Frontal Behavioral Inventory Research Articles

Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.

Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes. This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory. A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (β = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (β = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05). Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.

A systematic review of cognitive and behavioral tools to differentiate behavioral variant frontotemporal dementia from other conditions.

The behavioral variant of frontotemporal dementia (bvFTD) is thought to be the commonest clinical presentation of frontotemporal lobar degeneration and is predominantly characterized by changes in behavior. In patients lacking unequivocal biomarker evidence of frontotemporal neurodegeneration, the clinical diagnosis of bvFTD is often unstable. In response, we conducted a systematic review and critical appraisal of cognitive and behavioral tools that have sought to differentiate bvFTD from other conditions. A systematic literature review of PubMed, Scopus, and Web of Science was conducted on December 31, 2023 for cognitive and behavioral tools that differentiated bvFTD from other cohorts. Ninety-six studies were included. The quality appraisal of almost all studies was low and introduced a high risk of bias. The few studies that were of high quality had a prospective study design and recruited patients suspected (but not yet confirmed) to have bvFTD. These studies reported that behavioral tools (e.g., the Frontal Behavioral Inventory) and social cognition tests (e.g., the Ekman's Faces Test) had good test performance in differentiating bvFTD from a broad range of psychiatric and neurological conditions. Importantly, the review highlighted the extreme paucity of studies that have evaluated methods where, in Bayesian terms, there is genuine clinical uncertainty regarding a diagnosis of bvFTD. Most studies used healthy controls of typical Alzheimer's disease as comparators-groups that often have negligible pretest probability of bvFTD. In response, we propose a study design checklist for studies seeking to develop diagnostic algorithms in bvFTD research.

EVALUATION OF THE EFFECTIVENESS OF A COMPREHENSIVE PROGRAM OF REHABILITATION OFFERED ACCORDING TO DIFFERENT THERAPEUTIC PROTOCOLS IN REDUCING CHRONIC FRONTAL SYNDROME IN PATIENTS 10-YEARS FOLLOWING NEUROSURGERY FOR POST-TRAUMATIC INTRACEREBRAL HEMATOMA

The aim of the study was to evaluate the effectiveness of a Comprehensive Program of Rehabilitation (CPReh) offered according to different therapeutic protocols in reducing chronic frontal syndrome in patients 10 years following neurosurgery for post-traumatic intracerebral hematoma.Out of 568 adult car accident patients who underwent neurosurgery for post-traumatic intracerebral hematoma between 2004 and 2010 at the Department of Neurosurgery and Neurotraumatology of the Jagiellonian University's Collegium Medicum in Krakow, 90 patients with OFC injury and Chronic Frontal Syndrome were selected for the study. Patients were divided into three groups A, B and C of 30 each, matched for age, gender and injury severity. The Comprehensive Rehabilitation Program (CPReh) (cf. Pąchalska 2008) was applied in all groups ten years after hospitalization and surgery for intracerebral hematoma and was conducted according to three therapeutic Protocols:- Protocol 1 administered in group A, combained cognitive training (CT) and the "Life Academy" program administered twice a week. The activities were continued as long as the patient was able and willing to continue (average 24 months 1.18).- Protocol 2 administered in group B, included CT and the "Academy of Life" program also administered twice a week but lasting for the standard period of about a year (average 12 months 1.03).- Protocol 3 administered in group C, included CT and the "Community Base Treatment" program similarly administered twice a week and also lasting about a year as standard (average 12 months 1.27).Evaluation of the effects of rehabilitation using the Frontal Behavioral Inventory (FBInv) was conducted 2 times: Study I (baseline, 10 years follow up after operation)-before the start of rehabilitation, Study II (follow up) after the end of rehabilitation according to all protocols.all or most of the positive or negative symptoms tested by FBInv, including neurological, cognitive, emotional and behavioral ones. A modified CPReh program administered with Protocol 1. in which combined cognitive training (CT) and the "Academy of Life" program is provided twice a week, but which continues as long as the patient was able and willing to continue, is more effective in reducing these symptoms, like the standard CPReh program administered with Protocol 2 or 3 administered only up to a year as a standard. It was also found that the "Academy of Life " program has also been shown to be a more effective component of CPReh than the Community Base Treatment.The improvement achieved by group A, in which a modified CPReh administered with Protocol 1. that provided the patient the opportunity to continue rehabilitation as long as the patient was able and willing to continue was more effective in the reduction of Chronic Frontal Syndrome than the standard CPReh administered with Protocols 2. and 3. for the patients in groups B and C.

