Neurobehavioral Syndrome Research Articles

Prevalence of misophonia and its association with depression and obsessive-compulsive disorder among medical students.

Misophonia, a neurobehavioral syndrome, reduces tolerance to specific stimuli and impacts various domains of life. It is also strongly correlated with obsessive-compulsive disorder (OCD) and depression. This study aimed to investigate the prevalence of misophonia among medical students at King Saud University (KSU), Saudi Arabia, identify related sociodemographic factors, and assess misophonia association with OCD and depression. This cross-sectional study included 371 participants. The study tool was distributed electronically between November 19 and December 07, 2023. It consisted of 4 sections: a questionnaire developed by the research team, the Amsterdam Misophonia Scale (A-MISO-S), the Obsessive-Compulsive Inventory-Revised (OCI-R), and the Patient Health Questionnaire-9 (PHQ-9). The results indicated that 42.32% of the participants had previously experienced misophonia, with symptoms developing suddenly in 28.66%. The majority of participants had subclinical misophonia (71.16%) and minimal depression (37.47%), with a significant proportion experiencing mild-to-severe misophonia (28.84%) and varying degrees of depression (33.15%). Approximately 31.00% of the students exhibited likely OCD. The PHQ-9 and A-MISO-S scores showed weak positive correlations, whereas the OCI-R and A-MISO-S scores showed a moderate positive correlation. Furthermore, a moderate positive correlation was observed between the OCI-R and PHQ-9 scores. Multiple logistic regression analysis revealed that sex, family history of misophonia, depression severity, and OCD were significantly associated with clinical misophonia. This study underscores the significance of recognizing misophonia among medical students and its associated factors, such as OCD and depression. Further multicenter studies using more rigorous research methodologies are warranted.

Piled-up Risk Factors: a Case Report of Diogenes Syndrome

IntroductionDiogenes Syndrome (DS) is an uncommon neurobehavioral syndrome characterized by social isolation, extreme neglect of personal care and a tendency to excessively accumulate useless objects in the home, usually leading to unsanitary living conditions. It is further characterized by a lack of insight into the condition, leading to a refusal to seek assistance.ObjectivesTo outline the clinical features of primary DS, unassociated with other psychiatric conditions, emphasizing key risk factors contributing to its development.MethodsDescriptive report of a case of DS, based on an interview with the patient, review of his clinical file, and a non-systematic literature review using the PubMed database.ResultsWe report a case of a 62-year-old man, widowed since the age of 33, without children, living alone in a rural area in the north of Portugal. Currently retired, he worked as a Philosophy Professor. He had no known psychiatric history until 2015, when he attended two psychiatric appointments, due to anxiety and changes in sleep pattern. He has since lost psychiatric follow-up and in May 2022 he was brought to the emergency department by his neighbor, due to changes in his behavior. He was seen several times rummaging trough trash and he didn’t leave the house for a few weeks, resulting in a cluttered and unsanitary living space. He looked malnourished, unkempt and dirty. Despite not recognizing his behavior as problematic, he accepted hospitalization. No obsessive-compulsive, depressive or psychotic symptoms were detected, nor were dysfunctional personality traits. Reversible causes of dementia were excluded, a cranioencephalic CT scan revealed no abnormal findings and a neuropsychological assessment showed no changes in cognitive functions. Post-discharge, local health services provided home support, with meal delivery and house cleaning. However, he did not buy the medication and canceled the home support service several times, ending up being hospitalized again. After this second hospitalization in August 2023, he went to live with his brother in another city and has remained stable, medicated with an SSRI and low dose Aripiprazole.ConclusionsPrimary Diogenes Syndrome is rare and and its etiopathogenesis remains poorly understood. It is known that there is no distinction between genders, profession or socioeconomic status, and that it is more common in the elderly, single people, widowers and people with poor or non-existent social links with their local community. Familiarity with DS characteristics enables earlier recognition of such individuals, thereby facilitating prompt provision of social and clinical support in order to reduce morbidity, mortality, and enhance public health.Disclosure of InterestNone Declared

Neurobehavioral Changes Associated with Rheumatic Fever and Rheumatic Heart Disease: A Narrative Review

