Behavioral Variant FTD Research Articles

Clinical and neuroanatomical characterization of the semantic behavioral variant of frontotemporal dementia in a multicenter Italian cohort

BackgroundSemantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients.MethodsFifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry.ResultssbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants.ConclusionWe replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD.

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

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

Better living with non‐memory led dementia: results from a pilot randomised clinical trial of an online training programme for carers of people with PCA, PPA and bvFTD

AbstractBackgroundDementias starting with symptoms other than memory are low prevalent. Educational and training resources for caregivers of people living with these conditions are scarce and difficult to access. The aim of this trial is to test the feasibility of an online training program for carers of people with three non‐memory led dementias: Posterior Cortical Atrophy (PCA), Primary Progressive Aphasia (PPA) and behavioural variant FTD (bvFTD). The trial design is a randomised feasibility study.MethodSetting: Community. Participants were recruited from the organisation Rare Dementia Support (RDS). Participants: Carers of people with PCA, PPA and bvFTDIntervention: The experimental group was given access to an eight‐week online program consisting of 6 digital manuals addressing practical strategies to better support people living with PCA, PPA or bvFTD (depending on diagnosis of the care recipient). The control group was directed to RDS’s existing website (TAU).Outcome measures: Feasibility of recruitment, measurement tools (clinical outcomes, see Table 1) and acceptability. Measures were collected at baseline, immediate post intervention (8 weeks post‐randomisation) and 3 months post‐randomisation.Randomization: Allocation ratio was 2:1 (intervention: control) stratified by diagnosis carried out by a central computer system. Participants were unblinded to intervention. All measures were self‐reported online by the participants.ResultNumbers randomized: 31 participants were recruited. 30 participants were randomized (1/31 did not complete baseline) (21 to intervention, 9 to control group). Trial status: closed.Numbers analysed: 30 participants for intention to treat analysis (3 dropped out).Outcomes: Feasibility of recruitment (see Figure 1 Flowchart) is 40% (31 people consented/78 approached). Retention rate is 87%. The proportion of eligible participants who agree to participate is 97% (30/31).Assessment of feasibility of measurement tools (proposed clinical outcomes) shows 96% response rates at 8 weeks (29/30) and 90% (27/30) at 3 months. Acceptability: 100% of participants agreed to be randomised. Intervention coherence: 28% (6/21) participants interacted with facilitator during the intervention. Follow‐up qualitative interviews were conducted to gain a better understanding of how to improve intervention coherence.ConclusionThe trialled intervention shows excellent feasibility of recruitment, retention and measurement tools. Enhancement of intervention coherence is required.

Preliminary Data on the Rural‐Urban Commuting Area Codes for the ALLFTD Cohort

AbstractBackgroundThe rural‐urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural‐urban distribution of participants may provide important insights for clinical trial planning.MethodsThe current RUCA codes are generated from the 2010 decennial census and the 2006‐10 American Community Survey data. The codes are numbers (1‐10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows.ResultsRUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia‐related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small‐town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small‐town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small‐town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small‐town, 2.8% rural.ConclusionsAdditional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design.

In vivo characterization of tau accumulation in patients with frontotemporal dementia: A PET study with 18F‐florzolotau

AbstractBackgroundFrontotemporal dementia (FTD) is a group of neurodegenerative disorders with diverse clinical and neuropathological features. However, in vivo neuropathological assessments of FTD at an individual level have not hitherto been successful. Here, we aimed to classify patients with FTD based on topologies of tau protein aggregates captured by positron emission tomography (PET) with 18F‐florzolotau, which allows high‐contrast imaging of diverse tau fibrils in Alzheimer’s disease (AD) and non‐AD tauopathies.MethodTwenty‐six patients with FTD, consisting of 15 patients with behavioral variant FTD (bvFTD) and 11 patients with other FTD phenotypes, and 20 age‐ and gender‐matched healthy controls were studied. They underwent PET imaging of amyloid and tau depositions with 11C‐PiB and 18F‐florzolotau, respectively.ResultBy combining visual and semiquantitative analyses of PET images, the bvFTD patients were classified into the following subgroups: 1) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three‐repeat tauopathies (n = 3); 2) predominant tau accumulations in subcortical structures accompanied by various degrees of neocortical accumulations resembling four‐repeat tauopathies (n = 4); 3) amyloid and tau accumulations consistent with AD (n = 4); and 4) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localization of brain atrophy were not significantly different among the identified bvFTD subgroups. Patients with other FTD phenotypes were also classified into similar subgroups.ConclusionTo conclude, PET with 18F‐florzolotau potentially enables the characterization of each individual with FTD on a biological basis, thereby possibly contributing to diagnostic and therapeutic approaches to this illness.