Frontotemporal disorders: the expansive panoply of syndromes and spectrum of etiologies.

Frontotemporal lobe disorders (FTD) are amongst the most common brain neurodegenerative disorders. Their relatively covert, frequently subtle presentations and diverse etiologies, pose major challenges in diagnosis and treatments. Recent studies have yielded insights that the etiology in the majority are due to environmental and sporadic causes, rather than genetic in origin. To retrospectively examine the cognitive and behavioral impairments in the veteran population to garner the range of differing syndrome presentations and etiological subcategories with a specific focus on frontotemporal lobe disorders. The design is a retrospective, observational registry, case series with the collection of epidemiological, clinical, cognitive, laboratory and radiological data on people with cognitive and behavioral disorders. Inclusion criteria for entry were veterans evaluated exclusively at Orlando VA Healthcare System, neurology section, receiving a diagnosis of FTD by standard criteria, during the observation period dated from July 2016 to March 2021. Frontotemporal disorders (FTD) were delineated into five clinical 5 subtypes. Demographic, cardiovascular risk factors, cognitive, behavioral neurological, neuroimaging data and presumed etiological categories, were collected for those with a diagnosis of frontotemporal disorder. Of the 200 patients with FTD, further cognitive, behavioral neurological evaluation with standardized, metric testing was possible in 105 patients. Analysis of the etiological groups revealed significantly different younger age of the traumatic brain injury (TBI) and Gulf War Illness (GWI) veterans who also had higher Montreal Cognitive Assessment (MOCA) scores. The TBI group also had significantly more abnormalities of hypometabolism, noted on the PET brain scans. Behavioral neurological testing was notable for the findings that once a frontotemporal disorder had been diagnosed, the four different etiological groups consistently had abnormal FRSBE scores for the 3 principal frontal presentations of (i) abulia/apathy, (ii) disinhibition, and (iii) executive dysfunction as well as abnormal Frontal Behavioral Inventory (FBI) scores with no significant difference amongst the etiological groups. The most common sub-syndromes associated with frontotemporal syndromes were the Geschwind-Gastaut syndrome (GGS), Klüver-Bucy syndrome (KBS), involuntary emotional expression disorder (IEED), cerebellar cognitive affective syndrome (CCA), traumatic encephalopathy syndrome (TES) and prosopagnosia. Comparisons with the three principal frontal lobe syndrome clusters (abulia, disinhibition, executive dysfunction) revealed a significant association with abnormal disinhibition FRSBE T-scores with the GGS. The regression analysis supported the potential contribution of disinhibition behavior that related to this complex, relatively common behavioral syndrome in this series. The less common subsyndromes in particular, were notable, as they constituted the initial overriding, presenting symptoms and syndromes characterized into 16 separate conditions. By deconstructing FTD into the multiple sub-syndromes and differing etiologies, this study may provide foundational insights, enabling a more targeted precision medicine approach for future studies, both in treating the sub-syndromes as well as the underlying etiological process.

Clinical Manifestations.

The mild behavioral impairment checklist (MBI-C) designed to capture neuropsychiatric symptoms in the whole spectrum of elder with or without dementia, have been verified in mild behavioral impairment, mild cognitive impairment and Alzheimer's Disease, but never used in the behavioral variant of frontotemporal dementia (bvFTD). Fifty-two patients with bvFTD (mild, n = 30; moderate-severe, n = 22) and 82 community-dwelling elderly individuals (HCs) were enrolled. All subjects were assessed with a full neuropsychological scale including the MBI-C, Neuropsychiatric Inventory Questionnaire (NPI-Q), and Frontal Behavioral Inventory (FBI). Receiver operating characteristic curves were drawn to analyze the sensitivity and specificity of the MBI-C, NPI-Q, and FBI, and cutoff points were determined using the Youden index. The MBI-C and domain scores in all patients with bvFTD were significantly higher than those in HCs. The most common symptoms of bvFTD were apathy (82.7%) and impulse dyscontrol (80.8%). The MBI-C score was positively correlated with the NPI-Q, FBI, and Activities of Daily Living. For differentiating patients with both bvFTD and mild bvFTD from HCs, the optimal MBI-C cutoff point was 5/6 with a sensitivity of 100% and specificity of 82%, and its sensitivity was higher than that of the NPI-Q and FBI. The MBI-C is a sensitive tool for screening behavioral and psychological symptoms in patients with bvFTD, even in the early stages of the disease.

