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IntroductionAlthough 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.MethodsRetrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments.ResultsCommon 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.DiscussionThis 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.HighlightsThis 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.

BackgroundCognitive impairment and dementia are frequently under-recognized. Health system strategies anchored in primary care are essential to address gaps in timely, comprehensive diagnosis. The goal of this paper is to describe the adaptation of a tablet-based brain health assessment (TabCAT-BHA) intervention and the study protocol to test its effectiveness in improving the detection of cognitive impairment, including dementia.MethodsThis mixed-methods, pragmatic, cluster randomized, hybrid effectiveness-implementation trial is being conducted in two 18-month waves with 26 Kaiser Permanente Southern California primary care clinics, with 13 serving as intervention clinics and 13 as usual care clinics. Patients 65 years and older with memory concerns (n ~ 180,000) receiving care at the 26 clinics will be included in the analyses. Primary care clinics are provided the following practice supports as part of the TabCAT-BHA intervention: brief education and training on neurocognitive disorders and study workflows; digital tools to assess cognitive function and support clinician decision making and documentation; and registered nurse support during the work-up and post-diagnosis periods for primary care providers, patients, and families. The intervention was adapted based on engagement with multiple levels of clinical and operational leaders in the healthcare system. Effectiveness outcomes include rates of cognitive impairment diagnosis in primary care and rates of completed standardized cognitive assessments and specialist referrals with incident diagnoses. Implementation outcomes include acceptability-appropriateness-feasibility, adoption, and fidelity.ResultsWe identified seven themes organized by system-, provider-, and patient-level domains that were used to adapt the TabCAT-BHA intervention. Accordingly, changes were made to the provider education, diagnostic work-up, and post-diagnostic support. Results will be reported in fall of 2027.ConclusionsOur engagement with multiple primary and specialty care clinical and operational leaders to adapt the TabCAT-BHA intervention to these primary care clinics has informed the protocol to evaluate the interventions effectiveness for improving the detection of cognitive impairment, including dementia, in an integrated healthcare system.Trial registationClinicaltrials.gov: NCT06090578 (registered 10/24/23).

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

While animal models of Alzheimer's disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain precludes its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4-12 Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology-entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients (n = 50; age, 60 ± 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls (n = 35; age, 63 ± 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI-, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI- in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology.

IntroductionAssociations 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.MethodsCerebellar 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.ResultsDistinct 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.DiscussionOur 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.HighlightsCerebellar 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.

BackgroundPeople living with multiple sclerosis (MS) face a higher likelihood of being diagnosed with a depressive disorder than the general population. Although many low-cost screening tools and evidence-based interventions exist, depression in people living with MS is underreported, underascertained by clinicians, and undertreated.ObjectiveThis study aims to design a closed-loop tool to improve depression care for these patients. It would support regular depression screening, tie into the point of care, and support shared decision-making and comprehensive follow-up. After an initial development phase, this study involved a proof-of-concept pilot randomized controlled trial (RCT) validation phase and a detailed human-centered design (HCD) phase.MethodsDuring the initial development phase, the technological infrastructure of a clinician-facing point-of-care clinical dashboard for MS management (BRIDGE) was leveraged to incorporate features that would support depression screening and comprehensive care (Care Technology to Ascertain, Treat, and Engage the Community to Heal Depression in people living with MS [MS CATCH]). This linked a patient survey, in-basket messages, and a clinician dashboard. During the pilot RCT phase, a convenience sample of 50 adults with MS was recruited from a single MS center with 9-item Patient Health Questionnaire scores of 5-19 (mild to moderately severe depression). During the routine MS visit, their clinicians were either asked or not to use MS CATCH to review their scores and care outcomes were collected. During the HCD phase, the MS CATCH components were iteratively modified based on feedback from stakeholders: people living with MS, MS clinicians, and interprofessional experts.ResultsMS CATCH links 3 features designed to support mood reporting and ascertainment, comprehensive evidence-based management, and clinician and patient self-management behaviors likely to lead to sustained depression relief. In the pilot RCT (n=50 visits), visits in which the clinician was randomized to use MS CATCH had more notes documenting a discussion of depressive symptoms than those in which MS CATCH was not used (75% vs 34.6%; χ21=8.2; P=.004). During the HCD phase, 45 people living with MS, clinicians, and other experts participated in the design and refinement. The final testing round included 20 people living with MS and 10 clinicians including 5 not affiliated with our health system. Most scoring targets for likeability and usability, including perceived ease of use and perceived effectiveness, were met. Net Promoter Scale was 50 for patients and 40 for clinicians.ConclusionsCreated with extensive stakeholder feedback, MS CATCH is a closed-loop system aimed to increase communication about depression between people living with MS and their clinicians, and ultimately improve depression care. The pilot findings showed evidence of enhanced communication. Stakeholders also advised on trial design features of a full year long Department of Defense-funded feasibility and efficacy trial, which is now underway.Trial registrationClinicalTrials.gov NCT05865405; http://tinyurl.com/4zkvru9x.

