Radiogenomics of C9orf72 Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

Pathology-specific patterns of cerebellar atrophy in neurodegenerative disorders.

INTRODUCTION: Associations of cerebellar atrophy with specific neuropathologies in Alzheimer's disease and related dementias (ADRD) have not been systematically analyzed. This study examined cerebellar gray matter volume across major pathological subtypes of ADRD. METHODS: Cerebellar gray matter volume was examined using voxel-based morphometry in 309 autopsy-proven ADRD cases and 80 healthy controls. ADRD subtypes included AD, mixed Lewy body disease and AD (LBD-AD), and frontotemporal lobar degeneration (FTLD). Clinical function was assessed using the Clinical Dementia Rating (CDR) scale. RESULTS: Distinct patterns of cerebellar atrophy were observed in all ADRD subtypes. Significant cerebellar gray matter changes appeared in the early stages of most subtypes and the very early stages of AD, LBD-AD, FTLD-TDP type A, and progressive supranuclear palsy. Cortical atrophy positively predicted cerebellar atrophy across all subtypes. DISCUSSION: Our findings establish pathology-specific profiles of cerebellar atrophy in ADRD and propose cerebellar neuroimaging as a non-invasive biomarker for differential diagnosis and disease monitoring. HIGHLIGHTS: Cerebellar atrophy was examined in 309 patients with autopsy-proven neurodegeneration. Distinct patterns of cerebellar atrophy are found in all pathological subtypes of Alzheimer's disease and related dementias (ADRD). Cerebellar atrophy is seen in early-stage (Clinical Dementia Rating [CDR] ≤1) AD, Lewy body dementia (LBD), frontotemporal lobar degeneration with tau-positive inclusion (FTLD-tau), and FTLD-transactive response DNA binding protein (FTLD-TDP). Cortical atrophy positively predicts cerebellar atrophy across all neuropathologies.

Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.

INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Neuropsychiatric symptoms and imbalance of atrophy in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia is characterized by heterogeneous frontal, insular, and anterior temporal atrophy patterns that vary along left-right and dorso-ventral axes. Little is known about how these structural imbalances impact clinical symptomatology. The goal of this study was to assess the frequency of frontotemporal asymmetry (right- or left-lateralization) and dorsality (ventral or dorsal predominance of atrophy) and to investigate their clinical correlates. Neuropsychiatric symptoms and structural images were analyzed for 250 patients with behavioral variant frontotemporal dementia. Frontotemporal atrophy was most often symmetric while left-lateralized (9%) and right-lateralized (17%) atrophy were present in a minority of patients. Atrophy was more often ventral (32%) than dorsal (3%) predominant. Patients with right-lateralized atrophy were characterized by higher severity of abnormal eating behavior and hallucinations compared to those with left-lateralized atrophy. Subsequent analyses clarified that eating behavior was associated with right atrophy to a greater extent than a lack of left atrophy, and hallucinations were driven mainly by right atrophy. Dorsality analyses showed that anxiety, euphoria, and disinhibition correlated with ventral-predominant atrophy. Agitation, irritability, and depression showed greater severity with a lack of regional atrophy, including in dorsal regions. Aberrant motor behavior and apathy were not explained by asymmetry or dorsality. This study provides additional insight into how anatomical heterogeneity influences the clinical presentation of patients with behavioral variant frontotemporal dementia. Behavioral symptoms can be associated not only with the presence or absence of focal atrophy, but also with right/left or dorsal/ventral imbalance of gray matter volume.

Current Potential for Clinical Optimization of Social Cognition Assessment for Frontotemporal Dementia and Primary Psychiatric Disorders.

Dodich and colleagues recently reviewed the evidence supporting clinical use of social cognition assessment in behavioral variant frontotemporal dementia (Dodich et al., 2021). Here, we comment on their methods and present an initiative to address some of the limitations that emerged from their study. In particular, we established the social cognition workgroup within the Neuropsychiatric International Consortium Frontotemporal dementia (scNIC-FTD), aiming to validate social cognition assessment for diagnostic purposes and tracking of change across clinical situations.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer's disease.

Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer's disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer's disease. Using magnetoencephalography (MEG) at rest, we studied 30 Alzheimer's disease patients without subclinical epileptiform activity, 20 Alzheimer's disease patients with subclinical epileptiform activity and 35 age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with Alzheimer's disease by long-term video-EEG and a 1-h resting MEG with simultaneous EEG. Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillatory frequencies. We found that Alzheimer's disease patients with subclinical epileptiform activity have greater reductions in alpha imaginary coherence and greater enhancements in delta-theta imaginary coherence than Alzheimer's disease patients without subclinical epileptiform activity, and that these changes can distinguish between Alzheimer's disease patients with subclinical epileptiform activity and Alzheimer's disease patients without subclinical epileptiform activity with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini-Mental State Examination in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next-generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction together with cognitive and clinical correlates in patients with Alzheimer's disease.

Right temporal degeneration and socioemotional semantics: semantic behavioural variant frontotemporal dementia.

Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

INTRODUCTION: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. METHODS: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). RESULTS: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. DISCUSSION: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Perceptions of and Knowledge Acquisition about Brain Health and Aging among Latin American Immigrants:A QualitativePaper.

OBJECTIVES: Older immigrants of Latin American descent are disproportionately impacted by dementia, yet little is known about their dementia- and brain health-related knowledge. We explored perspectives on brain health and aging in this population to inform the development of culturally-relevant interventions. METHODS: Individual, semi-structured interviews were conducted with 30 Spanish-speaking immigrants over 60. Questions addressed knowledge about the brain, perceptions of healthy and unhealthy aging, ideas of how to take care of one's brain, and where knowledge was acquired. Responses were analyzed using thematic analysis. RESULTS: The following themes emerged: (1) Descriptions of the brain varied, from anatomy, cognition, and psychology to disease. (2) Perceptions of healthy aging included independence, memory, emotions, and orientation. (3) Ideas of how to care for the brain included physical, social, and cognitive engagement. (4) Knowledge was acquired in childhood, communities, healthcare settings, careers, and media. CONCLUSIONS: Results showed significant variability in knowledge. Findings may be leveraged to improve interventions that address brain health literacy disparities among older Latin American immigrants. CLINICAL IMPLICATIONS: Takeaways involve increasing education about the structure and functions of the brain, promoting realistic understandings of what nonnormative brain aging entails, and increasing knowledge of empirically-supported maintenance approaches. Dissemination may be increased via healthcare providers, community centers, churches, and media.

Influence of periaqueductal gray on other salience network nodes predicts social sensitivity.

The intrinsic connectivity of the salience network (SN) plays an important role in social behavior, however the directional influence that individual nodes have on each other has not yet been fully determined. In this study, we used spectral dynamic causal modeling to characterize the effective connectivity patterns in the SN for 44 healthy older adults and for 44 patients with behavioral variant frontotemporal dementia (bvFTD) who have focal SN dysfunction. We examined the relationship of SN effective connections with individuals' socioemotional sensitivity, using the revised self-monitoring scale, an informant-facing questionnaire that assesses sensitivity to expressive behavior. Overall, average SN effective connectivity for bvFTD patients differs from healthy older adults in cortical, hypothalamic, and thalamic nodes. For the majority of healthy individuals, strong periaqueductal gray (PAG) output to right cortical (p < .01) and thalamic nodes (p < .05), but not PAG output to other central pattern generators contributed to sensitivity to socioemotional cues. This effect did not exist for the majority of bvFTD patients; PAG output toward other SN nodes was weak, and this lack of output negatively influenced socioemotional sensitivity. Instead, input to the left vAI from other SN nodes supported patients' sensitivity to others' socioemotional behavior (p < .05), though less effectively. The key role of PAG output to cortical and thalamic nodes for socioemotional sensitivity suggests that its core functions, that is, generating autonomic changes in the body, and moreover representing the internal state of the body, is necessary for optimal social responsiveness, and its breakdown is central to bvFTD patients' social behavior deficits.

Psychosis in neurodegenerative disease: differential patterns of hallucination and delusion symptoms.