Altered Metabolic Connectivity within the Limbic Cortico‐Striato‐Thalamo‐Cortical Circuit in Presymptomatic and Symptomatic Behavioral Variant Frontotemporal Dementia

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico‐cortical transmission, with limited direct investigation of cortical‐subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico‐striato‐thalamic‐cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients.MethodThirty‐three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non‐carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed‐based metabolic connectivity based on [18F]‐fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford‐GSK‐Imanova Striatal Connectivity Atlas.ResultBvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers.ConclusionThese findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.

Abnormalities of Hippocampal Subfield and Amygdalar Nuclei Volumes and Clinical Correlates in Behavioral Variant Frontotemporal Dementia with Obsessive-Compulsive Behavior-A Pilot Study.

(1) Background: The hippocampus (HP) and amygdala are essential structures in obsessive-compulsive behavior (OCB); however, the specific role of the HP in patients with behavioral variant frontotemporal dementia (bvFTD) and OCB remains unclear. (2) Objective: We investigated the alterations of hippocampal and amygdalar volumes in patients with bvFTD and OCB and assessed the correlations of clinical severity with hippocampal subfield and amygdalar nuclei volumes in bvFTD patients with OCB. (3) Materials and methods: Eight bvFTD patients with OCB were recruited and compared with eight age- and sex-matched healthy controls (HCs). Hippocampal subfield and amygdalar nuclei volumes were analyzed automatically using a 3T magnetic resonance image and FreeSurfer v7.1.1. All participants completed the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Neuropsychiatric Inventory (NPI), and Frontal Behavioral Inventory (FBI). (4) Results: We observed remarkable reductions in bilateral total hippocampal volumes. Compared with the HCs, reductions in the left hippocampal subfield volume over the cornu ammonis (CA)1 body, CA2/3 body, CA4 body, granule cell layer, and molecular layer of the dentate gyrus (GC-ML-DG) body, molecular layer of the HP body, and hippocampal tail were more obvious in patients with bvFTD and OCB. Right subfield volumes over the CA1 body and molecular layer of the HP body were more significantly reduced in bvFTD patients with OCB than in those in HCs. We observed no significant difference in amygdalar nuclei volume between the groups. Among patients with bvFTD and OCB, Y-BOCS score was negatively correlated with left CA2/3 body volume (τb = -0.729, p < 0.001); total NPI score was negatively correlated with left GC-ML-DG body (τb = -0.648, p = 0.001) and total bilateral hippocampal volumes (left, τb = -0.629, p = 0.002; right, τb = -0.455, p = 0.023); and FBI score was negatively correlated with the left molecular layer of the HP body (τb = -0.668, p = 0.001), CA4 body (τb = -0.610, p = 0.002), and hippocampal tail volumes (τb = -0.552, p < 0.006). Mediation analysis confirmed these subfield volumes as direct biomarkers for clinical severity, independent of medial and lateral orbitofrontal volumes. (5) Conclusions: Alterations in hippocampal subfield volumes appear to be crucial in the pathophysiology of OCB development in patients with bvFTD.

The Beaumont behavioral intervention in a Chinese amyotrophic lateral sclerosis cohort

Objective The prevalence of behavior impairment (27.38%) in the Chinese amyotrophic lateral sclerosis (ALS) cohort is lower. We hypothesize that the screening scales used among studies might not be appropriate to diagnose behavioral disorders in ALS patients. So, we urgently need to find a behavior scale with a high detection rate designed specifically for ALS. This study aims to verify the Chinese translation of the Beaumont Behavioral Inventory (BBI) as an effective assessment in a Chinese ALS cohort. Methods Ninety-eighty ALS patients and ninety-three healthy controls were included in this cross-sectional study. All participants took emotional state, overall cognitive, sleep quality and gastroenteric function, and behavioral evaluation. Results The BBI scores showed a strong association with the amyotrophic lateral sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q) (rs = 0.71, p < 0.001) as well as a moderate correlation with the Frontal Behavioral Inventory (FBI) (rs = 0.55, p < 0.001). High internal consistency was demonstrated in patients using BBI-after items (Cronbach’s a = 0.89). When tested against clinical diagnoses, the optimal cutoff of total BBI score was identified at 5.5 (AUC = 0.95; SE = 0.02; 95% CI [0.91, 0.99]), the BBI reached optimal sensitivity and specificity values (91.5% and 87.2%). The BBI turned out to be more precise than the FBI (AUC = 0.76; SE = 0.05; 95% CI [0.66, 0.86]) and the ALS-FTD-Q (AUC = 0.84; SE = 0.04; 95% CI [0.77, 0.92]). Conclusion The Chinese version of BBI is a quicker and more efficient instrument for assessing behavioral impairment in the ALS population in China.