Clinical Manifestations.

Repetitive head impacts (RHI) occur routinely in sports like American football (AmFootball) and are the most well-established risk factor for chronic traumatic encephalopathy, a neurodegenerative tauopathy. However, RHI is not routinely evaluated in older adults with other suspected neurodegenerative diseases. The prevalence of RHI among older adults with neurodegenerative diseases and the influence on clinical symptoms is unknown. RHI was defined by AmFootball participation and analyzed based on frequency of any and "substantial" exposure (> 4 years). The Boston University Head Impact Exposure Assessment was administered to 195 older adult males at the UCSF Memory and Aging Center. Of these 106 (54%) were clinically normal (CN) participants in the Brain Aging Network for Cognitive Health (BRANCH) study and 89 (46%) were cognitively impaired participants from the Alzheimer's Disease Research Center. Diagnostic groups included AD-related phenotypes ("clinAD"; amnestic-predominant MCI/dementia, logopenic PPA; N = 26) and frontotemporal dementia spectrum conditions ("FTD"; behavioral variant FTD, semantic PPA, nonfluent PPA; N = 46). Our aims were: 1) investigate frequency of prior RHI between diagnostic groups (chi square), 2) compare age of symptom onset between participants with and without prior RHI (ANOVA), and 3) evaluate associations between RHI and cognition within the largest single diagnostic group (bvFTD N = 20; ANCOVA adjusted for age and education). Cohen's d effect sizes are reported. Males with clinAD (27%; χ2 = 8.3, p = .009; d = 0.53) and FTD (21%; χ2 = 5.6, p = .02, d = 0.40) were more likely than CN (7%) to have had substantial prior RHI. Prior RHI was associated with younger age of symptom onset (62.1±7.6 vs. 56.7±7.7 years old; p = .001, d = 0.69). This effect was stronger within clinAD (63.1±7.2 vs. 53.3±7.5; d = 1.3) than FTD (60.1±7.0 vs. 55.9±6.0; d = 0.54). In participants with bvFTD, those with prior RHI scored significantly worse on memory testing (w-scores -2.6±1.1 vs. -1.1±1.2, p = .02, d = 1.4). RHI through AmFootball is more common in AD and FTD than healthy controls. Prior RHI may contribute to variability in age of symptom onset in both AD and FTD. Exposure to RHI may also partly explain why some participants with bvFTD, a classically nonamnestic syndrome, develop memory decline. Prior RHI should be routinely evaluated in neurodegenerative disease workups.

Effectiveness of a virtual health coach intervention for caregivers of persons with frontotemporal degeneration