Prior research has revealed distinctive patterns of impaired language abilities across the three variants of Primary Progressive Aphasia (PPA): nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). However, little is known about whether, and to what extent, non-verbal cognitive abilities, such as processing speed, are impacted in PPA patients. This is because neuropsychological tests typically contain linguistic stimuli and require spoken output, being therefore sensitive to verbal deficits in aphasic patients. The aim of this study is to investigate potential differences in processing speed between PPA patients and healthy controls, and among the three PPA variants, using a brief non-verbal tablet-based task (Match) modeled after the WAIS-III digit symbol coding test, and to determine its neural correlates. Here, we compared performance on the Match task between PPA patients (n = 61) and healthy controls (n = 59) and across the three PPA variants. We correlated performance on Match with voxelwise gray and white matter volumes. We found that lvPPA and nfvPPA patients performed significantly worse on Match than healthy controls and svPPA patients. Worse performance on Match across PPA patients was associated with reduced gray matter volume in specific parts of the left middle frontal gyrus, superior parietal lobule, and precuneus, and reduced white matter volume in the left parietal lobe. To conclude, our behavioral findings reveal that processing speed is differentially impacted across the three PPA variants and provide support for the potential clinical utility of a tabled-based task (Match) to assess non-verbal cognition. In addition, our neuroimaging findings confirm the importance of a set of fronto-parietal regions that previous research has associated with processing speed and executive control. Finally, our behavioral and neuroimaging findings combined indicate that differences in processing speed are largely explained by the unequal distribution of atrophy in these fronto-parietal regions across the three PPA variants.

IntroductionProgressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are the most common four-repeat tauopathies (4RT), and both frequently occur with varying degree of Alzheimer's disease (AD) copathology. Intriguingly, patients with 4RT and patients with AD are at opposite ends of the wakefulness spectrum-AD showing reduced wakefulness and excessive sleepiness whereas 4RT showing decreased homeostatic sleep. The neural mechanisms underlying these distinct phenotypes in the comorbid condition of 4RT and AD are unknown. The objective of the current study was to define the alpha oscillatory spectrum, which is prominent in the awake resting-state in the human brain, in patients with primary 4RT, and how it is modified in comorbid AD-pathology.MethodIn an autopsy-confirmed case series of 4R-tauopathy patients (n = 10), whose primary neuropathological diagnosis was either PSP (n = 7) or CBD (n = 3), using high spatiotemporal resolution magnetoencephalography (MEG), we quantified the spectral power density within alpha-band (8-12 Hz) and examined how this pattern was modified in increasing AD-copathology. For each patient, their regional alpha power was compared to an age-matched normative control cohort (n = 35).ResultPatients with 4RT showed increased alpha power but in the presence of AD-copathology alpha power was reduced.ConclusionsAlpha power increase in PSP-tauopathy and reduction in the presence of AD-tauopathy is consistent with the observation that neurons activating wakefulness-promoting systems are preserved in PSP but degenerated in AD. These results highlight the selectively vulnerable impacts in 4RT versus AD-tauopathy that may have translational significance on disease-modifying therapies for specific proteinopathies.

Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

BackgroundAlzheimer's disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

INTRODUCTION: Cognition often remains unassessed in primary care. To improve early diagnosis of neurocognitive disorder (NCD) in Switzerland, the tablet-based UCSF brain health assessment (BHA) and brain health survey (BHS) were validated. METHODS: The German BHA, BHS, and Montreal Cognitive Assessment (MoCA) were administered to 67 patients with mild/major NCD and 50 controls. BHA includes subtests of memory, executive, visuospatial, and language functioning, and informant-based BHS asks about behavior and motor functioning. RESULTS: The complete instrument (BHA + BHS) was most accurate at detecting mild NCD (AUC = 0.95) and NCD without amyloid pathology (AUC = 0.96), followed by the BHA. All measures were accurate (all AUCs > 0.95) at distinguishing major NCD and NCD with amyloid pathology (Alzheimers disease [AD]) from controls. DISCUSSION: The German BHA and BHS are more sensitive to mild NCD and non-AD presentations than the MoCA and thus have a high potential to identify patients with NCD in primary care earlier than currently used screens.

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.

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 Scalable PrecisiOn Medicine Knowledge Engine (SPOKE), an open knowledge network that connects curated information from thirty-seven 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.

Background and objectivesProgressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD.MethodsParticipants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry.ResultsTwenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected).DiscussionExpressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

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

One influential framework for examining human moral cognition has been a dual process model, in which utilitarian judgment (e.g., infliction of harm for the greater good) is associated with cognitive control processes, while non-utilitarian judgment (e.g., avoiding such harms) is associated with emotional, automatic processes. Another framework of moral cognition, the two-dimensional model of utilitarian psychology, posits that utilitarian choices may reflect either instrumental harm, i.e., inflicting harm on an individual for the greater good; or impartial beneficence, i.e., impartially and altruistically acting for the benefit of the overall welfare. We evaluated preregistered hypotheses (https://osf.io/m425d) derived from these models of moral cognition in a sample of 275 neurologically healthy older adults. Our results suggest that both the dual process and two-dimensional models provided insights regarding utilitarian reasoning, including three cardinal domains of conflict between utilitarianism and common-sense morality: agent-centered permissions, special obligations, and personal rights. One prediction of the dual process-based model was supported by our findings, with higher emotionality associated with decreased endorsement of utilitarian judgments (b = - 0.12, p

Attaching semantic meaning to sensory information received from both inside and outside our bodies is a fundamental function of the human brain. The theory of Controlled Semantic Cognition (CSC) proposes that the formation of semantic knowledge relies on connections between spatially distributed modality-specific spoke-nodes, and a modality-general hub in the anterior temporal lobes (ATLs). This theory can also be applied to social semantic knowledge, though certain domain-specific spoke-nodes may make a disproportionate contribution to the understanding of social concepts. The ATLs have strong connections with spoke-node structures such as the subgenual ACC (sgACC) and the orbitofrontal cortex (OFC) that play an important role in predicting the hedonic value of stimuli. We hypothesized that in addition to the ATL semantic hub, a social semantic task would also require input from hedonic evaluation structures. We used voxel based morphometry (VBM) to examine structural brain-behavior relationships in 152 patients with neurodegeneration (Alzheimer's disease [N = 12], corticobasal syndrome (N = 18], progressive supranuclear palsy [N = 13], behavioral variant frontotemporal dementia [N = 56], and primary progressive aphasia (PPA) [N = 53]) using the Social Interaction Vocabulary Task (SIVT). This task measures the ability to correctly match a social term (e.g. "gossiping") with a visual depiction of that social interaction. As predicted, VBM showed that worse SIVT scores corresponded with volume loss in bilateral ATL semantic hub regions, but also in the sgACC, OFC, caudate and putamen (pFWE

IntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research.HighlightsThe ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses.

ObjectivesOlder 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.MethodsIndividual, 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.ResultsThe 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.ConclusionsResults showed significant variability in knowledge. Findings may be leveraged to improve interventions that address brain health literacy disparities among older Latin American immigrants.Clinical implicationsTakeaways 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.