Application of the mild behavioral impairment checklist in Chinese patients with the behavioral variant of frontotemporal dementia.

The mild behavioral impairment checklist (MBI-C) designed to capture neuropsychiatric symptoms in the whole spectrum of elder with or without dementia, have been verified in mild behavioral impairment, mild cognitive impairment and Alzheimer's Disease, but never used in the behavioral variant of frontotemporal dementia (bvFTD). Fifty-two patients with bvFTD (mild, n = 30; moderate-severe, n = 22) and 82 community-dwelling elderly individuals (HCs) were enrolled. All subjects were assessed with a full neuropsychological scale including the MBI-C, Neuropsychiatric Inventory Questionnaire (NPI-Q), and Frontal Behavioral Inventory (FBI). Receiver operating characteristic curves were drawn to analyze the sensitivity and specificity of the MBI-C, NPI-Q, and FBI, and cutoff points were determined using the Youden index. The MBI-C and domain scores in all patients with bvFTD were significantly higher than those in HCs. The most common symptoms of bvFTD were apathy (82.7%) and impulse dyscontrol (80.8%). The MBI-C score was positively correlated with the NPI-Q, FBI, and Activities of Daily Living. For differentiating patients with both bvFTD and mild bvFTD from HCs, the optimal MBI-C cutoff point was 5.5 with a sensitivity of 100% and specificity of 82%, and its sensitivity was higher than that of the NPI-Q and FBI. The MBI-C is a sensitive tool for screening behavioral and psychological symptoms in patients with bvFTD, even in the early stages of the disease.

Clinical relevance of disrupted topological organization of anatomical connectivity in behavioral variant frontotemporal dementia

AbstractBackgroundAbnormalities of neurodegenerative disease are not only involved in individual brain regions but also characterized by the alterations of a balance of connectomes. Graph theory is a novel approach to examine the balance of connectomes. However, the clinical relevance of white matter connectome changes in behavioral variant of frontotemporal dementia (bvFTD) is not well understood.MethodsIn this study, we used DTI image data from 24 patients with bvFTD and 28 normal controls to exploratory investigate the clinical relevance of white matter topological alterations.ResultsThe topological organization was disrupted in patients with bvFTD both globally and locally, some of which were correlated with the severity of behavior symptoms reflected as frontal behavior inventory (FBI), clinical statuses including the mini‐mental state examination (MMSE) and frontotemporal lobar degeneration‐clinical dementia rating scale (FTLD‐CDR). Notably, the nodal parameters of the lost hub regions including bilateral dorsolateral superior frontal gyrus, right orbital inferior frontal gyrus, left insula and left anterior cingulate gyrus were associated with the severity of cognitive and behavioral symptoms.ConclusionTopological measures would be a potential marker to explore the disease severity, mapping the large‐scale structural connectome of the brain will help to understand emergent cognitive behaviors in the disease condition of bvFTD.

Correlation between depression, loneliness, challenging behavior and MRI findings among persons with high‐risk for cognitive impairment (PWHRCIs)