AbstractBackgroundFrontotemporal degeneration (FTD) is a common cause of young‐onset dementia. A tremendous burden is placed on caregivers who often sacrifice their own self‐care needs in order to manage the cognitive decline and subsequent functional impairments of their loved one, contributing to extraordinarily high levels of stress and depression. Health coaching is a support intervention that is personalized and multidimensional, providing support for coping with stress while fostering self‐care. Here we report on the efficacy of a virtual health coach intervention (Virtual Caregiver Coach for You; ViCCY) aimed at increasing self‐care behaviors and reducing stress in FTD caregivers.MethodIn this pilot randomized control trial, 30 caregivers of persons with behavioral variant FTD (bvFTD) were randomly assigned to either the intervention group (ViCCY) which included 10 coaching sessions over 6 months plus targeted health information through the internet or the control group receiving standard care augmented with the targeted health information through the internet. Caregiver self‐report measures on self‐care (primary outcome), stress, depression and coping were collected at enrollment, 3 and 6 months. Using linear mixed‐effects models, we evaluated differences in change over time between the intervention and control groups.ResultsThere were no significant differences in baseline characteristics between the groups. There was a significant group‐by‐time interaction for self‐care monitoring (t58 = 2.37, p = 0.0210) and self‐care confidence (t58 = 2.32, p = 0.0239) on the Self‐Care Inventory, demonstrating that caregivers who received the ViCCY intervention improved in their self‐care over time. The intervention group also reported lower self‐neglect over time compared to the control group (Health Care Self Neglect Scale: t58 = ‐2.38, p = 0.0417). No differences were observed between the groups on the secondary outcome measures of stress, depression and coping.ConclusionsbvFTD caregivers are a unique population who defer their own self‐care in response to the stress of caregiving. This RCT shows promise for remotely delivered health coaching as an innovative way to increase support that is urgently needed to reduce poor outcomes in this distressed and underserved caregiver population.

Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.

Aphasic Binary Reversals as a Novel Biomarker Across Dementia Syndromes (P6-6.010)

Aphasic Binary Reversals as a Novel Biomarker Across Dementia Syndromes (P6-6.010)

Semantic Variant Primary Progressive Aphasia Associated with the C9orf72 Hexanucleotide Expansion – A Longitudinal Case Report (P13-6.004)

<h3>Objective:</h3> To highlight a rare phenotypic expression of the chromosome 9 open reading frame 72 (<i>C9orf72</i>) hexanucleotide expansion, and showcase three years of clinical, neuropsychological, MRI, and FDG-PET data. <h3>Background:</h3> The <i>C9orf72</i> expansion is associated with frontotemporal dementia, parkinsonism, ALS, or some combination of these phenotypes. Of the FTD variants, the behavioral variant FTD phenotype is most common. Language variants are rare, and there is little longitudinal data on such cases. <h3>Design/Methods:</h3> Case report. <h3>Results:</h3> The patient is a member of a large FTD/ALS kindred with the <i>C9orf72</i> expansion, and he has been followed longitudinally with annual visits over 3 years (4 evaluations) in the ALLFTD (www.allftd.org) natural history research program focused on frontotemporal lobar degeneration. At age 67 he began experiencing mild word finding difficulties, trouble identifying objects on a shopping list, and mild face blindness. These symptoms have progressed, and other than mild memory impairment and mild apathy, there are no other significant cognitive/behavioral/motor features. Neuropsychological testing has shown progressive deficits in high frequency object naming and loss of semantic word knowledge. MRI has demonstrated progressive atrophy of the left anterior temporal lobe. FDG-PET has shown progressive hypometabolism predominantly in the left anterior temporal lobe, with mild involvement of the prefrontal, cingulate, and parietal cortices. Clinical genetic testing has confirmed the presence of the hexanucleotide expansion in <i>C9orf72</i>. He now carries the diagnosis of semantic variant primary progressive aphasia (svPPA) and continues to be followed longitudinally. <h3>Conclusions:</h3> This report characterizes the clinical, neuropsychological, and multimodal neuroimaging findings that are typical of svPPA, which in this case is associated with the <i>C9orf72</i> expansion. This case displays the importance of assessing language in patients with a known <i>C9orf72</i> expansion when determining if a cognitive syndrome is present. <b>Disclosure:</b> Dr. Switzer has nothing to disclose. The institution of Dr. Fields has received research support from National Institutes of Health. The institution of Dr. Fields has received research support from Patient-Centered Outcomes Research Institute. The institution of Dr. Kantarci has received research support from Eli Lilly. The institution of Dr. Kantarci has received research support from NIH. The institution of Dr. Kantarci has received research support from ADDF. Dr. Lowe has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AVID Radiopharmaceutical. Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Inc. The institution of Dr. Lowe has received research support from AVID Radiopharmaceuticals. Dr. Corriveau-Lecavalier has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Botha has received research support from NIH. Dr. Knopman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for DIAN TU study. The institution of Dr. Knopman has received research support from NIH. Dr. Ramanan has nothing to disclose. Dr. Gavrilova has nothing to disclose. The institution of Maria Lapid has received research support from NIA. Ms. Forsberg has nothing to disclose. Mr. Nelson has nothing to disclose. Mr. Kolander has nothing to disclose. Dr. Boeve has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Rainwater Charitable Foundation. The institution of Dr. Boeve has received research support from Alector. The institution of Dr. Boeve has received research support from GE Healthcare. The institution of Dr. Boeve has received research support from Transposon. The institution of Dr. Boeve has received research support from Cognition Therapeutics. Dr. Boeve has received publishing royalties from a publication relating to health care.

