Analysis of convolutional neural networks for fronto-temporal dementia biomarker discovery.

PURPOSE: Frontotemporal lobe dementia (FTD) results from the degeneration of the frontal and temporal lobes. It can manifest in several different ways, leading to the definition of variants characterised by their distinctive symptomatologies. As these variants are detected based on their symptoms, it can be unclear if they represent different types of FTD or different symptomatological axes. The goal of this paper is to investigate this question with a constrained cohort of FTD patients in order to see if the heterogeneity within this cohort can be inferred from medical images rather than symptom severity measurements. METHODS: An ensemble of convolutional neural networks (CNNs) is used to classify diffusion tensor images collected from two databases consisting of 72 patients with behavioural variant FTD and 120 healthy controls. FTD biomarkers were found using voxel-based analysis on the sensitivities of these CNNs. Sparse principal components analysis (sPCA) is then applied on the sensitivities arising from the patient cohort in order to identify the axes along which the patients express these biomarkers. Finally, this is correlated with their symptom severity measurements in order to interpret the clinical presentation of each axis. RESULTS: The CNNs result in sensitivities and specificities between 83 and 92%. As expected, our analysis determines that all the robust biomarkers arise from the frontal and temporal lobes. sPCA identified four axes in terms of biomarker expression which are correlated with symptom severity measurements. CONCLUSION: Our analysis confirms that behavioural variant FTD is not a singular type or spectrum of FTD, but rather that it has multiple symptomatological axes that relate to distinct regions of the frontal and temporal lobes. This analysis suggests that medical images can be used to understand the heterogeneity of FTD patients and the underlying anatomical changes that lead to their different clinical presentations.

Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis.

BACKGROUND: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort. METHODS: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2. FINDINGS: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9-59·8; I2=77%), 60% (56-64; I2=35%) were women, and 80% (72-89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid ß in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75-87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56-75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90-97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93-100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90-97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54-88; I2=89%), Lewy body disease (44%, 25-62; I2=77%), and cerebrovascular injury (42%, 24-60; I2=88%). INTERPRETATION: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity. FUNDING: None.

Social cognition and behavioral changes in patients with posterior cortical atrophy.

Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual and visuospatial dysfunction. The consensus criteria state that patients should present "relatively spared behavior and personality" in early stages. However, limited research has focused on these symptoms in PCA. This study compared 157 patients with PCA in early stages of the disease with 352 healthy controls (HC), 202 typical AD (tAD), and 177 logopenic variant primary progressive aphasia (lvPPA) patients from the National Alzheimer's Coordinating Center (NACC) dataset. They were compared using clinician ratings of behavioral symptoms, informant- and clinician-filled questionnaires and patient-facing tests of behavior and social cognition. Results showed that PCA individuals exhibited many behavioral symptoms, the more frequently reported being anxiety, depression, apathy, and irritability. During cognitive testing, clinicians observed disorganized and reactive behaviors, but no insensitive behaviors. Informant reports indicated that PCA patients exhibited higher levels of inhibition and anxiety in response to stimuli associated with non-reward, novelty, and punishment. Social norms knowledge and empathy were overall preserved, although slight decreases in perspective-taking and socioemotional sensitivity were observed on informant-rated questionnaires. Except for more elevated neuropsychiatric symptoms in tAD, the three AD variants had similar profiles. Our findings provide insights into the social cognition and behavioral profiles of PCA, highlighting patterns of preservations and mild impairments, even in the early stages of the disease. These results contribute to a more complete understanding of non-visual symptoms in PCA and have implications for diagnostic and intervention strategies.

Atypical forms of Alzheimer's disease: patients not to forget.