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune conditions triggered by Group A Streptococcus skin or throat infections. If ARF/RHD is undetected, misdiagnosed or antibiotic treatment is not provided early, patients may develop cardiac failure, leading to premature death. Although it is an easily preventable disease, ARF/RHD remains the most significant cause of heart disease-associated deaths in people under 25 years old, both in low- and middle-income countries and among First Nations in high-income countries. Up to 30% of the patients with ARF/RHD present with a neurobehavioral condition – Sydenham’s chorea (SC). The clinical course of SC is mostly self-limiting and is characterized by the onset of involuntary choreiform movements and neuropsychiatric features such as obsessive-compulsive disorder, tics, depression and anxiety, psychosis, and attention-deficit hyperactivity disorder. While the precise mechanism as to why only a proportion of patients with ARF/RHD develop SC remains unknown, an impaired blood–brain barrier is considered to play a central role in its development. The most well-characterized neurobehavioral outcome is stroke which may occur in isolation or as part of systemic thromboembolism. Both infective endocarditis and mitral valve disease with or without aortic valve disease increase the embolic and ischemic stroke risk. ARF/RHD is known to significantly impact the quality of life with neuropsychiatric consequences. Another neurobehavioral syndrome which occurs in the absence of ARF/RHD is “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections” (PANDAS). PANDAS has been categorized as a subset of pediatric acute-onset neuropsychiatric syndromes. However, establishing a diagnosis of PANDAS has been challenging. In this review, we discuss the current status of our understanding regarding the different manifestations of poststreptococcal neurobehavioral changes. Particular attention is given to ARF/RHD-associated SC, and we highlight the areas for further research to understand the association between poststreptococcal sequelae and neurobehavioral abnormalities.

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI.

Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN). Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach. The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping. In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

Criminality in patients with autoimmune encephalitis: A case series.

Despite it being an immunotherapy-responsive neurological syndrome, patients with autoimmune encephalitis (AE) frequently exhibit residual neurobehavioural features. Here, we report criminal behaviours as a serious and novel postencephalitic association. This retrospective cohort study included 301 AE patients. Five of who committed crimes underwent direct assessments and records review alongside autoantibody studies. Five of 301 patients (1.7%) with AE exhibited criminal behaviours, which included viewing child pornography (n = 3), repeated shoplifting, and conspiracy to commit murder. All five were adult males, with LGI1 autoantibodies (n = 3), CASPR2 autoantibodies, or seronegative AE. None had evidence of premorbid antisocial personality traits or psychiatric disorders. Criminal behaviours began a median of 18 months (range = 15 months-12 years) after encephalitis onset. At the time of crimes, two patients were immunotherapy-naïve, three had been administered late immunotherapies (at 5 weeks-4 months), many neurobehavioural features persisted, and new obsessive behaviours had appeared. However, cognition, seizure, and disability measures had improved, alongside reduced autoantibody levels. Criminal behaviours are a rare, novel, and stigmatizing residual neurobehavioural phenotype in AE, with significant social and legal implications. With caution towards overattribution, we suggest they occur as part of a postencephalitis limbic neurobehavioural syndrome.

Mild Behavioral Impairment in Parkinson's Disease: An Updated Review on the Clinical, Genetic, Neuroanatomical, and Pathophysiological Aspects.

Neuropsychiatric symptoms (NPS), including depression, anxiety, apathy, visual hallucinations, and impulse control disorders, are very common during the course of Parkinson's disease (PD), occurring even at the prodromal and premotor stages. Mild behavioral impairment (MBI) represents a recently described neurobehavioral syndrome, characterized by the emergence of persistent and impactful NPS in later life, reflecting arisk of dementia. Accumulating evidence suggests that MBI is highly prevalent in non-demented patients with PD, also being associated with an advanced disease stage, more severe motor deficits, as well as global and multiple-domain cognitive impairment. Neuroimaging studies have revealed that MBI in patients with PD may be related todistinct patterns of brain atrophy, altered neuronal connectivity, and distribution of dopamine transporter (DAT) depletion, shedding more light on its pathophysiological background. Genetic studies in PD patients have also shown that specific single-nucleotide polymorphisms (SNPs) may be associated with MBI, paving the way for future research in this field. In this review, we summarize and critically discuss the emerging evidence on the frequency, associated clinical and genetic factors, as well as neuroanatomical and neurophysiological correlates of MBI in PD, aiming to elucidate the underlying pathophysiology and its potential role as an early "marker" of cognitive decline, particularly in this population. In addition, we aim to identify research gaps, and propose novel relative areas of interest that could aid in our better understanding of the relationship of this newly defined diagnostic entity with PD.