AbstractBackgroundthis study explored the relationships between depression, loneliness, challenging behaviors among persons with high‐risk for cognitive impairment (PWHRCIs). MRI findings were collected as well.MethodThis was a secondary analysis of a cross‐sectional study. Primary data were collected from the mother project “ Social Cognition, Nutrition and Cognitive Function in Middle Life: A Longitudinal Study ” (MOST‐107‐2314‐B‐182076) between 2018 to 08/14/2021. 176 participants were recruited, among which 24 participants had received MRI examination. Test battery included: Taiwanese version of Frontal Behavioral Inventory (TFBI) for challenging behaviors, the Geriatric Depression Scale Short Form (GDS‐SF) for depressive symptoms, the short‐form UCLA Loneliness scale (ULS‐8) for loneliness, the Mini‐Mental State Examination (MMSE) for global cognition, while MRI indicators included T1‐weighted image (T1W1), Resting‐state functional MRI (RS‐fMRI) and Diffusion Weighted Image (DWI).Resulthierarchical regression model results show: Model I, depressive symptoms predicted challenging behavior, explaining 12% of variance (R2 = .12). Model II, loneliness was added and significantly predicted challenging behavior with an 8% of increased variance. In total, Model II explained 20% of variance. Therefore, loneliness is a mediator between depressive symptoms and challenging behavior. 2. Loneliness was significantly correlated with the Brain Structural Networks (normalized characteristic path length) (r = ‐.47*, p&lt;.05). 3. Challenging behavior was significantly correlated with the Brain Structural Networks (normalized characteristic clustering coefficient and normalized characteristic path length) (r = .78, p&lt;.01; r = .83, p&lt;.01, respectively). 4. Challenging behavior was significantly correlated with the Brain Functional Networks (Small‐world index and normalized characteristic clustering coefficient) (r = ‐.57, p&lt;.05; r = ‐.49, p&lt;.05, respectively), while the network indicator was thought to be random.ConclusionThe results indicated that depression and loneliness an affect challenging behavior in PWHRCIs. The results of MRI findings also highlight the importance of loneliness which may slow down the structural connections in the brain to transmit messages. Challenging behavior is also associated with functional brain connectivity. Therefore, it is necessary to regularly assess the emotional factors of PWHRCIs and provide individualized care to avoid further damage to their brain.

Primary progressive apraxia of speech: Clinico-pathological associations of left-right hemispheric dominance (S8.008)

<h3>Objective:</h3> To determine whether there are differences in in demographics, clinicopathologic-neuroimaging or survival, between left-dominant, right-dominant, and symmetric PPAOS. <h3>Background:</h3> Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome associated with neuroimaging abnormalities affecting the lateral premotor cortex (LPC) and supplementary motor area (SMA). It is unclear whether relative greater damage to premotor regions in left/right hemisphere is associated with differences in baseline and/or longitudinal features. <h3>Design/Methods:</h3> Fifty-one prospectively recruited PPAOS patients who completed [¹⁸F]-fluorodeoxyglucose PET scanning were classified as left-dominant, right-dominant, or symmetric, based on visual assessment of the LPC and SMA on FDG-PET by independent raters. Statistical analyses were utilized to compared baseline and longitudinal features. Kaplan-Meyer curves and Cox proportional hazards were used to evaluate survival differences across groups. <h3>Results:</h3> 49% of PPAOS patients were identified as left-dominant, 31% as right-dominant, and 20% as symmetric. At baseline, there were no differences between groups. On longitudinal rates of clinical change, left-dominant PPAOS displayed a slower progression of Parkinsonian symptoms on the Unified Parkinson Disease Rating Scale-III (p=0.047), with a trend for slowest rates of progression in ideomotor apraxia (p=0.06) and motor speech severity (p=0.09) relative to other groups. Right-dominant PPAOS demonstrated the most rapid rates of progression of behavioral disturbances on the Frontal Behavioral Inventory (p=0.02), including disinhibition symptoms (p=0.02) and negative behaviors (p=0.05). The symmetric group had fastest worsening of dysarthria. There were no differences in survival, although a five-year increase in age at onset, but not group classification, was associated with shorter survival (Hazard Ratio = 1.32; p=0.007). Braak neurofibrillary tangle stage differed across groups (p=0.01). While not statistically significant, right-dominant PPAOS tended to have corticobasal degeneration (CBD) and left-dominant PPAOS had progressive supranuclear palsy (PSP) pathology at autopsy. <h3>Conclusions:</h3> Patients with PPAOS and a left-dominant pattern of hypometabolism on FDG-PET have the slowest rate of decline of clinical features. <b>Disclosure:</b> Miss Robinson has nothing to disclose. The institution of Joseph Duffy has received research support from NIH. Joseph Duffy has received publishing royalties from a publication relating to health care. Heather Clark has received personal compensation for serving as an employee of Mayo Clinic. The institution of Heather Clark has received research support from NIH. Heather Clark has received publishing royalties from a publication relating to health care. The institution of Rene Utianski has received research support from NIH. The institution of Dr. Machulda has received research support from NIH. Dr. Botha has received research support from NIH. Dr. Singh has nothing to disclose. Nha Trang Thu Pham has received personal compensation for serving as an employee of Mayo Clinic. Mr. Martin has nothing to disclose. The institution of Dr. Taner has received research support from NIH. Dr. Dickson has nothing to disclose. Dr. Lowe has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AVID Radiopharmaceutical. Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Inc. The institution of Dr. Lowe has received research support from AVID Radiopharmaceuticals. Dr. Whitwell has nothing to disclose. Dr. Josephs has nothing to disclose.

