ALS-FTD Patients Research Articles

Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.

Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis. A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed. The average age of onset for the 1672 ALS patients was 52.6 ± 11.2years (range 17-85years), with a median disease duration of 14months at the time of visit (interquartile range 9-24months, range 2-204months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset. This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.

Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.

Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) is a nuclear-encoded mitochondrial protein which is primarily mutated in the spectrum of familial and sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD). Endogenous CHCHD10 levels decline in the brains of ALS-FTD patients, and the CHCHD10S59L mutation in Drosophila induces dominant toxicity together with PTEN-induced kinase 1 (PINK1), a protein critical for the induction of mitophagy. However, whether and how CHCHD10 variants regulate mitophagy flux in the mammalian brain is unknown. Here, we demonstrate through in vivo and in vitro models, as well as human FTD brain tissue, that ALS/FTD-linked CHCHD10 mutations (R15L and S59L) impair mitophagy flux and mitochondrial Parkin recruitment, whereas wild-type CHCHD10 (CHCHD10WT) normally enhances these measures. Specifically, we show that CHCHD10R15L and CHCHD10S59L mutations reduce PINK1 levels by increasing PARL activity, whereas CHCHD10WT produces the opposite results through its stronger interaction with PARL, suppressing its activity. Importantly, we also demonstrate that FTD brains with TAR DNA-binding protein-43 (TDP-43) pathology demonstrate disruption of the PARL-PINK1 pathway and that experimentally impairing mitophagy promotes TDP-43 aggregation. Thus, we provide herein new insights into the regulation of mitophagy and TDP-43 aggregation in the mammalian brain through the CHCHD10-PARL-PINK1 pathway.

The involvement of language-associated networks, tracts, and cortical regions in frontotemporal dementia and amyotrophic lateral sclerosis: Structural and functional alterations.

Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality-of-life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS-FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied. A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language-associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS-FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72-negative ALS-FTD, C9orf72-positive ALS-FTD, behavioral-variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed. Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language-associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS-FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72-negative ALS-FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72-positive ALS-FTD patients do not. Language-associated tracts and networks are not only affected in language-variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype.

Hypometabolic and hypermetabolic brain regions in patients with ALS-FTD show distinct patterns of grey and white matter degeneration: A pilot multimodal neuroimaging study

BackgroundUp to 50% of amyotrophic lateral sclerosis (ALS) patients develop some degree of cognitive dysfunction and a small proportion of these develop frontotemporal dementia (FTD). Non-invasive techniques of magnetic resonance imaging (MRI) and [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) have demonstrated structural and metabolic abnormalities, respectively, in the brains of such patients with ALS-FTD. Although initial 18F-FDG PET studies in ALS patients showed only hypometabolism of motor and extramotor brain regions, subsequent studies have demonstrated hypermetabolic changes as well. Such contrasting findings prompted us to hypothesize that hypo- and hypermetabolic brain regions in ALS-FTD patients are associated with divergent degeneration of structural grey matter (GM) and white matter (WM). MethodsCerebral glucose metabolic rate (CMRglc), cortical thickness (CT), fractal dimension (FD), and graph theory WM network analyses were performed on clinical MRI and 18F-FDG PET images from 8 ALS-FTD patients and 14 neurologic controls to explore the relationship between GM-WM degeneration and hypo- and hypermetabolic brain regions. ResultsCMRglc revealed significant hypometabolism in frontal and precentral gyrus brain regions, with hypermetabolism in temporal, occipital and cerebellar regions. Cortical thinning was noted in both hypo- and hypermetabolic brain areas. Unlike CT, FD did not reveal widespread GM degeneration in hypo- and hypermetabolic brain regions of ALS-FTD patients. Graph theory analysis showed severe WM degeneration in hypometabolic but not hypermetabolic areas, especially in the right hemisphere. ConclusionOur multimodal MRI-PET study provides insights into potentially differential pathophysiological mechanisms between hypo- and hypermetabolic brain regions of ALS-FTD patients.