18F]RO948 tau positron emission tomography in genetic and sporadic frontotemporal dementia syndromes

PurposeTo examine [18F]RO948 retention in FTD, sampling the underlying protein pathology heterogeneity.MethodsA total of 61 individuals with FTD (n = 35), matched cases of AD (n = 13) and Aβ-negative cognitively unimpaired individuals (n = 13) underwent [18F]RO948PET and MRI. FTD included 21 behavioral variant FTD (bvFTD) cases, 11 symptomatic C9orf72 mutation carriers, one patient with non-genetic bvFTD-ALS, one individual with bvFTD due to a GRN mutation, and one due to a MAPT mutation (R406W). Tracer retention was examined using a region-of-interest and voxel-wise approaches. Two individuals (bvFTD due to C9orf72) underwent postmortem neuropathological examination. Tracer binding was additionally assessed in vitro using [3H]RO948 autoradiography in six separate cases.Results[18F]RO948 retention across ROIs was clearly lower than in AD and comparable to that in Aβ-negative cognitively unimpaired individuals. Only minor loci of tracer retention were seen in bvFTD; these did not overlap with the observed cortical atrophy in the cases, the expected pattern of atrophy, nor the expected or verified protein pathology distribution. Autoradiography analyses showed no specific [3H]RO948 binding. The R406W MAPT mutation carriers were clear exceptions with AD-like retention levels and specific in-vitro binding.Conclusion[18F]RO948 uptake is not significantly increased in the majority of FTD patients, with a clear exception being specific MAPT mutations.

Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p &lt; 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.

Distinct disease trajectories in frontotemporal dementia-motor neuron disease and behavioural variant frontotemporal dementia: A longitudinal study.

The heterogeneity of cognitive and behavioural disturbances in frontotemporal dementia-motor neuron disease (FTD-MND), and clinical differences between FTD-MND and FTD subtypes, have been illustrated cross-sectionally. This study aimed to examine the FTD-MND disease trajectory by comparing clinical features of FTD-MND and the behavioural variant FTD (bvFTD) longitudinally. Neuropsychological and disease severity assessments were conducted in a cohort of FTD-MND (baseline, n= 42; follow-up, n= 18) and bvFTD (baseline, n= 116; follow-up, n= 111) using a longitudinal, case-control design. Age-, sex-, and education-matched controls (n= 52) were recruited. Predictors of clinical progression were analyzed. Voxel-based morphometry analysis was undertaken to investigate the progression of brain atrophy. At baseline, FTD-MND was characterized by semantic and general cognition deficits, whereas bvFTD had greater behavioural disturbances. General cognition and language deteriorated in FTD-MND when followed longitudinally. Language deficits at baseline predicted cognitive deterioration and disease progression and correlated with progressive atrophy of language regions. Further deterioration in behaviour was evident in bvFTD over time. The rate of disease progression (i.e., general cognition, semantic association, and disease severity) was significantly faster in FTD-MND than in bvFTD. FTD-MND and bvFTD appear to have distinct disease trajectories, with more rapid progression in FTD-MND. Language impairments should be closely monitored in FTD-MND as potential predictors of cognitive deterioration and disease progression.

