Apraxia Patterns for the Differentiation between Alzheimer's Disease and Frontotemporal Dementia Variants.

Background and Objectives: Despite the increasing use of biomarkers, differentiation between Alzheimer's disease (AD), behavioral variant Frontotemporal Dementia (bvFTD), and Primary Progressive Aphasia (PPA) remains a challenge. Apraxia is a supportive feature for diagnosing AD but is underrepresented in other dementia types. Herein, we investigated the presence and characteristic profiles of limb, verbal, and non-verbal apraxia in three major dementia types. Materials and Methods: Test for Upper Limb Apraxia (TULIA) and Apraxia Battery for Adults-2 (ABA-2) were administered in patients with AD (n = 22), bvFTD (n = 41), and PPA (n = 22), with 20 individuals serving as healthy controls (HC). Composite and subdomain scores were compared between each patient group and the HC. Praxis profiles indicative of each dementia type and a possible predictive value were sought. Results: Apraxia provided high diagnostic accuracy for detecting dementia compared with HC (sensitivity: 63.6-100%, specificity: 79.2-100%). Patients with AD performed worse when imitating intransitive gestures as well as pantomiming transitive gestures (mean differences: 2.10 and 3.12, respectively), compared with bvFTD. PPA patients, compared with bvFTD, had comparable results in limb, verbal, and non-verbal praxis assessments, despite the greater deterioration in the outcome. Compared with patients with AD, PPA had increased pathological outcomes in verbal (86.4% vs. 40.9%) and non-verbal apraxia (31.8% vs. 0%), while bvFTD had increased pathological outcomes in verbal apraxia (85.4% vs. 44.5%). Finally, apraxia is correlated with cognitive decline. Conclusions: Apraxia profile evaluation could contribute to the differentiation between AD and Frontotemporal Dementia (FTD). Both TULIA and ABA-2 are reliable tools that can be performed as bed-side tests in clinical practice.

Real world data analysis of frontotemporal dementia: Implications for future clinical research.

Frontotemporal dementia (FTD) is a progressive decline of cognitive abilities associated with other neuropsychiatric comorbidities. A real-world data (RWD) analysis of a large electronic healthcare records (EHR) database identified the comorbidities of FTD. Deidentified EHRs in the TriNetX Network database from >155,000,000 individuals in the United States established an FTD Cohort (ICD-10 Code G31.0) of adult patients who visited a healthcare provider in 2022. The non-FTD cohort were age-matched individuals who had not received a diagnosis of ICD-10 Code G31.0, and who had visited a healthcare provider in 2022. The median age of both cohorts was 73 years. A comparative analysis was performed between the FTD and non-FTD cohorts. There were 6660 individuals (aged ≥18) with FTD and 11,810,060 individuals (aged ≥63) without a diagnosis of FTD, with healthcare visits in 2022. There were 25 ICD-10 Codes for disorders that were present in >10% of FTD patients, with a Relative Risk (RR) of ≥2.0 compared the non-FTD cohort. Multiple neuropsychiatric disorders had RRs ≥ 2.0, with minimal evidence for significant involvement of other organ systems. These data document that FTD, as known previously, is associated with multiple neuropsychiatric comorbidities. There was minimal evidence of comorbid involvement of other organ systems. These data provide a baseline of general FTD symptoms for the rapidly evolving analysis of genetic subvariants of FTD. These data also provide insights into the clinical management of FTD, as well as recommendations for specific endpoints in clinical trials.

Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

Disrupted social perception in frontotemporal dementia and Alzheimer's disease - Associated cognitive processes and clinical implications.