Online abridged behavioral neurology training for specialists in Latin America: EduBrainLat

AbstractBackgroundCurrently, dementia training is only offered in a few large medical centers in a handful of Latin America ́s biggest cities. Reduced access and the heterogeneous quality of dementia education for clinicians hinder the diagnosis and treatment of neurodegeneration in Latin America.AimThis project aims to fill the education gaps and increase specialist´s diagnostic and therapeutic skills in neurodegenerative diseases through an interactive online Spanish‐language pilot program tailored for Latin America.MethodsWe put together a 108 hour curriculum formed by four modules: basic aspects of behavioral neurology, neurobehavioral and neuropsychiatric syndromes,treatment, and other aspects of neurodegenerative diseases. It was delivered by 35 brain health experts and reviewers that coolaborate with the Global Brain Health Institute in at the University of California, San Francisco to a pilot group formed by 35 geriatricians, neurologists and psychiatrists from six Latin American Countries (Peru, Mexico, Chile, Colombia, Ecuador, and Venezuela). An initial and final evaluations were performed with the Spanish‐dementia knowledge assessment scale (Carnes et al, 2021), the Frontotemporal Dementia Knowledge Scale (Magrath et al 2021) and clinical cases. In addition, short evaluations submitted by professor were answered before and after each class. Separately, we requested feedback from the students about the course.ResultsComparing the overall scores between the initial and final evaluation, there was a 7% increase in the Geriatrician´s score, 4% in Neurologists´ score and 9% in the Psychiatrist’s score. The greatest increase was in Frontotemporal Dementia Knowledge. (Figures 1 and 2). The topics with the worse baseline scores were clinical evaluation attention, executive functions, and atypical Alzheimer´s Disease. We observed an increase in knowledge after every class. Most of the feedback brought to light that there were many topics that specialists had not had the opportunity to learn before such as sleep in neurodegeneration, traumatic encephalopathy, and atypical dementia syndromes.ConclusionIt is imperative to find ways of bringing education to regions where dementia prevalence is increasing, and specialist do not have enough knowledge. Online programs are feasible and effective strategies to close educational gaps.

Mild Behavioral impairment (MBI) and late-life psychiatric disorders: Differential clinical features and outcomes.

Mild Behavioral Impairment (MBI) refers to a late-onset neurobehavioral syndrome in which neuropsychiatric symptoms (NPS) represent early markers of dementia. Though being a promising diagnostic category for neurobiological research, in daily clinical practice, the boundaries and relationships between MBI and late-life psychiatric disorders are yet to be established. Particularly, no studies have been conducted so far on the prognostic implications of an MBI diagnosis in the psychogeriatric context.For these reasons, since June 2020, we are conducting a prospective longitudinal study on MBI in psychogeriatric patients. On June 2022, 144 elderly patients (≥50 years) referred to the outpatient clinic of the 2nd Psychiatric Unit of the University of Pisa had been recruited. Patients had been diagnosed with a primary psychiatric disorder (N=73, 50.6%), MBI (N=40, 27.8%) or dementia (N=31, 21.5%). Patients with MBI showed a significantly higher age at onset of psychiatric disorders and depressive episodes than patients diagnosed with primary psychiatric disorders. MCI and vascular leukoencephalopathy were also more common in patients with MBI. Moreover, compared to primary psychiatric disorders, MBI was associated with a significantly higher psychopathology severity, especially in the apathy and negative symptoms domain.Preliminary longitudinal analyses were also performed on a subsample of 83 patients followed-up for at least 3 months (on average for one year): at baseline 44 patients had been diagnosed with primary mood disorders including 23 patients in remission and 21 patients with current mood episodes; 22 patients had MBI and 17 were diagnosed with dementia. While at follow-up patients with mood episodes showed a significant decrease in psychopathology severity and increase in global functioning, those with MBI had no significant improvements.In conclusion, MBI is a common condition in psychogeriatric settings and shows distinctive clinical features that may help differential diagnosis. Moreover, the presence of MBI in patients with late-life psychiatric disorders may affect both clinical and functional outcomes. The recognition of patients with MBI symptoms, including apathy, might be useful for the early detection of individuals with poor prognosis.