Patients with neurodegenerative disorders experience a range of neuropsychiatric symptoms. The neural correlates have been explored for many individual symptoms, such as apathy and disinhibition. Atrophy patterns have also been associated with broadly recognized syndromes that bring together multiple symptoms, such as the behavioural variant of frontotemporal dementia. There is substantial heterogeneity of symptoms, with partial overlap of behaviour and affected neuroanatomy across and within dementia subtypes. It is not well established if there are anatomically distinct behavioural subphenotypes in neurodegenerative disease. The objective of this study was to identify shared behavioural profiles in frontotemporal dementia-spectrum and Alzheimer's disease-related syndromes. Additionally, we sought to determine the underlying neural correlates of these symptom clusters. Two hundred and eighty-one patients diagnosed with one of seven different dementia syndromes, in addition to healthy controls and individuals with mild cognitive impairment, completed a 109-item assessment capturing the severity of a range of clinical behaviours. A principal component analysis captured distinct clusters of related behaviours. Voxel-based morphometry analyses were used to identify regions of volume loss associated with each component. Seven components were identified and interpreted as capturing the following behaviours: Component 1-emotional bluntness, 2-emotional lability and disinhibition, 3-neuroticism, 4-rigidity and impatience, 5-indiscriminate consumption, 6-psychosis and 7-Geschwind syndrome-related behaviours. Correlations with structural brain volume revealed distinct neuroanatomical patterns associated with each component, including after controlling for diagnosis, suggesting that localized neurodegeneration can lead to the development of behavioural symptom clusters across various dementia syndromes.

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.

Openness is a multifaceted behavioral disposition that encompasses personal, interpersonal, and cultural dimensions. It has been suggested that the interindividual variability in openness as a personality trait is influenced by various environmental and genetic factors, as well as differences in brain functional and structural connectivity patterns along with their various associated cognitive processes. Alterations in degree of openness have been linked to several aspects of health and disease, being impacted by both physical and mental health, substance use, and neurologic conditions. This review aims to explore the current state of knowledge describing the neurobiological basis of openness and how individual differences in openness can manifest in brain health and disease.

The desire for novelty and variety in experiences, which may manifest in an inclination to engage with individuals from a diverse range of cultural backgrounds, collectively constitutes the personality dimension known as Openness to Experience. Empirical research has identified a positive correlation between trait openness and various expressions of creativity, such as divergent ideation, innovative problem-solving strategies, and cumulative creative accomplishments. This nexus between openness to interpersonal diversity, as an aspect of the larger personality trait of openness, and creativity has precipitated considerable scholarly interest across the disciplines of personality, social and organizational psychology, and neuroscientific investigation. In this paper, we review the neurobehavioral properties, including the cognitive processes and neural mechanisms, that connect these two constructs. Further, we explore how culture influences levels of openness and creativity in individuals and consider how creativity predisposes individuals toward openness to a plethora of experiences, including those occurring in culturally diverse contexts. This reciprocal entanglement of creativity and openness has been shown to foster a reduction in biases, augment conflict resolution capabilities, and generally yield superior outcomes in multicultural environments.

In semantic dementia (SD), asymmetric degeneration of the anterior temporal lobes is associated with loss of semantic knowledge and alterations in socioemotional behavior. There are two clinical variants of SD: semantic variant primary progressive aphasia (svPPA), which is characterized by predominant atrophy in the anterior temporal lobe and insula in the left hemisphere, and semantic behavioral variant frontotemporal dementia (sbvFTD), which is characterized by predominant atrophy in those structures in the right hemisphere. Previous studies of behavioral variant frontotemporal dementia, an associated clinical syndrome that targets the frontal lobes and anterior insula, have found impairments in baseline autonomic nervous system activity that correlate with left-lateralized frontotemporal atrophy patterns and disruptions in socioemotional functioning. Here, we evaluated whether there are similar impairments in resting autonomic nervous system activity in SD that also reflect left-lateralized atrophy and relate to diminished affiliative behavior. A total of 82 participants including 33 people with SD (20 svPPA and 13 sbvFTD) and 49 healthy older controls completed a laboratory-based assessment of respiratory sinus arrhythmia (RSA; a parasympathetic measure) and skin conductance level (SCL; a sympathetic measure) during a two-minute resting baseline period. Participants also underwent structural magnetic resonance imaging, and informants rated their current affiliative behavior on the Interpersonal Adjective Scale. Results indicated that baseline RSA and SCL were lower in SD than in healthy controls, with significant impairments present in both svPPA and sbvFTD. Voxel-based morphometry analyses revealed left-greater-than-right atrophy related to diminished parasympathetic and sympathetic outflow in SD. While left-lateralized atrophy in the mid-to-posterior insula correlated with lower RSA, left-lateralized atrophy in the ventral anterior insula correlated with lower SCL. In SD, lower baseline RSA, but not lower SCL, was associated with lower gregariousness/extraversion. Neither autonomic measure related to warmth/agreeableness, however. Through the assessment of baseline autonomic nervous system physiology, the present study contributes to expanding conceptualizations of the biological basis of socioemotional alterations in svPPA and sbvFTD.