BACKGROUND: Social perception refers to the ability to adapt and update one's behaviour in accordance with the current context and provides the foundation for many complex social and emotional interactions. Alterations in social cognition are a hallmark of the behavioural variant of frontotemporal dementia (bvFTD), yet the capacity for social perception in this syndrome remains unclear. METHODS: We examined social perception in 18 bvFTD and 13 Alzheimer's disease (AD) patients, in comparison with 17 healthy older controls, using a social perception task derived from the Dewey Story Test. Participants also completed a comprehensive neuropsychological battery and carers provided ratings of behavioural and neuropsychiatric changes. RESULTS: Overall, bvFTD and AD performance diverged significantly from control ratings on the social perception task, however, no significant difference was found between patient groups. Standardised values relative to the mean control rating revealed considerable variability within the patient groups in terms of the direction of deviation, i.e., over- or under-rating the vignettes relative to healthy controls (range z-scores = -1.79 to +1.63). Greater deviation from control ratings was associated with more pronounced memory (p = .007) and behavioural (p = .009) disturbances in bvFTD; whilst social perception performance correlated exclusively with verbal fluency in AD (p = .003). CONCLUSIONS: Social perception is comparably disrupted in bvFTD and AD, yet likely reflects the differential breakdown of distinct cognitive processes in each dementia syndrome. Our findings have important clinical implications for the development of targeted interventions to manage disease-specific changes in social perception in dementia.

Neuropsychological Profiles, Etiologies, and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study.

Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting. Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset). Methods: The patients' (n = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n = 55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n = 35) or non-neurodegenerative (MCI-o, n = 106) etiologies, and subjective cognitive decline (n = 14). Results: The most prevalent diagnoses were Alzheimer's disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p < 0.05). Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.

Neuropsychiatric Symptoms in Frontotemporal Dementia: More Than Just Noise?

Background: Neuropsychiatric symptoms cause significant suffering and poor quality of life for patients and their caregivers. They are not considered specific to frontotemporal dementia (FTD); therefore, their clinical role and impact might be underestimated. Objective: The aims of the present study are to: 1) describe the prevalence of neuropsychiatric symptoms in FTD starting from the prodromal stage, 2) define their association with disease severity, 3) identify symptoms which are unrelated to FTD-specific symptoms, and 4) assess their association with clinical features and outcomes. Results: In this retrospective study, we analyzed data of 461 FTD patients, including behavioral variant of FTD (bvFTD, n = 318) and primary progressive aphasia (PPA, n = 143). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory, and patients' staging and global disease severity were estimated using the Clinical Dementia Rating plus NACC FTLD. Results: The most common neuropsychiatric symptoms in prodromal FTD were irritability (48%), depression (35%), and anxiety (34%); delusions were reported in 6%of prodromal bvFTD cases. The severity of most neuropsychiatric symptoms increased with global disease severity. Psychosis (delusions and hallucinations) and mood symptoms (depression and anxiety) were mostly independent from FTD-specific symptoms. Psychosis was associated with older age, higher disease severity, shorter survival rate, and was higher in bvFTD than in PPA. Conclusions: Neuropsychiatric symptoms are common in patients with FTD, also in the prodromal phase. Psychosis might be unrelated to FTD pathology, and be associated with worse clinical outcomes. The prompt detection and treatment of these symptoms might improve patient's management and quality of life.

Navigating the dementia landscape: Biomarkers and emerging therapies.

The field of dementia research has witnessed significant developments in our understanding of neurodegenerative disorders, with a particular focus on Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). Dementia, a collection of symptoms arising from the degeneration of brain cells, presents a significant healthcare challenge, especially as its prevalence escalates with age. This abstract delves into the complexities of these disorders, the role of biomarkers in their diagnosis and monitoring, as well as emerging neurophysiological insights. In the context of AD, anti-amyloid therapy has gained prominence, aiming to reduce the accumulation of amyloid-beta (Aß) plaques in the brain, a hallmark of the disease. Notably, Leqembi recently received full FDA approval, marking a significant breakthrough in AD treatment. Additionally, ongoing phase 3 clinical trials are investigating novel therapies, including Masitinib and NE3107, focusing on cognitive and functional improvements in AD patients. In the realm of FTD, research has unveiled distinct neuropathological features, including the involvement of proteins like TDP-43 and progranulin, providing valuable insights into the diagnosis and management of this heterogeneous condition. Biomarkers, including neurofilaments and various tau fragments, have shown promise in enhancing diagnostic accuracy. Neurophysiological techniques, such as transcranial magnetic stimulation (TMS), have contributed to our understanding of AD and FTD. TMS has uncovered unique neurophysiological signatures, highlighting impaired plasticity, hyperexcitability, and altered connectivity in AD, while FTD displays differences in neurotransmitter systems, particularly GABAergic and glutamatergic circuits. Lastly, ongoing clinical trials in anti-amyloid therapy for AD, such as Simufilam, Solanezumab, Gantenerumab, and Remternetug, offer hope for individuals affected by this devastating disease, with the potential to alter the course of cognitive decline. These advancements collectively illuminate the evolving landscape of dementia research and the pursuit of effective treatments for these challenging conditions.