Longitudinal associations between mild behavioral impairment, sleep disturbance, and progression to dementia

AbstractBackgroundClinical guidelines recommend incorporating non‐cognitive markers into dementia screening to improve detection. Two of these markers are mild behavioral impairment (MBI) and sleep. MBI is a neurobehavioral syndrome capturing later‐life emergent and persistent neuropsychiatric symptoms, which represent a change from longstanding behavior or personality, as a high‐risk group for incident cognitive decline and dementia. Sleep disturbances include difficulties initiating and maintaining sleep, are common in older adults and are associated with greater risk for dementia. We investigated the longitudinal associations between MBI and sleep disturbance and their association with incident dementia.MethodsData were obtained from the National Alzheimer’s Coordinating Center. MBI was derived from Neuropsychiatric Inventory Questionnaire (NPI‐Q) based on a published algorithm. The presence of sleep disturbance was obtained from the NPI‐Q nighttime behaviors item. Cox proportional hazard regressions, adjusted for age, sex, education, and cognitive diagnosis, were used to determine the associations between 1) baseline MBI and incident sleep disturbance (n = 8348); 2) baseline sleep disturbance and incident MBI (n = 9679) and 3) baseline sleep disturbance, with and without concurrent MBI, and incident dementia (n = 12296).ResultsDemographics are summarized in Table 1. As per Table 2, the rate of developing sleep disturbance was 3.3‐fold higher in older adults with MBI at baseline compared to those without MBI (95%CI: 2.96‐3.67; p<0.001). Likewise, the rate of developing MBI was 2.1‐fold higher in older adults with baseline sleep disturbance compared to those without sleep disturbance (95%CI: 1.84‐2.36, p<0.001). The incidence rate of dementia was 2.23‐fold greater in older adults with both MBI and sleep disturbance, relative to sleep disturbance alone (95%CI: 1.65‐3.00; p<0.001).ConclusionsIn this group of dementia‐free older adults, we found a bidirectional relationship between MBI and sleep disturbance. Sleep disturbance was more strongly associated with incident dementia when co‐morbid with MBI. This relationship might suggest a common etiology for MBI and SD, as both were linked with incident dementia. Thus, including both sleep disturbance and MBI into modeling may improve dementia prognostication. Future studies should incorporate biomarkers and additional clinical markers for Alzheimer’s disease and other neurodegenerative disease into the modeling to better understand these relationships.

79 Concordance Between Theorized Cognitive Profiles, Medical Risk Factors, and Clinical Diagnoses Within Preschool-Aged Children

Objective:Early childhood is recognized as a critical window of rapid cognitive development. Unfortunately, many risk factors for atypical cognitive development may occur during this period, including genetic syndromes, congenital neuroanatomical malformations, pre- or perinatal injury, and neurological and medical disorders. The impact of these risk factors on cognitive functioning may not always map onto patterns typically observed in adults. Limited literature exists on the presentation of cognitive profiles within clinical populations in the preschool developmental period. The present study aimed to evaluate whether discrete a priori cognitive profiles consistent with common neurobehavioral syndromes emerge and are distinguishable on testing in early childhood in a mixed clinical sample. We also aimed to determine if there was a consistent association between known medical risk factors and resultant cognitive profiles.Participants and Methods:Participants included 163 children aged 1-5 years (M=48.5 months, SD=12.8 months) referred for neuropsychological evaluation. The sample was predominantly male (67.5%) and White (72.9%), followed by other/mixed race (11.6%), Black (9.7%), and Latino/Hispanic (5.8%). Cognitive abilities assessed included broad intellectual abilities, verbal abilities, nonverbal abilities, attention, and executive functioning. Continuous test scores were transformed into categorical ranges of performance, with scores classified as “above average,” “average,” “below average,” or “extremely low” to allow for profile classification. Theoretical clinical profiles consistent with common neurobehavioral syndromes were determined a priori by consensus among three authors (JK, AH, LM). Chi square tests of independence were conducted to compare membership across neurobehavioral diagnostic groups, clinical profile groups, and medical groups.Results:Based on cognitive data, 55.2% of the sample (n=90) was classified as Global Developmental Delay/Intellectual Disability, 19.6% (GDD/ID; n=32) was classified asLanguage Disorder, and 18.4% (n=30) was classified as Typical Cognitive Development. 4.3% (n=7) of the sample was classified as Attention-Deficit/Hyperactivity Disorder (ADHD), and 2.5% (n=4) was classified as Nondominant Hemisphere Dysfunction. As hypothesized, cognitive profile group membership was consistent with diagnostic impressions, as actual clinical diagnoses of Language Disorder, ADHD, GDD/ID, or a classification of typical cognitive development were significantly associated with theorized cognitive profile based on test performance alone (x2 (1,20) = 147.29, p < .001). Cognitive profile group membership was also significantly associated with referral source (1,28) = 62.88, p < .001) and the presence of a neurological disorder (1,4) = 14.64, p =.006).Conclusions:Findings support the presence of specific theorized cognitive profiles in preschoolers in a mixed clinical sample. Specifically, GDD/ID, Language Disorder, and typical cognitive development are discrete and consistently distinguishable cognitive profiles in this age range. Early life neurological risk factors are also significantly related to cognitive profile membership, suggesting that these factors may be useful in predicting cognitive development even in very young children. Future work is needed to examine the consistency of these profiles over time and their predictive value in estimating subsequent development, and the possibility of discriminating unique cognitive profiles for specific medical conditions in preschoolers.