Graph theory network analysis provides brain MRI evidence of a partial continuum of neurodegeneration in patients with UMN-predominant ALS and ALS-FTD

ObjectiveOur routine clinical neuroimaging showed hyperintense signal along the corticospinal tract only in some but not all patients with upper motor neuron (UMN)-predominant ALS. ALS patients with CST hyperintensity (ALS-CST+) and those without CST hyperintensity (ALS-CST−) present with nearly identical clinical UMN-predominant symptoms. Some previous studies have suggested that ALS patients with frontotemporal dementia (FTD) are on a continuum with ALS patients without FTD, while others have not.We aimed to determine whether: (a) ALS-CST+, ALS-CST–, and ALS-FTD patients show differential sites of predominant neurodegeneration occurring primarily cortically in the perikaryon or subcortically in the white matter (WM), or (b) UMN-predominant ALS is on a continuum with ALS-FTD. MethodsExploratory whole brain grey matter (GM) voxel-based morphometry and WM network analysis using graph theory approach were performed. In this exploratory study, MRI data from 58 ALS patients (ALS-FTD, n = 15; ALS-CST+, n = 19; ALS-CST−, n = 24) and 14 neurological controls were obtained. ResultsSignificant differences in degree measures (evaluating WM networks) were observed between ALS patients and controls in frontal, motor, extra-motor, subcortical, and cerebellar regions. GM atrophy was observed only in the ALS-FTD subgroup and not in the other ALS subgroups. ConclusionAlthough WM network disruption by the ALS disease process showed different patterns between ALS-CST+, ALS-CST−, and ALS-FTD subgroups, there were some overlaps, particularly in prefrontal regions and between ALS-CST+ and ALS-FTD patients. Our preliminary findings suggest a partial continuum of, at least, WM degeneration between these subgroups with predominance of cortical pathology (“neuronopathy”) in ALS-FTD patients and subcortical WM pathology (“axonopathy”) in ALS-CST+ and ALS-CST− patients.

Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons.

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

Factors That Influence Non-Motor Impairment Across the ALS-FTD Spectrum: Impact of Phenotype, Sex, Age, Onset and Disease Stage.

Objective: This study aimed to establish (1) the pattern and severity of neuropsychiatric symptoms and other non-motor symptoms of sleep and mood, across ALS phenotypes in comparison to bvFTD and (2) the contribution of non-modifiable factors including age, sex and disease state to the severity of symptoms experienced by ALS patients.Methods: Consecutive participants were recruited to the study and underwent a detailed clinical, cognitive, behavioral and neuroimaging assessment. Neuropsychiatric and other non-motor symptoms were determined using the Cambridge Behavioral Inventory, the CBI-R. The scores were converted to define impairment in terms of mild, moderate and severe symptoms for each subscale. Rate, severity and contribution of King's staging and modifiable factors were also determined and a regression model identified predictors of symptom severity.Results: In total, 250 participants (115 ALS, 98 bvFTD, and 37 ALS-FTD patients) were recruited. A similar pattern of neuropsychiatric symptom severity was identified (apathy, disinhibition and stereotypic behavior) for all behavioral phenotypes of ALS compared to bvFTD (all p > 0.05). Neuropsychiatric symptoms were also present in cases defined as ALSpure and the cognitive phenotype of ALS (ALSci) although they occurred less frequently and were at the milder end of the spectrum. Disordered sleep and disrupted mood were common across all phenotypes (all p < 0.05). The severity of sleep dysfunction was influenced by both sex and age (all p < 0.05). Neuropsychiatric symptoms, sleep and mood disorders were common early in the disease process and deteriorated in line with progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; all p < 0.05). Diagnostic phenotype, disease duration and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments.Conclusion: The current findings reveal strikingly similar patterns of changes across the subgroups of ALS and bvFTD, supporting the concept of the ALS-FTD spectrum. The findings further highlight the impact of non-motor and neuropsychiatric symptoms in patients with ALS, that are often as severe as that seen in ALS-FTD and bvFTD. This study advances understanding across the ALS-FTD spectrum that may accelerate the early identification of patient needs, to ensure prompt recognition of symptoms and thereby to improve clinical awareness, patient care and management.