PURPOSE OF REVIEW: The aim of this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and to emphasize innovative aspects in the clinic and research. The paper will mostly cover language (logopenic variant of primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) and dysexecutive (dAD) variants of AD. RECENT FINDINGS: MRI and PET can detect and differentiate typical and atypical AD variants, and novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), cortical mean diffusivity, and brain total creatine can also contribute. Together, these approaches have helped to characterize variant-specific distinct imaging profiles. Even within each variant, various subtypes that capture the heterogeneity of cases have been revealed. Finally, in-vivo pathology markers have led to significant advances in the atypical AD neuroimaging field. SUMMARY: Overall, the recent neuroimaging literature on atypical AD variants contribute to increase knowledge of these lesser-known AD variants and are key to generate atypical variant-specific clinical trial endpoints, which are required for inclusion of these patients in clinical trials assessing treatments. In return, studying these patients can inform the neurobiology of various cognitive functions, such as language, executive, memory, and visuospatial abilities.

Altered delay discounting in neurodegeneration: insight into the underlying mechanisms and perspectives for clinical applications.

Steeper delay discounting (i.e., the extent to which future rewards are perceived as less valuable than immediate ones) has been proposed as a transdiagnostic process across different health conditions, in particular psychiatric disorders. Impulsive decision-making is a hallmark of different neurodegenerative conditions but little is known about delay discounting in the domain of neurodegenerative conditions. We reviewed studies on delay discounting in patients with Parkinson's disease (PD) and in patients with dementia (Alzheimer's disease / AD or frontotemporal dementia / FTD). We proposed that delay discounting could be an early marker of the neurodegenerative process. We developed the idea that altered delay discounting is associated with overlapping but distinct neurocognitive mechanisms across neurodegenerative diseases: dopaminergic-related disorders of reward processing in PD, memory/projection deficits due to medial temporal atrophy in AD, modified reward processing due to orbitofrontal atrophy in FTD. Neurodegeneration could provide a framework to decipher the neuropsychological mechanisms of value-based decision-making. Further, delay discounting could become a marker of interest in clinical practice, in particular for differential diagnosis.

Behavioural disinhibition in frontotemporal dementia investigated within an ecological framework.

Disinhibition is a core symptom in behavioural variant frontotemporal dementia (bvFTD) particularly affecting the daily lives of both patients and caregivers. Yet, characterisation of inhibition disorders is still unclear and management options of these disorders are limited. Questionnaires currently used to investigate behavioural disinhibition do not differentiate between several subtypes of disinhibition, encompass observation biases and lack of ecological validity. In the present work, we explored disinhibition in an original semi-ecological situation, by distinguishing three categories of disinhibition: compulsivity, impulsivity and social disinhibition. First, we measured prevalence and frequency of these disorders in 23 bvFTD patients and 24 healthy controls (HC) in order to identify the phenotypical heterogeneity of disinhibition. Then, we examined the relationships between these metrics, the neuropsychological scores and the behavioural states to propose a more comprehensive view of these neuropsychiatric manifestations. Finally, we studied the context of occurrence of these disorders by investigating environmental factors potentially promoting or reducing them. As expected, we found that patients were more compulsive, impulsive and socially disinhibited than HC. We found that 48% of patients presented compulsivity (e.g., repetitive actions), 48% impulsivity (e.g., oral production) and 100% of the patients group showed social disinhibition (e.g., disregards for rules or investigator). Compulsivity was negatively related with emotions recognition. BvFTD patients were less active if not encouraged in an activity, and their social disinhibition decreased as activity increased. Finally, impulsivity and social disinhibition decreased when patients were asked to focus on a task. Summarising, this study underlines the importance to differentiate subtypes of disinhibition as well as the setting in which they are exhibited, and points to stimulating area for non-pharmacological management.

Brain Metabolic Profile in Presymptomatic GRN Carriers Throughout a 5-Year Follow-up.

BACKGROUND AND OBJECTIVES: GRN variants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG)-PET in identifying metabolic changes in presymptomatic GRN carriers (PS-GRN+) and to trace their longitudinal progression. METHODS: Participants were longitudinally evaluated over 5 years in a prospective cohort study focused on GRN disease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed. RESULTS: Among the 80 individuals enrolled in the study, 58 (27 PS-GRN+ and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS-GRN+ and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers (p < 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (-1.37%) was higher than that in controls (-0.21%, p = 0.004). Lower glucose uptake was associated with higher neurofilament increase (p = 0.003) and lower frontal cognitive scores (p = 0.014) in PS-GRN+. DISCUSSION: This study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinical GRN disease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials.