Longitudinal associations of emergent and persistent affective dysregulation symptoms with incident dementia in dementia‐free older adults

AbstractBackgroundNeuropsychiatric symptoms (NPS) are risk factors for dementia. Mild behavioral impairment (MBI) is a neurobehavioral syndrome that refines NPS assessment to improve dementia prognostication by identifying later‐life emergent and persistent NPS specifically as the at‐risk group. Affective dysregulation contributes to dementia risk and is an MBI domain characterized by the inability to regulate emotions. Here, we investigate the longitudinal association of MBI‐affective dysregulation with incident dementia in dementia‐free older adults from the National Alzheimer Coordinating Centre (NACC).MethodNACC participants with no history of psychiatric, neurological, or neurodevelopmental disorders were included. MBI‐affective dysregulation status was determined based on Neuropsychiatric Inventory Questionnaire (NPI‐Q) depression, anxiety, and elation scores at two consecutive visits. The comparator group involved participants with no NPS prior to dementia. Participants with dementia at baseline were excluded from the study. Kaplan‐Meier curves of dementia‐free survival over ten years were generated for MBI‐affective dysregulation versus no NPS. Cox proportional hazard models were implemented to assess the risk of dementia, adjusted for age, sex, years of education, race, APOE e4 status, and clinical cognitive diagnosis. Potential interactions were further explored for relevant model covariates.ResultThe final sample consisted of 3,446 participants with no NPS (mean age 73.1; 63.0% female), and 1,156 with MBI‐affective dysregulation (mean age 75.1; 53.9% female). MBI‐affective dysregulation was associated with lower chance of dementia‐free survival (log rank, p<0.001) and 1.67 times greater risk of dementia compared to no NPS (CI:1.4‐2, p<0.001). Moderation analysis revealed that in participants with normal cognition (NC), those with MBI‐affective dysregulation were at 2.56 times greater risk of dementia than those with no NPS (CI:1.87‐3.49, p<0.001). In mild cognitive impairment (MCI), the risk associated with MBI‐affective dysregulation was 1.4 times greater than no NPS (CI:1.14‐1.72, p = 0.02).ConclusionThe emergence of persistent affective dysregulation symptoms in dementia‐free older adults is associated with substantial risk for dementia. When emerging in individuals with NC, these persistent affective symptoms represent a greater risk compared to those with no NPS, compared to emergence of these symptoms in MCI. MBI‐affective dysregulation is an important risk factor for dementia and should be considered in clinical assessments.

Mild behavioral impairment linked to phenoconversion to Alzheimer’s disease and cortical thinning in mild cognitive impairment

AbstractBackgroundMild Behavioral Impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at‐risk state for dementia (Ismail Z, Alzheimers Dement, 2016). However, the associations between MBI and a risk of phenocoversion to dementia and its neuroanatomical correlates in MCI are still unclear.MethodA total 1326 older adults with MCI was followed for a mean of 3.0 ± 2.0 years. MBI was approximated using a transformation algorithm for the neuropsychiatric inventory at baseline. Two‐step cluster analysis was used to explore classes of 5 MBI domains (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content). A Cox regression analysis was applied to investigate the association between the clusters and phenoconversion to AD. A subset of participants (n = 225) underwent 3D T1‐weighted MRI scans and cortical thickness was compared among the clusters of MBI domains.ResultThe cluster analysis identified 3 groups of participants: (1) people without MBI (47.8%, asymptomatic); (2) people with only affective dysregulation (29.3%, affective dysregulation); (3) people with relatively high probability of affective dysregulation, followed by impulse dyscontrol and affective dysregulation (22.9%, multiple domains). Compared to the asymptomatic, multiple domains was associated with a higher risk of phenoconversion to AD (hazard ratio = 2.589 [1.981 – 3.385], p = < 0.001), but affective dysregulation did not predict phenoconversion (1.204 [0.896 – 1.620], p = 0.219) (Fig 1). MCI individuals with symptoms in multiple domains revealed thinning in the bilateral superior and inferior parietal, superior temporal, and prefrontal cortex, and the right precuneus compared to those with only affective dysregulation (Fig 2). We did not find differences in cortical thickness between phenocoverter and non‐phenoconverter, and interaction of clusters of MBI domains and phenoconversion.ConclusionThe multiple co‐occuring MBI domains in individuals with MCI are associated with a higher risk of phenoconversion to AD. Moreover, MCI individuals with symptoms in multiple domains revealed cortical thinning in the superior parietal and precuneus, which have suggested as AD signatures (Dickerson BC, Cereb Cortex, 2009). These results suggest that evaluation of MBI and neuroimaging characteristics could be useful for risk stratification in MCI individuals.