Prevalence and associated factors of apathy in Chinese ALS patients.

This study aimed to explore the prevalence and clinical correlates of apathy in amyotrophic lateral sclerosis (ALS) in a cohort of Chinese patients. A total of 1,013 ALS patients were enrolled in this study. Apathy was recorded during face-to-face interviews using Frontal Behavioral Inventory, and other patient characteristics, including depression, anxiety, and cognitive function, were collected using Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Chinese version of Addenbrooke's Cognitive Examination-revised. Health-related quality of life of ALS patients and their caregivers was also evaluated, and the potential factors associated with apathy were explored using forward binary regression analysis. Survival was analyzed using the Cox proportional hazards model. The prevalence of apathy in all patients was 28.9%. Patients in the late disease stage had a higher prevalence of apathy than those in the early disease stage. Furthermore, patients with apathy had a lower ALS Functional Rating Scale revised (ALSFRS-R) score, higher HDRS score, HARS score and higher proportion of reported problems in the anxiety/depression. Additionally, their caregivers had higher score of depression and higher Zarit-Burden Interview scores. Multivariate regression analysis revealed that apathy in ALS was associated with the onset region (p = 0.027), ALSFRS-R score (p = 0.007), depression (p = 0.001) and anxiety (p < 0.001). Apathy had a significant negative effect on survival in ALS patients (p = 0.032). Apathy is relatively common (28.9%) in Chinese patients with ALS. Apathy is related to both the severity of the disease, and the presentation of non-motor symptoms in ALS, such as depression and anxiety disorders. Apathy is an independent prognostic factor for survival and requires early intervention and management.

Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis.

The UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial. Genotype data of the UNC13A rs12608932 SNP (A-major allele; C-minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) - Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models. The rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33-0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (-11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered. Overall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement.

Standardization of the Italian ALS-CBS™ Caregiver Behavioral Questionnaire.

The present investigation aimed at testing the psychometrics and diagnostics of the Italian version of the Caregiver Behavioral Questionnaire (CBQ) from the ALS Cognitive Behavioral Screen (ALS-CBS™), as well as its case-control discrimination, in a cohort of non-demented patients with ALS. The caregivers of N = 265 non-demented patients with ALS and N = 99 healthy controls (HCs) were administered the CBQ and the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). For N = 98 patients, an in-depth behavioural/psychopathological assessment via the Frontal Behavioural Inventory (FBI), the Dimensional Apathy Scale (DAS), the State and Trait Anxiety Inventory-Form Y (STAI-Y), and the Beck Depression Inventory (BDI) was also available. Factorial and construct validity, internal reliability, and diagnostics against an abnormal ECAS-CI score were tested in patients. Case-control discrimination was explored through logistic regression. The CBQ was internally reliable (McDonald's ω = 0.90) and underpinned by a simple, unidimensional structure; it converged with ECAS-CI, FBI, and DAS scores and diverged from STAI-Y and BDI ones. A cutoff of ≤ 33 accurately detected abnormal ECAS-CI scores (AUC = 0.85), yielding optimal error- and information-based diagnostics. The CBQ was independent of demographic and disease-related variables and discriminated patients from HCs (p < 0.001). The Italian version of the CBQ from the ALS-CBS™ is a valid, reliable, diagnostically sound, and feasible screener for detecting frontotemporal-like behavioural changes in non-demented patients with ALS. Its adoption is thus recommended within clinical practice and research in the view of providing preliminary information on whether the administration of more extensive behavioural instruments is needed.

Unravelling neurotransmitters impairment in primary progressive aphasias.

Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of magnetic resonance imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p< .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p= .035) and serotonin transporter (p= .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p= .007) and serotonin transporter (p< .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features.

Altered metabolic connectivity within the limbic cortico-striato-thalamo-cortical circuit in presymptomatic and symptomatic behavioral variant frontotemporal dementia

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico-cortical transmission, with limited direct investigation of cortical-subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico-striato-thalamic-cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients.MethodsThirty-three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed-based metabolic connectivity based on [18F]-fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford-GSK-Imanova Striatal Connectivity Atlas.ResultsBvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers.ConclusionThese findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.