Diagnostic Performance of Socio-Emotional Informant-Based Questionnaires for the Clinical Detection of the Behavioral Variant of Frontotemporal Dementia.

BACKGROUND: Although social cognitive dysfunction is a major feature of the behavioral variant of frontotemporal dementia (bvFTD), quantitative measurement of social behavior changes is poorly available in clinical settings. OBJECTIVE: The aim of the study is to evaluate diagnostic accuracy of social-emotional questionnaires in distinguishing bvFTD from healthy control (HC) subjects and Alzheimer's disease (AD) patients. METHODS: We enrolled 29 bvFTD, 24 AD, and 18 HC subjects matched for age, sex, and education. Two informant-based measures of socio-emotional sensitivity and empathy (i.e., revised Self-Monitoring Scale (rSMS) and Interpersonal Reactivity Index (IRI)) were administered. One-way ANOVA was performed to compare groups, whereas Receiver Operating Characteristics (ROC) curve analysis tested questionnaire ability in distinguishing groups. A short version of IRI (sIRI) was obtained by excluding the non-contributing subscale (i.e., personal distress). RESULTS: Compared to HC and AD, bvFTD showed significantly lower scores in rSMS and IRI scores, except for IRI personal distress subscale. The sIRI showed an excellent performance in early diagnosis (bvFTD versus HC = AUC 0.95). Both sIRI and rSMS showed good performance in distinguishing bvFTD from AD (AUC 0.83). CONCLUSIONS: ROC analyses support the usefulness of informant social questionnaires in memory clinics and their potential value in screening procedures for research eligibility in forthcoming trials. In the timely diagnosis of bvFTD patients, IRI and rSMS may supply crucial information for the early detection of signs and symptoms affecting social-emotional skills, which might otherwise be underrecognized.

Prognostic value of motor and extramotor involvement in ALS.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in upper and lower motor neuron loss. ALS often has a focal onset of weakness, which subsequently spreads to other body regions. Survival is limited to two to five years after disease onset, often due to respiratory failure. Cognitive impairment is present in approximately 30% to 50% of patients and in 10%-15% of patients, the clinical criteria of frontotemporal dementia (FTD) are met. METHODS: In this retrospective single-center ALS cohort study, we examined the occurrence of cognitive and behavioral impairment in relation to motor impairment at disease presentation and studied its impact on survival. RESULTS: The degree of lower motor neuron involvement was associated with a worse survival, but there was no effect for upper motor neuron involvement. Patients who were cognitively normal had a significantly better survival compared to patients with cognitive or behavioral impairment and to patients with comorbid FTD. There was no significant difference regarding survival between patients with FTD and patients with cognitive or behavioral impairment. CONCLUSIONS: The extent of motor and extramotor involvement in patients with ALS at disease presentation holds complementary prognostic information.

Psychological and social impacts of frontotemporal dementia on caregivers and family members - A systematic review.

INTRODUCTION: Frontotemporal dementia (FTD) may impose substantial psychological and social burdens on caregivers and family members that are unique from other forms of dementia due to its distinctive clinical characteristics. This systematic review investigated these impacts on caregivers and family members. METHODS: A systematic search was conducted in the PubMed, Cochrane Library and Embase databases for relevant articles published from database inception to 23 March 2023. The methodological quality of the articles was evaluated using a checklist. RESULTS: Thirty-six articles (six qualitative and thirty quantitative), including 5129 participants, were included in this review. Like other forms of dementia, FTD caregivers had significant caregiver burden levels and psychological impacts. Caregiver burden was associated with behavioural symptoms (e.g., apathy and disinhibition) and motor symptoms. The costs of caring for a patient with FTD were found to be higher than those for Alzheimer's disease. FTD patients often face challenges in obtaining a correct diagnosis and experience significant delays and multiple misdiagnoses. Healthcare professionals may also be less familiar with FTD than with Alzheimer's, leading to delayed diagnosis. This can cause considerable stress and deprive patients and caregivers of early intervention. CONCLUSION: FTD is associated with significant costs and caregiver burden levels, and the difficulties faced by caregivers and family members can be unique and challenging in different aspects when compared to other forms of dementia. Better education about FTD for family members and healthcare professionals is required to improve the quality of life for both patients and caregivers, and more support needs to be provided at all stages of the disease.