Cognitive Profiles of Amyotrophic Lateral Sclerosis Differ in Resting-State Functional Connectivity: An fMRI Study.

BackgroundHalf of all amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) patients are classified as cognitively impaired, of which 10% have frontotemporal dementia (FTD), and an additional 40% suffer from a frontotemporal syndrome not severe enough to be described as dementia (cognitively impaired/ALSci). As changes in cerebral function measured by resting-state magnet resonance imaging (rs-fMRI) are known in ALS, we investigated whether group differences in resting-state functional connectivity (RSFC) networks could be observed between ALS patients with different cognitive profiles against healthy controls (HC). Furthermore, we correlated cognition and motor functioning with network connectivity.MethodsHealthy controls, 69, and 97 ALS patients underwent functional MRI scanning and cognitive assessment. The ALS patients were categorized as non-impaired (ALSni; n = 68), cognitively impaired (ALSci; n = 21), and ALS-FTD (n = 8). Group differences in connectivity of the default mode network (DMN), motor network (MN), and ventral attention network (VAN) were investigated using a full-factorial model; correlations between global cognitive performance, shifting, and motor symptom severity were established using Pearson’s correlation.ResultsAt a liberal alpha level of uncorrected p < 0.005 and a cluster size exceeding 20 voxels, we found widespread decreases in functional connectivity in all three networks when comparing ALS patients to HC. Similar patterns of hypoconnectivity in the bilateral motor cortices and frontotemporal emerged when comparing the ALSci and ALS-FTD patients to those not cognitively impaired. Hyperconnectivity in the DMN temporal gyrus correlated with worse global cognition; moreover, hyperconnectivity in the VAN thalamus, insula, and putamen correlated with worse shifting ability. Better-preserved motor function correlated with higher MN connectivity. Only the motor-related effects prevailed at a more conservative significance level of pFDR< 0.001.ConclusionResting-state functional connectivity differs between cognitive profiles of ALS and is directly associated with clinical presentation, specifically with motor function, and cognitive shifting.

Problem-focused coping underlying lower caregiver burden in ALS-FTD: implications for caregiver intervention

Objective: Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder which includes cognitive and behavioral symptoms akin to frontotemporal dementia (FTD). Despite the necessity of caregiver intervention to assist with the management of cognitive and behavioral symptoms, there has been a lack of research on the topic. A focus on caregiver coping may offer a promising foundation to guide the development of interventions as part of ALS care. Accordingly, the aim of the present study was to examine the relationships between caregiver coping, psychological morbidity and burden of care in the context of ALS cognitive and behavioral symptoms. Methods: Fifty-five patient-caregiver dyads were recruited from specialized ALS and FTD clinics. Specific coping strategies were examined using the COPE Inventory/Brief COPE and psychological morbidity and burden were assessed using the Depression, Anxiety, and Stress Scale–21 and Zarit Burden Interview. The relationship between coping, psychological morbidity and burden of care were analyzed using univariate and multivariate methods. Results: High-burden caregivers were more likely to be caring for patients with a diagnosis of ALS-FTD (p =.0001). Caregivers used problem-focused strategies (particularly planning) more frequently (M = 71.4, SD = 15.3) compared to emotion-focused (M = 60.8, SD = 12.3) and dysfunctional coping strategies (M = 42.2, SD = 8.6). A diagnosis of ALS-FTD (p=.0001) and problem-focused strategies (p=.024) emerged as significant predictors of caregiver burden. Caregiver anxiety, depression and stress were not predictive of caregiver burden (p=.151). Conclusions: Timely provision of caregiver support optimizing problem-focused coping strategies as part of multidisciplinary ALS care, particularly for caregivers of ALS-FTD patients may mitigate caregiver burden.