Diagnostic properties of the Italian ECAS Carer Interview (ECAS-CI)

BackgroundThis study aimed at providing diagnostic properties and normative cut-offs for the Italian ECAS Carer Interview (ECAS-CI).MaterialsN = 292 non-demented ALS patients and N = 107 healthy controls (HCs) underwent the ECAS-CI and the Frontal Behavioural Inventory (FBI). Two ECAS-CI measures were addressed: (1) the number of symptoms (NoS; range = 0–13) and (2) that of individual symptom clusters (SC; range = 0–6). Diagnostics were explored against an FBI score ≥ than the 95th percentile of the patients’ distribution.ResultsBoth the NoS and SC discriminated patient from HCs. High accuracy, sensitivity, and specificity were detected for both the NoS and SC; however, at variance with SC, the NoS showed better post-test features and did not overestimate the occurrence of behavioural changes. The ECAS-CI converged with the FBI and diverged from the cognitive section of the ECAS.DiscussionThe ECAS-CI is a suitable screener for behavioural changes in ALS patients, with the NoS being its best outcome measure (cut-off: ≥ 3).

Validity and diagnostics of the Reading the Mind in the Eyes Test (RMET) in non-demented amyotrophic lateral sclerosis (ALS) patients.

The aim of this study was to explore the construct validity and diagnostic properties of the Reading the Mind in the Eyes Test (RMET) in non-demented patients with amyotrophic lateral sclerosis (ALS). A total of 61 consecutive patients and 50 healthy controls (HCs) were administered the 36-item RMET. Additionally, patients underwent a comprehensive assessment of social cognition via the Story-Based Empathy Task (SET), which encompasses three subtests targeting Causal Inference, Emotion Attribution (SET-EA), and Intention Attribution (SET-IA), as well as global cognitive [the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and behavioral screening [the Frontal Behavioral Inventory (FBI); the Dimensional Apathy Scale (DAS); the Beck Depression Inventory (BDI); and the State and Trait Anxiety Inventory-Y]. The construct validity of the RMET was tested by regressing it within a stepwise model that encompassed as predictors the abovementioned cognitive and behavioral measures, covarying for demographic and motor confounders. Receiver-operating characteristics (ROC) analyses allowed exploring intrinsic and post-test properties of the RMET both in discriminating patients from HCs and in identifying patients with a defective SET-EA performance. The RMET was solely predicted by the SET-EA (p = 0.003) and SET-IA (p = 0.005). RMET scores showed high accuracy both in discriminating patients from HCs (AUC = 0.81) and in identifying patients with a defective SET-EA score (AUC = 0.82), with adequate-to-optimal both intrinsic and post-test properties. The RMET is a convergently and divergently valid measure of affective social cognition in non-demented ALS patients, also featuring optimal intrinsic and post-test diagnostic properties in both case-control and case-finding scenarios.

Motor, cognitive and behavioural profiles of C9orf72 expansion-related amyotrophic lateral sclerosis

IntroductionAmyotrophic lateral sclerosis (ALS) individuals carrying the hexanucleotide repeat expansion (HRE) in the C9orf72 gene (C9Pos) have been described as presenting distinct features compared to the general ALS population (C9Neg). We aim to identify the phenotypic traits more closely associated with the HRE and analyse the role of the repeat length as a modifier factor.MethodsWe studied a cohort of 960 ALS patients (101 familial and 859 sporadic cases). Motor phenotype was determined using the MRC scale, the lower motor neuron score (LMNS) and the Penn upper motor neuron score (PUMNS). Neuropsychological profile was studied using the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Frontal Behavioral Inventory (FBI), the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI). A two-step PCR protocol and Southern blotting were performed to determine the presence and the size of C9orf72 HRE, respectively.ResultsC9orf72 HRE was detected in 55/960 ALS patients. C9Pos patients showed a younger onset, higher odds of bulbar onset, increased burden of UMN signs, reduced survival and higher frequency of concurrent dementia. We found an inverse correlation between the HRE length and the performance at ECAS ALS-specific tasks (P = 0.031). Patients also showed higher burden of behavioural disinhibition (P = 1.6 × 10–4), lower degrees of depression (P = 0.015) and anxiety (P = 0.008) compared to C9Neg cases.ConclusionsOur study provides an extensive characterization of motor, cognitive and behavioural features of C9orf72-related ALS, indicating that the C9orf72 HRE size may represent a modifier of the cognitive phenotype.