The neutral past: emotional (dys)regulation of autobiographical memory in behavioural variant frontotemporal dementia.

BACKGROUND: While affective disturbances are a key symptomatic indicator of behavioural variant frontotemporal dementia (bvFTD), little is known about how patients process the emotional load of their autobiographical (i.e. personal) memories. METHODS: We assessed the interplay of emotional regulation and autobiographical memory by inviting 18 bvFTD and 20 control participants to remember past personal events. For each memory, participants rated its emotional valence "then" (i.e. when the event has occurred) vs "now" (i.e. when retrieving the event). RESULTS: Patients with bvFTD described their memories as neutral at both times (p = .85), while control participants rated their memories as more positive during "then" than during "now" (p = .013). Autobiographical retrieval triggered fewer emotional words (p < .001) and less specificity (p < .001) in bvFTD patients compared to control participants. CONCLUSIONS: The lack of significant differences between the emotional characteristics during "then" than "now" in patients with bvFTD (and the flattening of both) may mirror their hampered ability for emotional generation, which may be associated with difficulties in reframing their past experiences to modify and adapt their meaning. The hampered emotional regulation in bvFTD may also be associated with an avoidance strategy and a passive attitude toward the past.

Development of a Speech-based Composite Score for Remotely Quantifying Language Changes in Frontotemporal Dementia.

BACKGROUND: Changes to speech and language are common symptoms across different subtypes of frontotemporal dementia (FTD). These changes affect the ability to communicate, impacting everyday functions. Accurately assessing these changes may help clinicians to track disease progression and detect response to treatment. OBJECTIVE: To determine which aspects of speech show significant change over time and to develop a novel composite score for tracking speech and language decline in individuals with FTD. METHOD: We recruited individuals with FTD to complete remote digital speech assessments based on a picture description task. Speech samples were analyzed to derive acoustic and linguistic measures of speech and language, which were tested for longitudinal change over the course of the study and were used to compute a novel composite score. RESULTS: Thirty-six (16 F, 20 M; M age = 61.3 years) individuals were enrolled in the study, with 27 completing a follow-up assessment 12 months later. We identified eight variables reflecting different aspects of language that showed longitudinal decline in the FTD clinical syndrome subtypes and developed a novel composite score based on these variables. The resulting composite score demonstrated a significant effect of change over time, high test-retest reliability, and a correlation with standard scores on various other speech tasks. CONCLUSION: Remote digital speech assessments have the potential to characterize speech and language abilities in individuals with FTD, reducing the burden of clinical assessments while providing a novel measure of speech and language abilities that is sensitive to disease and relevant to everyday function.

Facial expression recognition deficits in frontotemporal dementia and Alzheimer's disease: a meta-analytic investigation of effects of phenotypic variant, task modality, geographical region and symptomatic specificity.

Deficits in social cognition may be present in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Here, we conduct a qualitative synthesis and meta-analysis of facial expression recognition studies in which we compare the deficits between both disorders. Furthermore, we investigate the specificity of the deficit regarding phenotypic variant, domain-specificity, emotion category, task modality, and geographical region. The results reveal that both FTD and AD are associated with facial expression recognition deficits, that this deficit is more pronounced in FTD compared to AD and that this applies for the behavioral as well as for language FTD-variants, with no difference between the latter two. In both disorders, overall emotion recognition was most frequently impaired, followed by recognition of anger in FTD and by fear in AD. Verbal categorization was the most frequently used task, although matching or intensity rating tasks may be more specific. Studies from Oceania revealed larger deficits. On the other hand, non-emotional control tasks were more impacted by AD than by FTD. The present findings sharpen the social cognitive phenotype of FTD and AD, and support the use of social cognition assessment in late-life neuropsychiatric disorders.