The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) in frontotemporal dementia

Objectives To examine the usefulness of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS) as a cognitive screening tool for the detection of behavioral variant frontotemporal dementia (bvFTD). A secondary aim was to determine whether people with FTD combined with ALS (ALS-FTD) exhibit a similar ECAS profile to that of people with bvFTD alone. Methods: Patients with ALS-FTD and bvFTD and healthy controls were recruited. Participants were administered the ECAS, which comprises tests of language, verbal fluency, executive functions, memory, and visual-spatial functions. They also carried out analogous, full-length cognitive tests that examine naming, spelling, sentence completion, and social cognition skills. Results: The study cohort comprised 20 ALS-FTD patients, 23 with bvFTD, and 30 controls. Highly significant group differences were elicited for all cognitive domains, reflecting poorer performance in patients compared to controls. No significant differences in overall test scores were found between ALS-FTD and bvFTD patients, although ALS-FTD patients showed a higher frequency of impairment on verbal fluency. Correlative analyses revealed inter-relationships in patients (but not controls) between scores in different domains, most marked in bvFTD. There were strong correlations between performance on ECAS subtests and analogous cognitive tasks. Conclusion: The ECAS is a sensitive and valuable tool for the assessment of FTD. Executive, language and behavioral breakdown may, however, compromise performance in other cognitive domains, reducing the specificity of the ‘frontotemporal’ cognitive profile. Subtle differences observed between ALS-FTD and bvFTD raise questions regarding the precise relationship between bvFTD with and without ALS.

Theme 11 Cognitive and psychological assessment and support

Background: Within the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum there is considerable heterogeneity in clinical presentation and survival.Objectives: The current study aimed to examine how initial symptoms (motor compared to cognitive) may affect survival, with specific focus on structural cognitive and behavioural differences between ALS-FTD and bvFTD cohorts.Methods: Cognitive and behavioural profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD patients). The initial presentation of ALS-FTD was categorized into either motor or cognitive, based on symptoms combined with carer reports. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale.Results: In the ALS-FTD group, 69% were categorized as having an initial cognitive presentation and 31% a motor presentation. Those patients with motor presentation of ALS-FTD experienced a significantly shorter survival of 33 months, compared to 63 months (p<0.007) in those with a cognitive presentation of ALS-FTD. On cognitive testing there were no differences between motor versus cognitive onset ALS-FTD. When compared to bvFTD, ALS-FTD, particularly the cognitive presentation, was characterized by reduced language function (p<0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both cognitive and motor presentation ALS-FTD had poorer emotion processing (p = 0.01) compared to bvFTD. On structural imaging analyses both motor and cognitive onset ALS-FTD patients had greater motor cortex and dorsal lateral prefrontal cortex atrophy compared to bvFTD patients. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival.Discussion and conclusions: In ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar overall cognitive impairment, suggesting that disease progression in ALS-FTD may be critically linked to physiological and motor changes. Survival is also associated with motor cortex atrophy which is increased in ALS-FTD.These results provide further suggestions in relation to the categorization of clinical trial patients into fast and slow progressors.

Effect of phenotypic presentation on survival in ALS-FTD

Within the Amyotrophic Lateral Sclerosis (ALS)–Frontotemporal dementia (FTD) spectrum there is much heterogeneity in survival. The current study aimed to examine how initial symptoms: motor versus cognitive affected survival, the cognitive/ behavioural profile between ALS- FTD and bvFTD and how brain atrophy patterns differ. The cognitive and behavioural profile was examined 55 ALS-FTD and 40 bvFTD patients. The initial presentation was categorized into motor versus cognitive based on carer report. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale. In the ALS-FTD group, 39 were categorized as having an initial cognitive presentation, 16 had a motor presentation, which was associated with a much shorter survival of 33 months versus 63 months (p < .007). On cognitive testing there no differences found between motor versus cognitive ALS-FTD. When comparing ALS- FTD to bvFTD, ALS-FTD was characterized by reduced language (p < .001), verbal fluency (p = .001), naming (p = .007). and emotion processing (p = .01). ALS-FTD patients had more motor cortex atrophy than bvFTD patients, and those with a cognitive of ALS-FTD presentation had increased orbitofrontal atrophy compared to those with a motor presentation. Within the diagnosis of ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar cognitive changes, suggesting that disease progression in ALS-FTD may be related to non- cognitive factors including metabolic and physiological changes. These results provide possible markers to categorise patients into fast versus slow progressors, aiding in clinical trial development.