BackgroundIn Alzheimer's disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy.ObjectiveTo assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others' perspectives) and emotional empathy (the ability to experience others' feelings) in AD.MethodsOlder adults (n = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer's type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy.ResultsAβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy.ConclusionsAcross AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.

IntroductionPersons with behavioral variant frontotemporal dementia (bvFTD) can exhibit apparently antisocial behaviors. An example is their tendency to adopt utilitarian choices in sacrificial moral dilemmas, i.e. harmful actions to promote overall welfare. Moral cognition models interpret such tendencies as deriving from a lack of emotional engagement and selective impairment in prosocial sentiments.MethodsWe applied a qualitative approach to test those theoretical assumptions and to further explore the emotional experiences and values of people with bvFTD while they contemplate moral scenarios. We conducted semistructured interviews with 14 participants: 7 persons with bvFTD and 7 older healthy controls. Transcripts were coded using ATLAS.ti 5.0.ResultsDuring the moral reasoning task, persons with bvFTD reported more positive emotions than negative and showed significantly less cognitive precision in their moral reasoning compared to controls. Persons with bvFTD also organized their choices predominantly around kindness and altruism, and their responses reflected higher rule compliance. Our study showed that bvFTD persons' utilitarian responses to moral dilemmas did not arise from an emotionally disengaged or antisocial perspective. Instead, they were underpinned by positive emotionality and prosocial values.DiscussionThese findings enrich current understandings of moral cognition and highlight the importance of incorporating mixed methods approaches in dementia research that take into consideration the viewpoint of cognitively impaired individuals.

Enhanced emotional empathy, the ability to share others' affective experiences, can be a feature of Alzheimer's disease (AD), but whether emotional empathy increases in the preclinical phase of the disease is unknown. We measured emotional empathy over time (range = 0 - 7.3 years, mean = 2.4 years) in 86 older adults during a period in which they were cognitively healthy, functionally normal, and free of dementia symptoms. For each participant, we computed longitudinal trajectories for empathic concern (i.e., an other-oriented form of emotional empathy that promotes prosocial actions) and emotional contagion (i.e., a self-focused form of emotional empathy often accompanied by feelings of distress) from informant ratings of participants' empathy on the Interpersonal Reactivity Index. Amyloid-β (Aβ) positron emission tomography (PET) scans were used to classify participants as either Aβ positive (Aβ+, n = 23) or negative (Aβ-, n = 63) based on Aβ-PET cortical binding. Participants also underwent structural and task-free functional magnetic resonance imaging approximately two years on average after their last empathy assessment, at which time most participants remained cognitively healthy. Results indicated that empathic concern, but not emotional contagion, increased more over time in Aβ+ participants than in Aβ- participants despite no initial group difference at the first measurement. Higher connectivity between certain salience network node-pairs (i.e., pregenual anterior cingulate cortex and periaqueductal gray) predicted longitudinal increases in empathic concern in the Aβ+ group but not in the Aβ- group. The Aβ+ participants also had higher overall salience network connectivity than Aβ- participants despite no differences in gray matter volume. These results suggest gains in empathic concern may be a very early feature of AD pathophysiology that relates to hyperconnectivity in the salience network, a system that supports emotion generation and interoception. A better understanding of emotional empathy trajectories in the early stages of AD pathophysiology will broaden the lens on preclinical AD changes and help clinicians to identify older adults who should be screened for AD biomarkers.

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.