Late life onset of persistent psychosis and incident dementia: risk stratification by baseline cognitive status

AbstractBackgroundMild Behavioral Impairment (MBI) is a validated neurobehavioral syndrome characterized by later life emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. Psychosis is one of the five domains of MBI, although dementia risk with MBI‐psychosis is not well quantified. Here, we assessed the longitudinal association of MBI‐psychosis with incident dementia in dementia‐free participants.MethodData were obtained from the National Alzheimer Coordinating Centre (NACC). Participants with neurodevelopmental, neurological and/or psychiatric disorders were excluded. Participants with normal cognition (NC) or mild cognitive impairment (MCI) at baseline were included. MBI‐psychosis status was defined based on persistence of Neuropsychiatric Inventory Questionnaire delusions and hallucinations symtoms across two consecutive visits. Kaplan‐Meier curves of ten‐year dementia‐free survival probability were generated for MBI‐psychosis versus those with no NPS prior to dementia diagnosis. Cox proportional hazard models were implemented to assess the risk of dementia, adjusted for age, sex, education, race, APOE e4 status, and clinical cognitive diagnosis. Interaction terms were included for relevant demographic variables. Secondary analyses were implemented to compare the risk associated with MBI‐psychosis to MBI without psychosis.ResultThe final sample consisted of 3,446 participants with no NPS (age = 73.1±9.6; 63% female; 13.2% MCI), and 58 with MBI‐psychosis (age = 74.9±9.9; 55.2% female; 69% MCI). MBI‐psychosis was associated with lower chance of dementia‐free survival over ten years and 3.36 times greater risk for dementia compared to no NPS (CI:2.19‐5.15, p<0.001). Moderation analysis revealed that in NC, those with MBI‐psychosis were at 8.15 times greater risk of dementia than those with no NPS (CI:2.57‐25.88, p<0.001). In MCI, the MBI‐psychosis‐associated dementia risk was 3.08 times greater (CI:1.95‐4.85, p<0.001). In the secondary analysis comparing MBI‐psychosis to MBI without psychosis (n = 2068), MBI‐psychosis was associated with 2.29 times greater risk of dementia (CI: 1.52‐3.4, p<0.001).ConclusionAlthough psychosis is an infrequently endorsed MBI domain, when present, it is associated with substantial risk for dementia. This risk differs between cognitive strata and is significantly greater when MBI‐psychosis emerges in NC versus MCI. The emergence of persistent psychotic symptoms in later life should be flagged for clinical attention, and a dementia assessment considered.

A review of current evidence for mild behavioral impairment as an early potential novel marker of Alzheimer's disease.

Mild behavioral impairment (MBI) is a neurobehavioral syndrome that occurs in the absence of cognitive impairment later in life (≥50 years of age). MBI is widespread in the pre-dementia stage and is closely associated with the progression of cognitive impairment, reflecting the neurobehavioral axis of pre-dementia risk states and complementing the traditional neurocognitive axis. Despite being the most common type of dementia, Alzheimer's disease (AD) does not yet have an effective treatment; therefore, early recognition and intervention are crucial. The Mild Behavioral Impairment Checklist is an effective tool for identifying MBI cases and helps identify people at risk of developing dementia. However, because the concept of MBI is still quite new, the overall understanding of it is relatively insufficient, especially in AD. Therefore, this review examines the current evidence from cognitive function, neuroimaging, and neuropathology that suggests the potential use of MBI as a risk indicator in preclinical AD.

