior insula, supramarginal gyrus, rostral prefrontal cortex), respectively. Age, sex, years of education, and Montreal Cognitive Assessment scores were included as model covariates. The false discovery rate approach was used to correct for multiple comparisons, with a p ‐value of .05 considered significant. Results For the DMN, MBI+ individuals exhibited reduced FC between the PCC and the medial prefrontal cortex, compared to MBI–. For the SN, MBI+ individuals exhibited reduced FC between the ACC and left anterior insula. Conclusion MBI in dementia‐free older adults is associated with reduced FC in networks known to be disrupted in dementia. Our results complement the evidence linking MBI with Alzheimer's disease biomarkers. Highlights Resting‐state functional magnetic resonance imaging was completed in 95 dementia‐free persons from FAVR and COMPASS‐ND studies. Participants were stratified by informant‐rated Mild Behavioral Impairment Checklist (MBI‐C) score, ≥6 for MBI+. MBI+ participants showed reduced functional connectivity (FC) within the default mode network and salience network. These FC changes are consistent with those seen in early‐stage Alzheimer's disease. MBI may help identify persons with early‐stage neurodegenerative disease.

Background Dementia has an increasing global burden with over 40 million affected individuals. With sub‐optimal advances in drug development, there is an increasing shift to determine risk of dementia in the non‐demented population. Assessment of neuropsychiatric symptoms (NPS) may offer an opportunity to capture the at‐risk group earlier. Mild Behavioural Impairment (MBI) is a validated neurobehavioural syndrome, characterized by the emergence of sustained NPS in older adults as an at‐risk state for dementia. Cognitively, subjective cognitive decline (SCD) is a dementia at‐risk group in which cognitive symptoms are reported in the absence of objective findings. The apolipoprotein epsilon 4 (ApoE ε4) gene is a well‐known risk marker for dementia. We aim to determine the frequency of ApoE homozygosity in SCD, stratified by MBI status cross‐sectionally, and calculate the hazard of incident cognitive decline in this group longitudinally. Method Data from 5005 participants in the National Alzheimer’s Coordinating Center (NACC) were used to capture older adults who were cognitively normal, but had subjective cognitive complaints (SCD). We determined MBI status (+/‐) using a previously published transformation algorithm of NPI‐Q scores. We tabulated ApoE genotype in both groups. We compared proportion of ApoE homozygousity (APOE ε4+/+)in the MBI+ versus the MBI‐ group. Additionally, a Cox proportional hazards regression will be done to capture hazard of incident mild cognitive impairment in MBI+ versus MBI‐. Result A two‐sample test of proportions of MBI+/‐ status stratified by ApoE ε4+/+resulted in significant differences between groups with homozygosity more frequent in MBI+ versus MBI‐ (p<0.001). We will also present the results of the Cox proportional hazards regression analysis. Conclusion In older adults with subjective cognitive decline, ApoE ε4 allele homozygosity was more frequently seen in the MBI+ group. These findings provide additional evidence for the utility in determining MBI status in SCD.

BackgroundMild Behavioral Impairment (MBI), characterized by de novo emergent and persistent neuropsychiatric symptoms in later life, may be used to improve early detection of neurodegenerative disease. While alterations in resting‐state networks have been demonstrated in early‐stage Alzheimer’s disease (AD), few studies have explored these networks in MBI. Here, we assessed activity in the default mode network (DMN) and the salience network (SN), using resting‐state functional magnetic resonance imaging (fMRI), in association with MBI. We hypothesized that the strength of functional connectivity (FC) within the DMN and SN would be reduced in dementia‐free persons with MBI (MBI+), relative to those without (MBI‐).MethodsData from dementia‐free participants in three prospective cohort studies were pooled. MBI+ status was determined using the MBI‐checklist. Imaging data were acquired using 3T MRI. Seed‐based connectivity analyses were performed using the CONN toolbox. The DMN included the posterior cingulate cortex (PCC), medial prefrontal cortex (MPFC), and lateral parietal (LP) regions, with the PCC as the seed. The SN included the anterior cingulate cortex (ACC), anterior insula (AI), rostral prefrontal cortex (RPFC), and supramarginal gyrus (SMG), with the ACC as the seed. FC maps of the DMN and SN were computed for each MBI group; difference maps were extracted to identify regions with significantly different connectivity across MBI groups. A threshold of p<0.05 was used with false discovery rate correction for multiple comparisons at the cluster level; a p<0.001 uncorrected for voxel level was used for group comparisons. All analyses were covaried for age, sex, years of education, and Montreal Cognitive Assessment scores.ResultsOf the 95 participants, 32 were MBI+ and 63 MBI‐ (mean age 71.7; 54.7% female). Within the DMN, MBI+ individuals had lower functional connectivity between the PCC and MPFC, compared to MBI‐ (β=‐0.15, p=0.004). Within the SN, MBI+ was associated with lower functional connectivity between the ACC and left AI (β=‐0.12, p=0.028).ConclusionOur findings suggest that in dementia‐free individuals, MBI is associated with decreased functional connectivity in networks disrupted in AD. This result lends additional support to MBI as a potential early marker of disease.