Brain Structural and Perfusion Signature of Amyotrophic Lateral Sclerosis With Varying Levels of Cognitive Deficit.

To characterize the patterns of brain atrophy and perfusion as measured by arterial spin labeling (ASL)-MRI, in amyotrophic lateral sclerosis (ALS) patients with varying levels of cognitive deficit, including ALS with frontotemporal dementia (FTD). A total of 55 ALS patients and 20 healthy controls (HCs) were included, and all participants underwent neuropsychological assessments and MRI scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, n = 27), ALS with cognitive impairment (ALS-Ci, n = 17), and ALS-FTD (n = 11). Voxel-based comparisons of gray matter (GM) changes and cerebral blood flow (CBF) were conducted among the subgroups. The whole-brain comparisons of GM changes and CBF among ALS-Ci, ALS-Cn, and HCs were not significantly different. However, the ALS-FTD patients demonstrated a similar pattern of GM loss and hypoperfusion with more significant alterations in the left frontal and temporal lobe compared with the HCs, ALS-Cn, and ALS-Ci patients. Decreased CBF was found in many of the same brain areas wherein structural alterations occurred, although isolated GM loss and hypoperfusion were also observed. In addition, for both GM and CBF abnormalities, a similar pattern of changes was found in the comparisons of ALS-FTD vs. ALS-Ci, ALS-FTD vs. ALS-Cn, and ALS-FTD vs. HCs, with the differences being most significant between ALS-FTD and HCs. The cognitive status of ALS patients is associated with different patterns of GM changes and cerebral perfusion. ASL-MRI might be a useful tool with which to investigate the pathological burden of ALS and to disclose the early signature of possible cognitive impairment.

S56. Comparing brain structural and perfusion MRI changes across ALS-FTD continuum

Introduction Clinical, genetic, and pathological findings suggest a close relationship between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study is aim to compare brain structural and perfusion MRI changes across the spectrum between ALS and ALS-FTD. Methods An age- and sex matched sample of 20 healthy controls (HC), 27 ALS patients without dementia and 11 ALS-FTD patients were included. All subjects underwent a brain MRI, including structural images, arterial spin labeling and diffusion tensor imaging. Whole-brain voxel-based analyses were conducted to study the patterns of cortical atrophy, cerebral blood flow (CBF) and microstructural white matter changes within the three groups. Results The comparison of grey matter, CBF, fractional anisotropy (FA) and mean diffusivity (MD) between ALS and HC revealed no differences. ALS-FTD patients showed widespread cortical atrophy, decreased CBF, reduced FA and increased MD compared to HC and ALS. The hypoperfusion region of ALS-FTD patients agreed with those of significant grey matter loss, including bilateral frontal lobe, temporal lobe, and precentral gyrus. White matter changes mainly located in bilateral corticospinal tract and corpus callosum. It is noteworthy that, in term of all four kinds of data, ALS-FTD with HC and ALS-FTD with ALS, revealed a similar pattern of significant alterations, and changes were more widespread in the former comparison. Conclusion Perfusion changes corresponded well with structural changes in motor and extramotor areas in patients with ALS-FTD. Both structural and perfusion MRI findings lend support to the concept of ALS-FTD disease continuum.