Disentangling Clinical Profiles of Apathy in Behavioral Variant Frontotemporal Dementia.

BACKGROUND: Apathy is highly frequent in behavioral variant frontotemporal dementia (bvFTD). It is presumed to involve different pathophysiological mechanisms and neuroanatomical regions. OBJECTIVE: We explored the hypothesis that subgroups showing distinct profiles of apathy and distinct patterns of atrophy within frontal lobes could be disentangled in bvFTD. METHODS: Using data-driven clustering applied to 20 bvFTD patients, we isolated subgroups according to their profiles on the three subscales of the Dimensional Apathy Scale (DAS). We explored their apathy profiles and atrophy patterns. Apathy profiles were characterized through both subjective measures of apathy by questionnaires and measures including objective behavioral metrics. Atrophy patterns were obtained by voxel-based morphometry, contrasting each bvFTD subgroup with healthy controls (N = 16). RESULTS: By clustering based on DAS dimensions, we disentangled three subgroups of bvFTD patients, with distinct apathy profiles and atrophy patterns. One subgroup, which presented the smallest pattern of atrophy (including orbitofrontal cortex) with a right asymmetry, was characterized by high self-reported emotional and initiation apathy and by a self-initiation deficit reversible by external guidance. In other subgroups showing more diffuse bilateral atrophies extending to lateral prefrontal cortex, apathy was not reversible by external guidance and more difficulty to focus on goal-management was observed, especially in the subgroup with the largest atrophy and highest levels of executive apathy. CONCLUSION: Distinct clinical profiles of apathy, corresponding to distinct anatomical subtypes of bvFTD, were identified. These findings have implications for clinicians in a perspective of precision medicine as they could contribute to personalize treatments of apathy.

The temporal lobe in typical and atypical Alzheimer disease.

Alzheimer disease (AD) is defined neuropathologically by abnormal extra-cellular ß-amyloid plaques combined with intraneuronal tau aggregation. Patients sharing the same neuropathological features but presenting different clinical manifestations and evolutions have led to the notion of AD spectrum. This spectrum encompasses typical and atypical forms of AD. For all of them, specific parts of the temporal lobes, as well as their structural and functional connections with other brain regions, are affected. In typical amnestic late-onset Alzheimer's disease (>65 years old; LOAD), tau pathology gradually spreads to the brain from the medial temporal lobe (MTL). MTL is an inhomogeneous structure consisting of several subregions densely connected to each other and to other cortical and subcortical brain regions. These regions play a crucial role in the storage of information in episodic memory. In less common early-onset AD (<65 years old; EOAD), a large proportion of patients presents atypical clinical manifestations, in which memory impairment is not inaugural and predominant. Instead, these patients have predominant and/or isolated deficits in language, visuospatial, motor, or executive/behavioral functions. In atypical variants, brain damage is mainly centered on the posterior regions, with relative sparing of the MTL. However, the temporal lobe also appears to be variably and specifically damaged in some subtypes of EOAD. For example, the left superior temporal gyrus is the core of brain damage in the language variant, as well as the ventral regions of the temporal lobe play an important role in the clinic of the visual variant.

Right-side spatial neglect and white matter disconnection after left-hemisphere strokes.

Spatial neglect usually concerns left-sided events after right-hemisphere damage. Its anatomical correlates are debated, with evidence suggesting an important role for fronto-parietal white matter disconnections in the right hemisphere. Here, we describe the less frequent occurrence of neglect for right-sided events, observed in three right-handed patients after a focal stroke in the left hemisphere. Patients were tested 1 month and 3 months after stroke. They performed a standardized paper-and-pencil neglect battery and underwent brain MRI with both structural and diffusion tensor (DT) sequences, in order to assess both grey matter and white matter tracts metrics. Lesions were manually reconstructed for each patient. Patients presented signs of mild right-sided neglect during visual search and line bisection. One patient also showed pathological performance in everyday life. Structural MRI demonstrated left parietal strokes in two patients, in the region extending from the postcentral gyrus to the temporo-parietal junction. One of these two patients also had had a previous occipital stroke. The remaining patient had a left frontal stroke, affecting the precentral, the postcentral gyri and the basal ganglia. DT MRI tractography showed disconnections in the fronto-parietal regions, concerning principally the superior longitudinal fasciculus (SLF). These results suggest an important role for left SLF disconnection in right-side neglect, which complements analogous evidence for right SLF disconnection in left-side neglect.