Background Mild behavioural impairment (MBI) is characterized by late‐life emergent and persistent neuropsychiatric symptoms (NPS). It is as an at‐risk state for incident cognitive decline and dementia. For some, MBI may be the first observable manifestation of a neurodegenerative process such as Alzheimer’s disease (AD). Methods We examined associations between MBI and established dementia imaging and CSF markers, in 789 participants with mild cognitive impairment (MCI). Study data were obtained from the French MEMENTO cohort study. Neuropsychiatric Inventory (NPI) scores were used to determine MBI scores using a published algorithm. NPI data at baseline and 6‐month visits were used to categorize patients into MBI+ (persistent NPS i.e., NPS at both time points) and MBI‐ (no NPS or NPS at either but not both time points). MRI and CSF measurements were completed at baseline. Linear regressions were fitted to assess if MBI status at 6 months was associated with reduced thickness or volume in each of the a priori selected regions associated with Braak stages 1‐5: entorhinal cortex, hippocampus, fusiform gyrus, inferior temporal cortex and frontal pole. To assess if MBI status was associated with CSF biomarkers (Aβ42, Aβ40, t‐tau, p‐tau, Aβ42/Aβ40, p‐tau/Aβ42 and t‐tau/Aβ42), seven linear regressions were conducted. All models controlled for age, sex, education, and mini‐mental state examination scores. Volume and thickness analysis further controlled for total intracranial volume. Results MBI+ (persistent NPS) status was associated with decreased entorhinal thickness and smaller hippocampal volume compared to MBI‐ (Table 1). There were no differences between MBI+ and MBI‐ groups in thickness of the Braak stage 3‐5 regions (Table 1). In the subset of MCI participants with CSF data (n=155), compared to MBI‐, MBI+ had lower CSF Aβ42 levels, higher CSF p‐tau/Aβ42 and t‐tau/Aβ42 ratios (Table 2). Conclusion In a memory clinic sample of older adults with MCI, MBI was associated with AD markers and served as a proxy marker to capture AD changes in a non‐demented sample. These findings extend the literature linking MBI with known dementia biomarkers and emphasize the importance of appropriately ascertained NPS, in this case with respect to symptom persistence, in dementia detection and prognostication.

Background: Mild behavioral impairment (MBI) refers to the de novo emergence of persistent neuropsychiatric symptoms in older adults and has been associated with cognitive decline and incident dementia. The purpose of this study was to identify the structural neural correlates of MBI using a hypothesis-driven region-of-interest (ROI) approach. Method:The study cohort consisted of 744 participants (60.3% female; mean and SD of age = 71.0 ± 9.7 years; mean and SD of education: 15.8 ± 5.3 years) without dementia from the National Alzheimer's Coordinating Centre dataset. Structural T1weighted images for each participant were processed and segmented using FreeSurfer and then normalized by age, sex, intracranial volume, scanner characteristics, and image quality to generate adjusted measures of grey matter volume (GMV) for each ROI. Our primary ROIs included five regions, each representing one Braak stage: entorhinal cortex (stage I), hippocampus (stage II), fusiform gyrus (stage III), inferior temporal cortex (stage IV), and frontal pole (stage V). We also included three hippocampal subfields (CA1, CA3, CA4) and four ROIs commonly associated with various psychiatric disorders (amygdala, insula, anterior cingulate, prefrontal cortex) as a secondary analysis. All ROIs are anatomically highlighted in Figure 1. Participants were classified as MBI+ if they presented with MBI symptoms derived from the Neuropsychiatric Inventory Questionnaire for two consecutive visits one year apart. Logistic regressions adjusting for cognitive diagnosis (cognitively normal, n = 568; mild cognitive impairment, n = 176) were used to model the relationship between ROI GMV (predictor) and MBI status (outcome).Result: As shown in Table 1, lower GMV in early Braak stage ROIs (entorhinal cortex and hippocampus) was associated with MBI+ status. This trend was maintained for all hippocampal subfield ROIs. However, mid-late Braak stage ROI (fusiform gyrus, inferior temporal cortex, frontal pole) GMVs were not associated with MBI status. For psychiatric disorder ROIs, lower GMV in only the amygdala was associated with MBI+ status.