F45. Genetic analysis of TIA1 gene in Chinese patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive lethal neurodegenerative disorder characterized by affecting the upper and lower motor neurons of the brain, brainstem and spinal cord. Approximately 15% of ALS patients also suffering from frontotemporal dementia (FTD). Very recently, six missense mutations affecting the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1) were identified in 1039 non-Hispanic white ALS and ALS-FTD patients. Mutations in the TIA1 gene were suggest to account for ∼2% FALS and <0.5% sporadic ALS (SALS). Those data suggest that TIA1 mutations might be a rare cause of ALS ± FTD. Studies analyzing Asian ALS patient cohorts have not been reported. Previous studies have shown that mutations in the ALS causal genes varied among ethnic populations, such as the G4C2 repeat expansion in the C9orf72 gene is rare in Asian people. To investigate the frequency and spectrum of TIA1 mutations further, we firstly performed mutational screening of TIA1 in a large cohort of ALS/ALS-FTD patients of Chinese origin. The study included 576 Chinese ALS/ALS-FTD patients (FALS = 28; SALS = 535; ALS-FTD = 13) and 500 neurologically normal control subjects. All participants were of Han descent and from mainland China. ALS/ALS-FTD patients were registered at ALS clinic of Neurology Department, Peking Union Medical College Hospital from January 2016 to August 2017. TIA1 (NM_022173) exons 11, 12 and 13 encoding the prion-like LCD domain of TIA1 were sequenced in all 576 cases. Resulting chromatograms were aligned to reference human genome ( UCSC hg19) using CodonCode Aligner tool. All patients harboring mutations of the TIA1 were examined other common ALS causal genes including SOD1, ANXA11, FUS, OPTN, UBQLN2, TARDB and C9orf72. Besides, the identified mutations were subsequently screened in 500 controls. TIA1 sequence analysis revealed a novel heterozygous missense mutation, c.973A>G (p.N325D), in a sporadic ALS case. The variant was not present in our 500 neurologically normal controls as well as several public data bases includingExAC, gnomAD, 1000 Genomes Project and SNP150. The p.N325D substitution affects an highly conserved amino acid in the prion-like LCD domain. Moreover, Four distinct programs – PolyPhen2, Mutation Taster, SIFT and CADD – all predicted p.N325D as a damaging mutation. In conclusion, we have identified a novel mutation in the TIA1 gene in SALS patients of Chinese origin. Our findings provide an overview of the TIA1 mutation in Chinese ALS patients. We propose that the TIA1 mutation is not a frequent mutation in Chinese ALS patients.

Connectivity-based characterisation of subcortical grey matter pathology in frontotemporal dementia and ALS: a multimodal neuroimaging study.

Frontotemporal dementia (FTD) phenotypes have distinctive and well-established cortical signatures, but their subcortical grey matter profiles are poorly characterised. The comprehensive characterisation of striatal and thalamic pathology along the ALS-FTD spectrum is particularly timely, as dysfunction of frontostriatal and cortico-thalamic networks contribute to phenotype-defining cognitive, behavioral, and motor deficits. Ten patients with behavioral-variant FTD, 11 patients with non-fluent-variant primary progressive aphasia, 5 patients with semantic-variant primary progressive aphasia, 14 ALS-FTD patients with C9orf72 hexanucleotide expansions, 12 ALS-FTD patients without hexanucleotide repeats, 36 ALS patients without cognitive impairment and 50 healthy controls were included in a prospective neuroimaging study. Striatal, thalamic, hippocampal and amygdala pathology was evaluated using volume measurements, density analyses and connectivity-based segmentation. Significant volume reductions were identified in the thalamus and putamen of non-fluent-variant PPA patients. Marked nucleus accumbens and hippocampal atrophy was observed in the behavioral-variant FTD cohort. Semantic-variant PPA patients only exhibited volumetric changes in the left hippocampus. C9-positive ALS-FTD patients showed preferential density reductions in thalamic sub-regions connected to motor and sensory cortical areas. C9-negative ALS-FTD patients exhibited striatal pathology in sub-regions projecting to rostral-motor and executive cortical areas. The bulk of striatal and thalamic pathology in non-fluent-variant PPA patients was identified in foci projecting to motor areas. Subcortical density alterations in svPPA patients were limited to basal ganglia regions with parietal projections. Striatal and thalamic changes in FTD exhibit selective, network-defined vulnerability patterns mirroring cortical pathology. Multi-modal cortico-basal imaging analyses confirm that the subcortical grey matter profiles of FTD phenotypes are just as distinct as their cortical signatures. Our findings support emerging concepts of network-wise degeneration, preferential circuit vulnerability and disease propagation along connectivity patterns.