Potential Biomarkers of impulsivity in mild traumatic brain injury: A pilot study

Very few studies have investigated cognition and impulsivity following mild traumatic brain injury (mTBI) in the general population. Furthermore, the neurobiological mechanisms underlying post-TBI neurobehavioral syndromes are complex and remain to be fully clarified. Herein, we took advantage of machine learning based-modeling to investigate potential biomarkers of mTBI-associated impulsivity. Twenty-one mTBI patients were assessed within one-month post-TBI and their data were compared to 19 healthy controls on measures of impulsivity (Barratt Impulsiveness Scale – BIS), executive functioning, episodic memory, self-report cognitive failures and blood biomarkers of inflammation, vascular and neuronal damage. mTBI patients were significantly more impulsive than controls in BIS total and subscales. Serum levels of sCD40L, Cathepsin D, IL-4, Neuropilin-1, IFN-α2, and Copeptin were associated with impulsivity in mTBI patients. Besides showing that mTBI are associated with impulsivity in non-military people, we unveiled different pathophysiological pathways potentially implicated in mTBI-related impulsivity.

Effects of race, baseline cognition, and APOE on the association of affective dysregulation with incident dementia: A longitudinal study of dementia-free older adults

BackgroundAffective symptoms are dementia risk factors. Mild behavioral impairment (MBI) is a neurobehavioral syndrome that refines incorporation of psychiatric symptomatology into dementia prognostication by stipulating symptoms must emerge de novo in later life and persist for ≥6 months. Here, we investigated the longitudinal association of MBI-affective dysregulation with incident dementia. MethodsNational Alzheimer Coordinating Centre participants with normal cognition (NC) or mild cognitive impairment (MCI) were included. MBI-affective dysregulation was operationalized as Neuropsychiatric Inventory Questionnaire-measured depression, anxiety, and elation at two consecutive visits. Comparators had no neuropsychiatric symptoms (no NPS) in advance of dementia. Cox proportional hazard models were implemented to assess the risk of dementia, adjusted for age, sex, years of education, race, cognitive diagnosis, and APOE-ε4 status, with interaction terms as appropriate. ResultsThe final sample included 3698 no-NPS (age:72.8; 62.7 % female), and 1286 MBI-affective dysregulation participants (age:75; 54.5 % female). MBI-affective dysregulation had lower dementia-free survival (p < 0.0001) and greater incidence of dementia (HR = 1.76, CI:1.48–2.08, p < 0.001) versus no NPS. Interaction analyses revealed that MBI-affective dysregulation was associated with higher dementia incidence in Black participants than White (HR = 1.70, CI:1.00–2.87, p = 0.046), NC than MCI (HR = 1.73, CI:1.21–2.48, p = 0.0028), and APOE-ε4 noncarriers than carriers (HR = 1.47, CI:1.06–2.02, p = 0.0195). Of MBI-affective dysregulation converters to dementia, 85.5 % developed Alzheimer's disease, which increased to 91.4 % in those with amnestic MCI. LimitationsMBI-affective dysregulation was not stratified by symptom to further examine dementia risk. ConclusionsEmergent and persistent affective dysregulation in dementia-free older adults is associated with substantial risk for dementia and should be considered in clinical assessments.

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7-11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups (n = 10-13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

Mild behavioral impairment linked to progression to Alzheimer's disease and cortical thinning in amnestic mild cognitive impairment.

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for dementia. However, the associations between MBI and a risk of progression to Alzheimer's disease (AD) and its neuroanatomical correlates in mild cognitive impairment (MCI) are still unclear. A total 1,184 older adults with amnestic MCI was followed for a mean of 3.1 ± 2.0 years. MBI was approximated using a transformation algorithm for the Neuropsychiatric Inventory at baseline. A two-step cluster analysis was used to identify subgroups of individuals with amnestic MCI based on profiles of 5 MBI domain symptoms (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content). A Cox regression analysis was applied to investigate differences in the risk of progression to AD between subgroups. A subset of participants (n = 202) underwent 3D T1-weighted MRI scans at baseline and cortical thickness was compared between the subgroups of amnestic MCI patients. The cluster analysis classified the patients into 3 groups: (1) patients without any MBI domain symptoms (47.4%, asymptomatic group); (2) those with only affective dysregulation (29.4%, affective dysregulation group); (3) those with multiple MBI domain symptoms, particularly affective dysregulation, decreased motivation and impulse dyscontrol (23.2%, complex group). Compared to the asymptomatic group, the complex group was associated with a higher risk of progression to AD (hazard ratio = 2.541 [1.904-3.392], p < 0.001), but the affective dysregulation group was not (1.214 [0.883-1.670], p = 0.232). In cortical thickness analysis, the complex group revealed cortical thinning bilaterally in the inferior parietal, lateral occipital, lateral superior temporal, and frontopolar regions compared with the affective dysregulation group. The multiple co-occuring MBI domains in individuals with amnestic MCI are associated with a higher risk of progression to AD and cortical thinning in temporal, parietal and frontal areas. These results suggest that evaluation of MBI could be useful for risk stratification for AD and appropriate intervention in MCI individuals.