121 The Queen Square tests of auditory cognition: defining hearing deficits and dis- ability in dementia

BackgroundHearing impairment has emerged as a potent association of cognitive decline in dementia and a promising treatment target. To realise this promise, we need to resolve fundamental questions concerning the roles of peripheral versus central auditory deficits in different dementias.MethodsUsing a novel psychoacoustic battery – the Queen Square Tests of Auditory Cognition (QSTAC)– we combined pre-existing and novel measures of peripheral and central hearing functions, to charac- terise discrete ‘auditory phenotypes’ across dementia syndromes. Customised auditory symptom ques- tionnaires (completed by patients’ caregivers) were used to capture daily-life hearing-related disability and care burden. Patient groups: Alzheimer’s disease, frontotemporal dementia, primary progressive aphasia (PPA) and control. Neuroanatomical associations of specific hearing deficits were assessed using voxel-based morphometry.ResultsSyndromic signatures of peripheral and central auditory dysfunction were identified. Alzheimer’s disease was associated with prominent impairments of auditory scene analysis and dichotic listening. PPA syndromes and behavioural variant FTD (BvFTD) were principally associated with deficits of sound pattern analysis, sound identity, emotion recognition and degraded speech perception, which stratified according to sub-syndrome (logopoenic, semantic, nonfluent).ConclusionsTaken together, our findings suggest that major dementias have characteristic and differenti- ated auditory phenotypes, reflecting a complex interplay of peripheral hearing and auditory cognitive dysfunction.jeremy.johnson@doctors.org.uk

Schizotypal traits across the amyotrophic lateral sclerosis–frontotemporal dementia spectrum: pathomechanistic insights

BackgroundPsychiatric presentations similar to that observed in primary psychiatric disorders are well described across the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum. Despite this, schizotypal personality traits associated with increased risks of clinical psychosis development and poor psychosocial outcomes have never been examined. The current study aimed to provide the first exploration of schizotypal traits and its neural underpinnings in the ALS–FTD spectrum to gain insights into a broader spectrum of psychiatric overlap with psychiatric disorders.MethodsSchizotypal traits were assessed using the targeted Schizotypal Personality Questionnaire in 99 participants (35 behavioural variant FTD, 10 ALS–FTD and 37 ALS patients, and 17 age-, sex- and education-matched healthy controls). Voxel-based morphometry analysis of whole-brain grey matter volume was conducted.ResultsRelative to controls, pervasive schizotypal personality traits across positive and negative schizotypy and disorganised thought disorders were identified in behavioural variant FTD, ALS (with the exception of negative schizotypy) and ALS–FTDALS–FTD patients (all p < .013), suggesting the presence of a wide spectrum of subclinical schizotypal symptoms beyond classic psychotic symptoms. Atrophy in frontal, anterior cingulate and insular cortices, and caudate and thalamus was involved in positive schizotypy, while integrity of the cerebellum was associated with disorganised thought disorder traits.ConclusionsThe frontal–striatal–limbic regions underpinning manifestation of schizotypy in the ALS–FTDALS–FTD spectrum are similar to that established in previous schizophrenia research. This finding expands the concept of a psychiatric overlap in ALS–FTD and schizophrenia, and suggests potentially common underlying mechanisms involving disruptions to frontal-striatal-limbic networks, warranting a transdiagnostic approach for future investigations.