Differential Patterns of Domain-Specific Cognitive Complaints and Awareness Across the Alzheimer's Disease Spectrum.

Background: Characterizing self- and informant-reported cognitive complaints, as well as awareness of cognitive decline (ACD), is useful for an early diagnosis of Alzheimer's disease (AD). However, complaints and ACD related to cognitive functions other than memory are poorly studied. Furthermore, it remains unclear which source of information is the most useful to distinguish various groups on the AD spectrum. Methods: Self- and informant-reported complaints were measured with the Everyday Cognition questionnaire (ECog-Subject and ECog-StudyPartner) in four domains (memory, language, visuospatial, and executive). ACD was measured as the subject-informant discrepancy in the four ECog scores. We compared the ECog and ACD scores across cognitive domains between four groups: 71 amyloid-positive individuals with amnestic AD, 191 amnestic mild cognitive impairment (MCI), or 118 cognitively normal (CN), and 211 amyloid-negative CN controls, selected from the ADNI database. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog and ACD scores in discriminating clinical groups. Results: Self- and informant-reported complaints were generally distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). Both groups of CN participants presented on average more memory and language complaints than their informant. MCI participants showed good agreement with their informants. AD participants presented anosognosia in all domains, but especially for the executive domain. The four ECog-StudyPartner sub-scores allowed excellent discrimination between groups in almost all classifications and performed significantly better than the other two classifiers considered. The ACD was excellent in distinguishing the participants with AD from the two groups of CN participants. The ECog-Subject was the least accurate in discriminating groups in four of the six classifications performed. Conclusion: In research, the study of complaint and anosognosia should not be reduced solely to the memory domain. In clinical practice, non-amnestic complaints could also be linked to Alzheimer's disease. The presence of an informant also seems necessary given its accuracy as a source of information.

A temporal classification method based on behavior time series data in patients with behavioral variant of frontotemporal dementia and apathy.

Background Apathy is a common behavioral syndrome that occurs across neurological and psychiatric disorders. An influential theoretical framework defined apathy as the quantitative reduction of self-generated voluntary and purposeful behaviors. There is evidence in the literature of the multidimensional nature of apathy with cognitive, behavioral, and emotional dimensions. To date, apathy has been assessed using various scales and questionnaires. Alternative objective and ecological measurements of apathy are needed. New method We used the ECOCAPTURE protocol and an ethological approach to investigate behavior in bvFTD patients under ecological conditions (a waiting room) while they freely explored a novel environment. Data were collected by behavioral coding from 7-minute video using an ethogram and transformed into behavior time series data. We present an approach considering behavioral kinetics to assess behavior. We aimed to construct a new behavior analysis method, called ECOCAPTURE kinetics, using temporal classification for behavior time series data analysis. To develop our classifier, we retained a nonelastic Euclidian metric, combined with a convolutional approach. Results We applied the ECOCAPTURE kinetics method to a cohort of 20 bvFTD patients and 18 healthy controls. We showed that bvFTD patients can be classified according to their behavioral kinetics into three groups. Each subgroup was characterized by specific behavior disorders and neuropsychological profile. Comparison with Existing Method(s) The ECOCAPTURE kinetics method is different from those of the classical approach of measuring behavior, producing time budgets, frequency of behavior occurrences, or kinematic diagrams. Conclusions This approach can be extended to any behavioral study encoding time.

An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia.

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal. In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls. We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the "semantic appraisal" network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the "salience" network. Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Functional connectivity correlates of reduced goal-directed behaviors in behavioural variant frontotemporal dementia.