Prediction of Cognitive Decline by Behavioral Symptoms in Neuropsychiatric Disorders

Background: Neuropsychiatric disorders are described by their neurological, behavioral, and cognitive symptoms. However, behavioral symptoms may often be overlooked due to the current approach in neurology. Objectives: This study investigated the relationship between behavioral symptoms and cognitive functioning in neurological disorders. The second aim was to predict neurocognitive patterns by behavioral symptoms as independent variables. Methods: Behavioral symptoms were collected based on semi-structured neuropsychiatric interviews with 211 patients admitted to the neuropsychiatry department of Ayatollah Kashani hospital in Isfahan by both a neuropsychiatry fellow and an attending neuropsychiatrist. A neuropsychiatry fellow assessed all patients using the neuropsychiatry unit cognitive (NUCog) assessment tool. We used a generalized linear model (GLM) to indicate the effect of behavioral symptoms on the risk of decline in cognitive domains. Due to the use of all available samples, this study had no age limit, and the patients were 15 to 92 years old. Results: The regression coefficient of NUCog subscale scores for behavioral symptoms using GLM revealed that education level had a positive relationship with the scores of attention (P &lt; 0.001), visuoconstruction (P &lt; 0.001), memory (P &lt; 0.001), executive function (P &lt; 0.001), language (P &lt; 0.001), and the total score of NUCog (P &lt; 0.001). Patients with apathy had lower scores on the memory subscale (P = 0.002) and total NUCog (P = 0.021). Similarly, patients with delusion had lower scores on memory (P = 0.006) and executive function (P = 0.026). There was a negative relationship between agitation and attention (P = 0.049), visuoconstruction (P = 0.015), memory (P = 0.018), executive function (P = 0.005), and total score of NUCog (P = 0.007). Sleep disturbances were accompanied by lower memory scores (P = 0.056) and lower mean NUCog scores (P = 0.052). Visual hallucination was associated with declined performance in attention (P = 0.057). Conclusions: Behavioral assessment can help predict cognitive patterns in patients with neurobehavioral syndromes.

Mild behavioral impairment is associated with sleep apnea, insomnia and brain white matter hyperintensity burden

AbstractBackgroundMild behavioral impairment (MBI) is a neurobehavioral syndrome associated with increased risk for Alzheimer’s disease (AD) and other neurodegenerative disorders. White matter hyperintensities (WMH) are brain lesions associated with cerebrovascular insult and contribute to cognitive decline across the cognitive spectrum (normal cognition, mild cognitive impairment (MCI) and dementia). Sleep disturbance is common among older adults with cognitive impairment and like MBI, is a modifiable AD risk factor that can affect brain structure including WMH. We sought to examine the prevalence of MBI and its relationship with sleep and WMH in a community cohort of older adults.MethodParticipants enrolled in the Wake Forest AD Research Center (ADRC) Clinical Core cohort (N = 633, mean age = 70.4 years) provided history of sleep apnea and insomnia, underwent neuropsychological assessment and neuropsychiatric symptom assessment, as reported by an informant on the Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI scores were derived from the NPI‐Q severity and included 10 symptoms reflecting affective dysregulation, impulse control, decreased motivation, social inappropriateness and abnormal perception or thought content, and excluded NPI‐Q questions on sleep and appetite. T1 and T2 FLAIR MRI were obtained; T1 and FLAIR were segmented to quantify WMH volume, which was scaled by head size and log transformed. Global cognitive status was assessed using the clinical dementia rating (CDR) global score.ResultIn our sample, 24% of participants had MBI. Normal cognition (CDR = 0) participants had significantly lower rates of MBI compared to both MCI (CDR = 0.5) and dementia (CDR ≥ 1, Figure 1, p&lt;.001). MBI scores were also significantly higher in participants with than without sleep apnea (Fig. 2, p = 0.003) and insomnia (Figure 3, p = 0.043). Further, WMH volume was higher in participants with MBI (Figure 4, p&lt;.001).ConclusionMBI increased in prevalence with cognitive impairment. Sleep disturbances and greater WMH burden in our MBI participants may increase their risk of cognitive decline for normal cognition and MCI groups and relate to poor behavioral and health outcomes in participants with dementia. Future studies will assess interactions of sleep, MBI and WMH across cognitive groups and their association with risk of conversion to MCI or AD.