In vivo hypothalamic regional volumetry across the frontotemporal dementia spectrum

BackgroundFrontotemporal dementia (FTD) is a spectrum of diseases characterised by language, behavioural and motor symptoms. Among the different subcortical regions implicated in the FTD symptomatology, the hypothalamus regulates various bodily functions, including eating behaviours which are commonly present across the FTD spectrum. The pattern of specific hypothalamic involvement across the clinical, pathological, and genetic forms of FTD has yet to be fully investigated, and its possible associations with abnormal eating behaviours have yet to be fully explored. MethodsUsing an automated segmentation tool for volumetric T1-weighted MR images, we measured hypothalamic regional volumes in a cohort of 439 patients with FTD (197 behavioural variant FTD [bvFTD]; 7 FTD with associated motor neurone disease [FTD-MND]; 99 semantic variant primary progressive aphasia [svPPA]; 117 non-fluent variant PPA [nfvPPA]; 19 PPA not otherwise specified [PPA-NOS]) and 118 age-matched controls. We compared volumes across the clinical, genetic (29 MAPT, 32 C9orf72, 23 GRN), and pathological diagnoses (61 tauopathy, 40 TDP-43opathy, 4 FUSopathy). We correlated the volumes with presence of abnormal eating behaviours assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). ResultsOn average, FTD patients showed 14% smaller hypothalamic volumes than controls. The groups with the smallest hypothalamic regions were FTD-MND (20%), MAPT (25%) and FUS (33%), with differences mainly localised in the anterior and posterior regions. The inferior tuberal region was only significantly smaller in tauopathies (MAPT and Pick’s disease) and in TDP-43 type C compared to controls and was the only regions that did not correlate with eating symptoms. PPA-NOS and nfvPPA were the groups with the least frequent eating behaviours and the least hypothalamic involvement. ConclusionsAbnormal hypothalamic volumes are present in all the FTD forms, but different hypothalamic regions might play a different role in the development of abnormal eating behavioural and metabolic symptoms. These findings might therefore help in the identification of different underlying pathological mechanisms, suggesting the potential use of hypothalamic imaging biomarkers and the research of potential therapeutic targets within the hypothalamic neuropeptides.

Extensive genetic and phenotypic description of MAPT p.R406W in the Flanders‐Belgian population

The missense mutation p.R406W in the MAPT gene is associated with frontotemporal lobar degeneration (FTLD) pathology and an atypical, Alzheimer's disease (AD)-like phenotype. In our Flanders-Belgian patient cohort, we identified 10 p.R406W carriers. Of 3 index carriers, we sampled family members, generating a total cohort of 55 p.R406W carriers. We analyzed phenotypical and genetic characteristics. Longitudinal follow-up over 19 years provided clinical and neuropathologic data. We investigated potential modifying effects on phenotype of MAPT H1/H2 and APOE genotypes. Of 55 p.R406W carriers, 39 were symptomatic. Allele-based haplotype sharing analysis confirmed a genetic kinship among all carriers suggesting a common ancestor. The frequent diagnoses were dementia (unspecified) (43.6%), AD (28.2%) and behavioral variant FTD (bvFTD) (25.6%). Average onset age and disease duration were 59.8 and 12.7 years (ranges 40-75, 5-25). at death differed significantly between clinical subgroups (69.3 in bvFTD, 78.3 in AD). Common symptoms among carriers were disinhibition and behavioral problems in all groups (72.7%). CSF biomarker profiles showed decreased Aβ1-42 and Aβ1-42 / Aβ1-40 ratio, and elevated P-tau and T-tau. Neuropathology was FTLD-tau. We observed a in carriers of an APOE ε4 allele compared to non-carriers. We observed a nonconforming clinical phenotype of p.R406W carriers in the Flemish-Belgian cohort with 25.6 % bvFTD. Contrary to previous reports, prominent behavioral symptoms were highly frequent in the entire cohort (72.7%). Ages at onset and death varied widely but, intriguingly, correlated with clinical diagnosis, lower in bvFTD than AD phenotypes. CSF biomarkers showed some AD-like abnormalities.