Although psychosis is a defining feature of Lewy body disease, psychotic symptoms occur in a subset of patients with every major neurodegenerative disease. Few studies, however, have compared disease-related rates of psychosis prevalence in a large autopsy-based cohort, and it remains unclear how diseases differ with respect to the nature or content of the psychosis. We conducted a retrospective chart review of 372 patients with autopsy-confirmed neurodegenerative pathology: 111 with Alzheimer's disease, 59 with Lewy body disease and concomitant Alzheimer's disease, 133 with frontotemporal lobar degeneration (FTLD) with tau inclusions (including progressive supranuclear palsy, corticobasal degeneration or Pick's disease), and 69 with FTLD and TDP inclusions (FTLD-TDP, including types A-C). Psychosis content was classified by subtype, and the frequency of each subtype was compared among pathological diagnoses using logistic regression. A total of 111 of 372 patients had psychosis. Compared to other groups, patients with Lewy body disease/Alzheimer's disease pathology were significantly more likely to have hallucinations and were more likely to have more than one subtype of hallucination. Patients with Braak Parkinson stage 5-6 Lewy body disease were significantly more likely than those with no Lewy body disease to have visual hallucinations of misperception, peripheral hallucinations, hallucinations that moved, hallucinations of people/animals/objects, as well as delusions regarding a place and delusions of misidentification. The feeling of a presence occurred significantly more frequently in patients with Lewy body disease/Alzheimer's disease than all other pathologies. Patients with FTLD-TDP were significantly more likely to have delusions, and for the delusions to occur in the first 3 years of the disease, when compared to patients with Alzheimer's disease and FTLD-tau, though rates were not significantly greater than patients with Lewy body disease/Alzheimer's disease. Paranoia occurred more frequently in the FTLD-TDP and Lewy body disease/Alzheimer's disease categories compared to patients with Alzheimer's disease or FTLD-tau. Patients with FTLD-TDP pathology had delusions of misidentification as frequently as patients with Lewy body disease/Alzheimer's disease, and were significantly more likely to have self-elevating delusions such as grandiosity and erotomania compared to patients with other pathologies including FTLD-tau. These data show that the nature and content of psychosis can provide meaningful information about the underlying neurodegenerative pathology, emphasizing the importance of characterizing patients' psychoses for prediction of the neuropathological diagnosis, regardless of a patient's clinical syndrome.

Clinical, neuroimaging, and neuropathological characterization of a patient with Alzheimer's disease syndrome due to Pick's pathology.

The most common neurodegenerative syndrome associated with Pick's disease pathology (PiD) is behavioral variant frontotemporal dementia (bvFTD), which features profound social behavioral changes. Rarely, PiD can manifest as an Alzheimer's disease (AD)-type dementia with early memory impairment. We describe a patient with AD-type dementia and pure PiD pathology who showed slowly progressive memory impairment, early social changes, and paucity of motor symptoms. Atrophy and PiD were found mainly in frontotemporal regions underlying social behavior. This report may help predict the pathology of patients with atypical AD, which will ultimately be critical for enrolling suitable subjects into disease-modifying clinical trials.

Building a Precision Medicine Delivery Platform for Clinics: The University of California, San Francisco, BRIDGE Experience.

Despite an ever-expanding number of analytics with the potential to impact clinical care, the field currently lacks point-of-care technological tools that allow clinicians to efficiently select disease-relevant data about their patients, algorithmically derive clinical indices (eg, risk scores), and view these data in straightforward graphical formats to inform real-time clinical decisions. Thus far, solutions to this problem have relied on either bottom-up approaches that are limited to a single clinic or generic top-down approaches that do not address clinical users' specific setting-relevant or disease-relevant needs. As a road map for developing similar platforms, we describe our experience with building a custom but institution-wide platform that enables economies of time, cost, and expertise. The BRIDGE platform was designed to be modular and scalable and was customized to data types relevant to given clinical contexts within a major university medical center. The development process occurred by using a series of human-centered design phases with extensive, consistent stakeholder input. This institution-wide approach yielded a unified, carefully regulated, cross-specialty clinical research platform that can be launched during a patient's electronic health record encounter. The platform pulls clinical data from the electronic health record (Epic; Epic Systems) as well as other clinical and research sources in real time; analyzes the combined data to derive clinical indices; and displays them in simple, clinician-designed visual formats specific to each disorder and clinic. By integrating an application into the clinical workflow and allowing clinicians to access data sources that would otherwise be cumbersome to assemble, view, and manipulate, institution-wide platforms represent an alternative approach to achieving the vision of true personalized medicine.