Fear of Falling as a Behavioral Symptom in Neurocognitive Impaired Patients: Evidence from an Underrepresented Population.

BACKGROUND: Fear of falling (FoF) is a condition associated with falls, multi-morbidity, and functional impairment. To date it remains unknow which clinical, somatic, socio-demographic, behavioral, and emotional factors are associated with FoF and how these factors interact in people with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). OBJECTIVE: Identify the association of FoF with clinical, socio-demographic, and neuropsychiatric factors in patients with AD and bvFTD. METHODS: We evaluated 98 participants, 58 with AD and 40 with bvFTD at mild or moderate stages and assess FoF using the Falls Efficacy Scale-International. Additionally, we analyzed cognitive, physical performance variables, functional impairment, and affective and behavioral symptoms associated with FoF using standardized scales and a regression model analysis. RESULTS: The prevalence of FoF in AD and bvFTD was 51% and 40%, respectively. In the AD group, physical performance [F (3, 53) = 4.318, p = 0.009], the behavioral symptoms model [F (19, 38) = 3.314, p = 0.001], and the anxiety model [F (1, 56) = 13.4, p≤0.01] showed statistically significant values. In addition, the presence of hallucinations assessed with the Neuropsychiatric Inventory and social behavior assessed with the Mild Behavioral Impairment Checklist were significant. In contrast, in the bvFTD group, a homologous group of models was evaluated but we did not find any significant results. CONCLUSION: FoF in people with AD was related to physical performance, neuropsychiatric symptoms such as apathy and hallucinations, and affective symptoms such as anxiety. However, this pattern was not seen in the bvFTD group, and therefore further studies are required.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

BACKGROUND: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. METHODS: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. RESULTS: The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. CONCLUSIONS: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Cortical signature of depressive symptoms in frontotemporal dementia: A surface-based analysis.

BACKGROUND AND OBJECTIVES: Depressive symptoms are frequently reported in patients affected by frontotemporal dementia (FTD). At structural MRI, cortical features of depressed FTD patients have been poorly described. Our objective was to investigate correlations between cortical measures and depression severity in FTD patients. METHODS: Data were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database. We included 98 controls and 92 FTD patients, n = 38 behavioral variant FTD (bvFTD), n = 26 non-fluent variant Primary Progressive Aphasia (nfvPPA), and n = 28 semantic variant Primary Progressive Aphasia (svPPA). Patients underwent clinical and cognitive evaluations, as well as a 3D T1-weighted MRI on a 3 Tesla scanner (Siemens, Trio Tim system). Depression was evaluated by means of Geriatric Depression Scale (GDS). Surface-based analysis was performed on T1-weighted images to evaluate cortical thickness, a measure of gray matter integrity, and local gyrification index (lGI), a quantitative metric of cortical folding. RESULTS: Patients affected by svPPA were more depressed than controls at NPI and depression severity at GDS was higher in svPPA and bvFTD. Severity of depression correlated with a decrease in lGI in left precentral and superior frontal gyrus, supramarginal and postcentral gyrus and right precentral, supramarginal, superior parietal and superior frontal gyri. Furthermore, depression severity correlated positively with cortical thickness in the left medial orbitofrontal cortex. DISCUSSION: We found that lGI was associated with depressive symptoms over brain regions involved in the pathophysiology of major depressive disorder. This finding provides novel insights into the mechanisms underlying psychiatric symptoms in FTD.

Culpability for offenses in frontotemporal dementia and other brain disorders.