We explored the resting state functional connectivity correlates of apathy assessed as a multidimensional construct, using behavioral metrics, in behavioral variant frontotemporal dementia (bvFTD). We recorded the behavior of 20 bvFTD patients and 16 healthy controls in a close-to-real-life situation including a free phase (FP-in which actions were self-initiated) and a guided phase (GP-in which initiation of actions was facilitated by external guidance). We investigated the activity time and walking episode features as quantifiers of apathy. We used the means ((FP + GP)/2) and the differences (FP-GP) calculated for these metrics as well as measures by questionnaires to extract apathy dimensions by factor analysis. We assessed two types of fMRI-based resting state connectivity measures (local activity and seed-based connectivity) and explored their relationship with extracted apathy dimensions. Apathy in bvFTD was associated with lower time spent in activity combined with walking episodes of higher frequency, lower acceleration and higher duration. Using these behavioral metrics and apathy measures by questionnaires, we disentangled two dimensions: the global reduction of goal-directed behaviors and the specific deficit of self-initiation. Global apathy was associated with lower resting state activity within prefrontal cortex and lower connectivity of salience network hubs while the decrease in self-initiation was related to increased connectivity of parietal default-mode network hubs. Through a novel dimensional approach, we dissociated the functional connectivity correlates of global apathy and self-initiation deficit. We discussed in particular the role of the modified connectivity of lateral parietal cortex in the volitional process.

Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention.

Given the unknown therapeutic value of targeting Alzheimer's disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer's disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.

Primary progressive aphasias associated with C9orf72 expansions: Another side of the story.

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72-related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications.

OBJECTIVE: Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. METHODS: We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. RESULTS: pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades. CONCLUSIONS: This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression. TRIAL REGISTRATION NUMBERS: NCT02590276 and NCT04014673.

ECOCAPTURE@HOME: Protocol for the Remote Assessment of Apathy and Its Everyday-Life Consequences.

Apathy, a common neuropsychiatric symptom associated with dementia, has a strong impact on patients' and caregivers' quality of life. However, it is still poorly understood and hard to define. The main objective of the ECOCAPTURE programme is to define a behavioural signature of apathy using an ecological approach. Within this program, ECOCAPTURE@HOME is an observational study which aims to validate a method based on new technologies for the remote monitoring of apathy in real life. For this study, we plan to recruit 60 couples: 20 patient-caregiver dyads in which patients suffer from behavioral variant Fronto-Temporal Dementia, 20 patient-caregiver dyads in which patients suffer from Alzheimer Disease and 20 healthy control couples. These dyads will be followed for 28 consecutive days via multi-sensor bracelets collecting passive data (acceleration, electrodermal activity, blood volume pulse). Active data will also be collected by questionnaires on a smartphone application. Using a pool of metrics extracted from these passive and active data, we will validate a measurement model for three behavioural markers of apathy (i.e., daytime activity, quality of sleep, and emotional arousal). The final purpose is to facilitate the follow-up and precise diagnosis of apathy, towards a personalised treatment of this condition within everyday life.

Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant.

OBJECTIVE: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. METHODS: Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. RESULTS: Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONS: This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.

Frontotemporal dementia subtypes based on behavioral inhibition deficits.

INTRODUCTION: We aimed to investigate phenotypic heterogeneity in the behavioral variant of frontotemporal dementia (bvFTD) through assessment of inhibition deficits. METHODS: We assessed occurrences of 16 behavioral inhibition deficits from video recordings of 15 bvFTD patients (early stage) and 15 healthy controls (HC) in an ecological setting. We extracted dimensions of inhibition deficit and analyzed their correlations with cognitive and clinical measures. Using these dimensions, we isolated patient clusters whose atrophy patterns were explored. RESULTS: After identifying two patterns of inhibition deficit (compulsive automatic behaviors and socially unconventional behaviors), we isolated three behavioral clusters with distinct atrophy patterns. BvFTD-G0 (N = 3), an outlier group, showed severe behavioral disturbances and more severe ventromedial prefrontal cortex/orbitofrontal cortex atrophy. Compared to bvFTD-G1 (N = 6), bvFTD-G2 (N = 6) presented higher anxiety and depression along with less diffuse atrophy especially in midline regions. DISCUSSION: Identifying clinico-anatomical profiles through behavior observation could help to stratify bvFTD patients for adapted treatments.