A biomedical open knowledge network harnesses the power of AI to understand deep human biology.

Knowledge representation and reasoning (KR&R) has been successfully implemented in many fields to enable computers to solve complex problems with AI methods. However, its application to biomedicine has been lagging in part due to the daunting complexity of molecular and cellular pathways that govern human physiology and pathology. In this article we describe concrete uses of SPOKE, an open knowledge network that connects curated information from 37 specialized and human-curated databases into a single property graph, with 3 million nodes and 15 million edges to date. Applications discussed in this article include drug discovery, COVID-19 research and chronic disease diagnosis and management.

Salience driven attention is pivotal to understanding others' intentions.

Interpreting others' beliefs, desires and intentions is known as "theory of mind" (ToM), and is often evaluated using simplified measurement tools, which may not correctly reflect the brain circuits that are required for real-life ToM functioning. We aimed to identify the brain structures necessary to correctly infer intentions from realistic scenarios by administering The Awareness of Social Inference Test, Enriched subtest to 47 patients with behavioural variant frontotemporal dementia, 24 patients with progressive supranuclear palsy syndrome, 31 patients with Alzheimer's syndrome, and 77 older healthy controls. Neuroimaging data was analyzed using voxel based morphometry, and participants' understanding of intentions was correlated with voxel-wise and region-of interest data. We found that structural integrity of the cinguloinsular cortex in the salience network (SN) was more pivotal for accurate ToM than previously described, emphasizing the importance of the SN for selectively recognizing and attending to social cues during ToM inferences.

The Role of Spirituality in Conceptualizations of Health Maintenance and Healthy Aging Among Latin American Immigrants.

OBJECTIVES: We aimed to investigate ways in which spirituality was conceptualized in relationship to maintaining brain health and healthy aging in a cohort of older adults who immigrated to the United States from diverse regions of Latin America, in order to ultimately develop culturally-tailored brain health promotion approaches. DESIGN: We conducted a qualitative study using semi-structured interviews. SETTING: Participants were recruited from community centers and by a memory care center at a large academic medical center. PARTICIPANTS: We interviewed 30 Spanish-speaking immigrants over age 60. Questions addressed perspectives about the brain, aging, and dementia. Interviews were coded for themes. MEASUREMENTS: Thematic analysis was used to analyze participants' responses. RESULTS: We identified 5 themes: (1) expressing gratitude to God for mental and physical health, (2) putting the onus of life and death in God's hands, (3) using church as a place to socialize and build community as an approach to leading a healthy lifestyle, (4) using prayer as nourishment for the soul and the brain, and (5) gaining inner-peace and calm, and thus maintaining a healthy life, due to a connection with God. CONCLUSION: The incorporation of customized spiritual interventions may be a mechanism by which to increase the effectiveness of brain health promotion efforts.

Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia.

Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

Measuring Behavior and Social Cognition in FTLD.

Because changes to socioemotional cognition and behavior are an early and central symptom in many of the FTLD syndromes, an objective and standardized approach to patient identification and staging relies on availability of validated socioemotional measures. Such tests should reflect functioning in key selectively vulnerable brain networks central to socioemotional behavior, specifically the intrinsically connected networks underpinning salience (SN) and semantic appraisal (SAN). There have been many challenges to the development of appropriate tests for patients with the FTLD syndromes, including the difficulty of creating standardized evaluations for the highly idiosyncratic deficits caused by salience-driven attention impairments, the trade-off between behaviorally or psychophysiologically precise measures versus the need for easily administered measures that can scale to broader clinical contexts, and the complexities of measuring socioemotional behavior across linguistically and culturally diverse samples. A subset of available socioemotional tests are reviewed with respect to evidence for their ability to reflect structural and functional changes to the FTLD-specific SN and SAN networks, and their differential diagnostic utility in the neurodegenerative disease syndromes is discussed.