Diagnostic value of plasma P‐tau217 in frontotemporal dementia spectrum disorders

AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p &lt; 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

In‐depth phenotypic description of pathogenic TBK1 mutations: A frequent cause of FTD and ALS in the Flanders‐Belgian population

Pathogenic LOF and missense mutations in the TBK1 gene are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We report the prevalence and phenotype of TBK1 mutation carriers in the Flanders-Belgian population.Screening Flanders-Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) patient cohorts for mutations in TBK1 revealed 19 carriers of pathogenic mutations. We sampled and screened family members, totaling a carrier cohort of 47 individuals. We collected clinical and neuropathological data.Overall, frequency of TBK1 mutations was 2.0%, with 1.3% in FTD, 3.6% in ALS and 4.3% in FTD-ALS. Among 47 carriers, 30 were affected: FTD (n = 11, 36.7%), ALS (n = 10, 33.3%), unspecified dementia (n = 5, 16.7%), FTD-ALS (n = 2, 6.7%), mild cognitive impairment (n = 1, 3.3%) and Alzheimer's disease (n = 1, 3.3%). In the FTD group, behavioral variant FTD (bvFTD) was the most common phenotype (81.8%) but primary progressive aphasia also occurred (18.2%). Mean onset age and disease duration were 63.0 and 6.4 years (ranges 41-86 and 0-24 years). ALS patients had a significantly shorter disease duration averaging 2.6 years (range 0-6). Neuropathology confirmed FTLD-TDP type B.Pathogenic mutations in TBK1 are a frequent cause of FTD, ALS and particularly of FTD plus ALS in the Flanders-Belgian population. The most common phenotypes were FTD (81.8% bvFTD, 18.2% PPA), ALS and unspecified dementia. Disease duration significantly correlated with clinical phenotype. Neuropathology showed FTLD-TDP type B.

Local neurodegeneration and global connectivity adaptation across the FTD‐AD spectrum

AbstractBackgroundNeurodegenerative diseases involve weakened functional connectivity in disease‐targeted brain areas. Equally important but overlooked is the hyperconnectivity that appears in other brain areas (Hillary and Grafman, TICS 2017). Hyperconnectivity has been attributed to processes like disinhibition, imbalance, compensation, and reserve. It is critical to understand the neuroanatomical mechanism underlying hyperconnectivity because this functional process may accelerate subsequent disease progression. We performed structure‐function mapping for patients across subtypes and stages of the frontotemporal dementia‐Alzheimer’s disease atrophy spectrum. Our goal is to develop a comprehensive model relating diverse focal atrophy patterns to corresponding brain‐wide functional connectivity reconfigurations.MethodWe studied patients with Alzheimer’s disease (AD), behavioral variant FTD (bvFTD), semantic and nonfluent variant primary progressive aphasia (svPPA/nfvPPA), cortical basal syndrome (CBS), and healthy controls (HC). We included subjects who received a clinical diagnosis at the UCSF Memory and Aging Center and had structural and task‐free functional MRI scans (n=281). Each subject’s gray matter atrophy map was measured using voxel‐based morphometry volume loss in 273 ROIs. Functional connectivity matrices (273x273) were derived for each subject. We combined data for all patients and controls into a structural data matrix (281x273) and a functional data matrix (281x37128). We then performed partial least squares regression to find components that maximized the covariance between structure and function.ResultThe first PLS component captured the relationship between global atrophy burden and a distributed pattern of functional connectivity loss in unimodal cortical areas and enhancement in subcortical‐cortical pathways (r=0.64; Figure 1). The second PLS component showed svPPA‐like anterior temporal atrophy corresponding to atrophy‐proximal connectivity deficits, with enhancements in contralateral frontoparietal areas (r=0.67). The third PLS component revealed a spectrum from anterior (bvFTD) to posterior (AD), contrasting frontal‐insular atrophy, connectivity deficits, and parietal connectivity enhancements versus parietal atrophy, connectivity deficits, and frontal connectivity enhancements (r=0.51).ConclusionSpecific atrophy subtypes across the FTD‐AD spectrum associate with proximal functional connectivity reductions. Intriguingly, these subtypes also exhibit concomitant functional connectivity enhancements in more distal areas. The enhancements are of the same magnitude as the deficits and may represent a general principle of functional “load‐shifting” (Jones et al, Brain 2016) away from disease‐targeted areas.