Mutation analysis of the TIA1 gene in Chinese patients with amyotrophic lateral sclerosis and frontotemporal dementia

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. Frontotemporal dementia (FTD) is a group of dementia syndromes characterized by the progressive deterioration of behaviors, executive dysfunction, and verbal impairment. Increasing evidence indicates that these 2 diseases share a common genetic etiology and pathophysiological mechanism. Recently, rare mutations in the low-complexity domain of the RNA-binding protein T-cell–restricted intracellular antigen-1 (TIA1) gene were identified in Caucasian ALS and ALS-FTD patients. However, no comprehensive mutation analysis of the TIA1 gene has been performed in Chinese patients with ALS and FTD. In this study, we screened the low-complexity domain of TIA1 in a cohort of 241 ALS and 51 FTD patients in mainland China. As a result, 2 novel missense mutations (p.P352L and p.I300T) were identified in 2 sporadic patients with ALS, while no mutation was found in FTD cases. To the best of our knowledge, this report presented the first mutation analysis of the TIA1 gene in patients with ALS and FTD in Chinese population. Our findings broaden the known mutational spectrum in patients with ALS and further confirm TIA1 as a novel causative gene of ALS.

NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients

We evaluated the genetic impact of the amyotrophic lateral sclerosis (ALS) risk gene never in mitosis gene a–related kinase 1 (NEK1) in a Belgian cohort of 278 patients with ALS (n = 245) or ALS with frontotemporal dementia (ALS-FTD, n = 33) and 609 control individuals. We identified 2 ALS patients carrying a loss-of-function (LOF) mutation, p.Leu854Tyrfs*2 and p.Tyr871Valfs*17, that was absent in the control group. A third LOF variant p.Ser1036* was present in 2 sibs with familial ALS but also in an unrelated control person. Missense variants were common in both patients (3.6%) and controls (3.0%). The missense variant, p.Arg261His, which was previously associated with ALS risk, was detected with a minor allele frequency of 0.90% in patients compared to 0.33% in controls. Taken together, NEK1 LOF variants accounted for 1.1% of patients, although interpretation of pathogenicity and penetrance is complicated by the observation of occasional LOF variants in unaffected individuals (0.16%). Furthermore, enrichment of additional ALS gene mutations was observed in NEK1 carriers, suggestive of a “second hit” model were NEK1 variants may modify disease presentation of driving mutations.

Behavioral and affective features of amyotrophic lateral sclerosis patients

Evaluating the cognitive and behavioral features in amyotrophic lateral sclerosis (ALS) patients is important for therapy and care. Fifty-seven ALS, 5 ALS with the behavioral variant of frontotemporal dementia (FTD) (ALS-FTD), 12 FTD patients, and 35 control subjects were evaluated by 10 different tests for cognitive and behavioral (mini-mental state examination (MMSE), Hasegawa dementia rating scale – revised (HDS-R), frontal assessment battery (FAB), Montreal cognitive assessment (MoCA), ALS-frontotemporal dementia-Questionnaire (ALS-FTD-Q), and anosognosia scale), affective (depression, apathy, and behavioral and psychological symptoms of dementia (BPSD)), and activities of daily living (ADL) assessments. The motor functions of ALS patients were evaluated by ALS functional rating scale – revised (ALSFRS-R) and modified Norris scale.ALS-FTD-Q scores showed intermediate behavioral disturbances of ALS patients between ALS-FTD and FTD patients and control subjects, but FAB, MoCA, and anosognosia scales did not. Both FAB and MoCA scores were significantly correlated with MMSE and HDS-R in ALS patients, but ALS-FTD-Q was not. ALS-FTD-Q score was significantly correlated with ALSFRS-R, apathy, BPSD, and ADL scores in ALS patients.Thus, in ALS patients, both FAB and MoCA tests were useful to assess frontal cognitive impairments, while ALS-FTD-Q was useful to detect mild behavioral and affective disturbances.