Background: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease). Objective: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline. Methods: Cognitively normal participants were followed up annually at Alzheimer’s Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome. Results: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42–5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57–6.34] for MBI+SCD- (20.7%), and 8.15 [5.71–11.64] for MBI+SCD+(30.9%). Conclusion: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.

Background: Assessing neuropsychiatric symptoms (NPS) in older adults is important for determining dementia risk. Mild behavioral impairment (MBI) is an at-risk state for cognitive decline and dementia, characterized by emergent NPS in later life. MBI has significantly higher dementia incidence than late life psychiatric conditions. However, its utility as a proxy for neurodegeneration has not been demonstrated. Plasma neurofilament light (NfL) is a validated biomarker of axonal damage, and has been shown to associate with hallmarks of neurodegeneration. Objective: The purpose of this investigation was to identify associations between NfL rate of change and the presence of MBI symptomatology. Methods: We evaluated the association of MBI with changes in NfL in a cohort (n = 584; MBI + n = 190, MBIn = 394) of non-demented participants from the Alzheimer's Disease Neuroimaging Initiative. MBI was determined by transforming Neuropsychiatric Inventory Questionnaire items using a published algorithm. Change in NfL was calculated over 2 years. Results: Time*MBI status was the only significant interaction to predict change in NfL concentrations (F(1,574) = 4.59, p = 0.032), even after controlling for age, mild cognitive impairment, and demographics. Analyses reclassifying 64 participants with new onset MBI over 2 years similarly demonstrated greater increases in NfL (F(1,574) = 5.82, p = 0.016).

Background: Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy of ML models but have barely been used for this purpose. Objectives: To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI. Method: Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer's Disease Neuroimaging Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis. Results: In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve [ROC-AUC] = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73).

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.

Background: Agitation and aggression are common in dementia and pre-dementia. The dementia risk syndrome mild behavioral impairment (MBI) includes these symptoms in the impulse dyscontrol domain. However, the neural circuitry associated with impulse dyscontrol in neurodegenerative disease is not well understood. The aim of this work is to investigate if regional micro-and macro-structural brain properties are associated with impulse dyscontrol symptoms in older adults with normal cognition, mild cognitive impairment, and Alzheimer's disease.Methods: Clinical, neuropsychiatric, and T1-weighted and diffusion-tensor MRI (DTI) data from 80 individuals with and 123 individuals without impulse dyscontrol, were obtained from the Alzheimer's Disease Neuroimaging Initiative. Linear mixed effect (LME) models were used to assess if impulse dyscontrol was related to regional DTI and volumetric parameters.Results: Impulse dyscontrol was present in 17% of participants with NC, 43% with MCI, and 66% with AD. Impulse dyscontrol was associated with: 1) lower fractional anisotropy, and greater mean, axial, and radial diffusivity in the fornix; 2) lesser fractional anisotropy, and greater radial diffusivity in the superior fronto-occipital fasciculus; 3) greater axial diffusivity in the cingulum; 4) grey matter atrophy, speci cally, lower cortical thickness and greater surface area in the parahippocampal gyrus. Conclusion:Our ndings provide evidence that well-established atrophy patterns of AD are prominent in the presence of impulse dyscontrol, even when disease status is controlled for, and possibly in advance of dementia. Our ndings support the growing evidence base for impulse dyscontrol symptoms as an early manifestation of Alzheimer's disease. BackgroundAgitation, aggression, and impulsivity are common in dementia and are associated with caregiver stress and poorer outcomes (1, 2). These symptoms are clinically meaningful, often requiring intervention -both non-pharmacological and pharmacological (3). Agitation in individuals with neurocognitive disorders is associated with emotional distress and symptoms of excessive motor activity, verbal aggression, or physical aggression (4). In a recent systematic review, the prevalence of agitation/aggression in patients with Alzheimer's disease (AD) was estimated to be 40% (5). Agitation can also present in advance of dementia in those with mild cognitive impairment (MCI), subjective cognitive decline (SCD), or even normal cognition (6-9). In the population-based Mayo Clinic Study of Aging, which enrolled participants ≥ 70 years of age, prevalence of irritability was 7.6% in normal cognition (NC) and 19.4% in MCI, while prevalence of agitation was 2.8% in NC and 9.1% in MCI (5). Importantly, in a subsequent analysis, these same impulse dyscontrol symptoms when present at study baseline predicted incident MCI. Hazard ratio for incident MCI with baseline irritability was 1.84 and for agitation hazard was 3.06 relative to the absence of symptoms (10). Thus, neuropsychiatric symptoms in ol...