The responsibility of persons with brain disorders who commit offenses may depend on how their disorders alter brain mechanisms for culpability. Criminal behavior can result from brain disorders that alter social cognition including a neuromoral system of intuitive moral emotions that are absolute (deontological) normative codes and that includes an emotion-mediated evaluation of intentionality. This neuromoral system has its hub in the ventromedial prefrontal cortex (VMPFC) with other frontal, anterior temporal-amygdalar, insular, and right temporoparietal connections. Among brain disorders, investigators report offenses in persons with brain tumors, epilepsy, and traumatic brain injury, but it is those with a form of dementia with VMPFC pathology, behavioral variant frontotemporal dementia (bvFTD), who are most prone to criminal behavior. This review presents four new patients with bvFTD who were interviewed after committing offenses. These patients knew the nature of their acts and the wrongness of the type of action but lacked substantial capacity to experience the criminality of their conduct at the intuitive, deontological, moral emotional level. Disease in VMPFC and its amygdalar connections may impair moral emotions in these patients. These findings recommend evaluation for the experience of moral emotions and VMPFC-amygdala dysfunction among persons with antisocial behavior, with or without brain disease.

Hemispheric contributions toward interoception and emotion recognition in left-vs right-semantic dementia.

BACKGROUND: The hemispheric contributions toward interoception, the perception of internal bodily cues, and emotion recognition remains unclear. Semantic dementia cases with either left-dominant (i.e., left-SD) or right-dominant (i.e., right-SD) anterior temporal lobe atrophy experience emotion recognition difficulties, however, little is known about interoception in these syndromes. Here, we hypothesised that right-SD would show worse interoception and emotion recognition due to right-dominant atrophy. METHODS: Thirty-five participants (8 left-SD; 6 right-SD; 21 controls) completed a monitoring task. Participants pressed a button when they: (1) felt their heartbeat, without pulse measurement (Interoception); or (2) heard a recorded heartbeat (Exteroception-control). Simultaneous ECG was recorded. Accuracy was calculated by comparing the event frequency (i.e., heartbeat or sound) to response frequency. Emotion recognition was assessed via the Facial Affect Selection Task. Voxel-based morphometry analyses identified neural correlates of interoception and emotion recognition. RESULTS: Right-SD showed worse interoception than controls and left-SD (both p's < 0.001). Both patient groups showed worse emotion recognition than controls (right-SD: p < .001; left-SD: p = .018), and right-SD showed worse emotion recognition than left-SD (p = .003). Regression analyses revealed that worse emotion recognition was predicted by right-SD (p = .002), left-SD (p = .005), and impaired interoception (p = .004). Interoception and emotion were associated with the integrity of right-lateralised structures including the insula, temporal pole, thalamus, superior temporal gyrus, and hippocampus. CONCLUSION: Our study provides the first evidence for impaired interoception in right-SD, suggesting that impaired emotion recognition in this syndrome is driven by inaccurate internal monitoring. Further we identified a common neurobiological basis for interoception and emotion in the right hemisphere.

Frontal variant Alzheimer's disease: A systematic narrative synthesis.

BACKGROUND: Frontal variant Alzheimer's disease (fvAD) is considered a rare form of Alzheimer's disease (AD) which may be misdiagnosed as behavioural variant frontotemporal dementia (bvFTD). The literature has tended to conflate behavioural and executive dysfunction in fvAD cohorts and uses both AD diagnostic criteria and bvFTD diagnostic criteria to classify fvAD cohorts. The primary aim of this narrative synthesis was to summarise neuropsychological findings in fvAD cohorts in the context of established AD pathology. METHODS: EMBASE, PsycINFO, PROQUEST and MEDLINE databases were searched for studies eligible for inclusion. Studies with both neuropsychological and biomarker evidence were included in the final narrative synthesis. RESULTS: Ten studies were reviewed, including samples totalling 342 fvAD participants, 178 typical AD participants and 250 bvFTD participants. The review revealed areas worthy of further investigation that may aid differential diagnosis, including the degree of executive dysfunction in fvAD cohorts relative to bvFTD cohorts, the onset of behavioural and cognitive symptomatology, and similarities between fvAD and typical AD cognitive profiles. CONCLUSION: There was insufficient neuropsychological evidence to clearly differentiate fvAD and bvFTD cognitive phenotypes, however, the review has highlighted distinctive features of the two disorders that may guide differential diagnosis in future research. Moreover, the review has highlighted issues involving disparate diagnostic criteria used to classify fvAD cohorts, contributing to variation in findings.

Gaps in clinical research in frontotemporal dementia: A call for diversity and disparities-focused research.

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.