In frontotemporal dementia (FTD), left-lateralized atrophy patterns have been associated with elevations in certain positive emotions. Here, we investigated whether positive emotional reactivity was enhanced in semantic variant primary progressive aphasia (svPPA), an FTD syndrome that targets the left anterior temporal lobe. Sixty-one participants (16 people with svPPA, 24 people with behavioral variant FTD, and 21 healthy controls) viewed six 90-sec trials that were comprised of a series of photographs; each trial was designed to elicit a specific positive emotion, negative emotion, or no emotion. Participants rated their positive emotional experience after each trial, and their smiling behavior was coded with the Facial Action Coding System. Results indicated that positive emotional experience and smiling were elevated in svPPA in response to numerous affective and non-affective stimuli. Voxel-based morphometry analyses revealed that greater positive emotional experience and greater smiling in the patients were both associated with smaller gray matter volume in the left superior temporal gyrus (pFWE

Background and objectivesChanges in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes.MethodsAsymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy.Results1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p

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

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.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

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

Researchers typically study physiological responses either after stimulus onset or when the emotional valence of an upcoming stimulus is revealed. Yet, participants may also respond when they are told that an emotional stimulus is about to be presented even without knowing its valence. Increased physiological responding during this time may reflect a 'preparation for action'. The generation of such physiological responses may be supported by frontotemporal regions of the brain that are vulnerable to damage in frontotemporal lobar degeneration. We examined preparatory physiological responses and their structural and functional neural correlate in five frontotemporal lobar degeneration clinical subtypes (behavioural variant frontotemporal dementia, n = 67; semantic variant primary progressive aphasia, n = 35; non-fluent variant primary progressive aphasia, n = 30; corticobasal syndrome, n = 32; progressive supranuclear palsy, n = 30). Comparison groups included patients with Alzheimer's disease (n = 56) and healthy controls (n = 35). Preparatory responses were quantified as cardiac interbeat interval decreases (i.e. heart rate increases) from baseline to an 'instruction period', during which participants were told to watch the upcoming emotional film but not provided the film's valence. Patients' behavioural symptoms (apathy and disinhibition) were also evaluated via a caregiver-reported measure. Compared to healthy controls and Alzheimer's disease, the frontotemporal lobar degeneration group showed significantly smaller preparatory responses. When comparing each frontotemporal lobar degeneration clinical subtype with healthy controls and Alzheimer's disease, significant group differences emerged for behavioural variant frontotemporal dementia and progressive supranuclear palsy. Behavioural analyses revealed that frontotemporal lobar degeneration patients showed greater disinhibition and apathy compared to Alzheimer's disease patients. Further, these group differences in disinhibition (but not apathy) were mediated by patients' smaller preparatory responses. Voxel-based morphometry and resting-state functional MRI analyses revealed that across patients and healthy controls, smaller preparatory responses were associated with smaller volume and lower functional connectivity in a circuit that included the ventromedial prefrontal cortex and cortical and subcortical regions of the salience network. Diminished preparatory physiological responding in frontotemporal lobar degeneration may reflect a lack of preparation for actions that are appropriate for an upcoming situation, such as approaching or withdrawing from emotional stimuli. The ventromedial prefrontal cortex and salience network are critical for evaluating stimuli, thinking about the future, triggering peripheral physiological responses, and processing and interpreting interoceptive signals. Damage to these circuits in frontotemporal lobar degeneration may impair preparatory responses and help explain often-observed clinical symptoms such as disinhibition in these patients.

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.

Dementia caregiving, besides encompassing various challenges in tandem to the diagnosis of the care recipient, is associated with decreased psychological well-being and mental health. Accordingly, caregivers' wellbeing has an impact on the quality of care they provide and on the relationship quality with the person in their care. The aim of the present study is to examine the effectiveness of a mindfulness-based intervention on relational and psychological wellbeing, tailored to the needs of dementia caregivers. This clinical trial (NCT04977245) will apply a randomized controlled mixed method design. Caregivers will be randomly allocated to either the mindfulness intervention or the active control group. The intervention arm is based on experiential learning and is targeted to promote caregivers' well-being and empowerment. Assessments will include, standardized self-report questionnaires, task performance measures, and qualitative measures. All assessments will be held at three time points (baseline; t0, 0 months, post-intervention; t1, 2 months, and after maintenance; t2, 3 months) focused on three core domains (1. relational well-being, 2. psychological well-being, and 3. dementia patient's lifestyle/activities). The primary outcome will be relational well-being, and data will be analyzed using linear mixed modelling.

BackgroundCognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up.ObjectiveOur objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation.MethodsA qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis.ResultsWe identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations.ConclusionApproaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

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.

The uncinate fasciculus (UF) connects fronto-insular and temporal gray matter regions involved in visceral emotional reactivity and semantic appraisal, but the precise role of this tract in socioemotional functioning is not well-understood. Using the Revised-Self Monitoring (RSMS) informant questionnaire, we examined whether fractional anisotropy (FA) in the right UF corresponded to socioemotional sensitivity during face-to-face interactions in 145 individuals (40 healthy older adults [NC], and 105 patients with frontotemporal lobar degeneration [FTLD] syndromes in whom this tract is selectively vulnerable, including 31 behavioral variant frontotemporal dementia [bvFTD], 39 semantic variant primary progressive aphasia [svPPA], and 35 nonfluent variant primary progressive aphasia [nfvPPA]). Voxelwise and region-of-interest-based DWI analyses revealed that FA in the right but not left UF significantly predicted RSMS score in the full sample, and in NC and svPPA subgroups alone. Right UF integrity did not predict RSMS score in the bvFTD group, but gray matter volume in the right orbitofrontal cortex adjacent to the UF was a significant predictor. Our results suggest that better socioemotional sensitivity is specifically supported by right UF white matter, highlighting a key neuro-affective relationship found in both healthy aging and neurologically affected individuals. The finding that poorer socioemotional sensitivity corresponded to right UF damage in svPPA but was more robustly influenced by gray matter atrophy adjacent to the UF in bvFTD may have important implications for endpoint selection in clinical trial design for patients with FTLD.

BackgroundNeuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD.MethodsUsing empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography, in patients with AD.ResultsPatients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions.ConclusionsOur results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD.FundingThis study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM and GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer's Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

IntroductionNeurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD.MethodsIn a well-characterized clinicopathological cohort of AD patients (n = 13), we quantified neuronal synchrony within alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination.ResultsAbnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination.DiscussionReduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.

Backgroundβ-amyloid (Aβ) and tau positron emission tomography (PET) detect the pathological changes that define Alzheimer's disease (AD) in living people. Cognitive measures sensitive to Aβ and tau burden may help streamline identification of cases for confirmatory AD biomarker testing.MethodsWe examined the association of Brain Health Assessment (BHA) tablet-based cognitive measures with dichotomized Aβ -PET status using logistic regression models in individuals with mild cognitive impairment (MCI) or dementia (N = 140; 43 Aβ-, 97 Aβ+). We also investigated the relationship between the BHA tests and regional patterns of tau-PET signal using voxel-wise regression analyses in a subsample of 60 Aβ+ individuals with MCI or dementia.ResultsFavorites (associative memory), Match (executive functions and speed), and Everyday Cognition Scale scores were significantly associated with Aβ positivity (area under the curve [AUC] = 0.75 [95% CI 0.66-0.85]). We found significant associations with tau-PET signal in mesial temporal regions for Favorites, frontoparietal regions for Match, and occipitoparietal regions for Line Orientation (visuospatial skills) in a subsample of individuals with MCI and dementia.ConclusionThe BHA measures are significantly associated with both Aβ and regional tau in vivo imaging markers and could be used for the identification of patients with suspected AD pathology in clinical practice.

BACKGROUND: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice. METHOD: F-FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent-sample t-tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow-up), linear mixed effects modeling was used to investigate pre- to post-disclosure changes in the 15-item Geriatric Depression Scale (GDS). RESULT: Of participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non-learners (p's > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre- to post-increase of 0.31 GDS points/year (95%CI: -0.08, 0.69, p = 0.12), whereas non-learners showed a slight decline (-0.15 points/year, 95%CI: -0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: -0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals. CONCLUSION: The majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.