The term frontotemporal lobar degeneration (FTLD) refers to a group of progressive brain diseases, which preferentially involve the frontal and temporal lobes. Depending on the primary site of atrophy, the clinical manifestation is dominated by behavior alterations or impairment of language. The onset of symptoms usually occurs before the age of 60 years, and the mean survival from diagnosis varies between 3 and 10 years. The prevalence is estimated at 15 per 100,000 in the population aged between 45 and 65 years, which is similar to the prevalence of Alzheimer's disease in this age group. There are two major clinical subtypes, behavioral-variant frontotemporal dementia and primary progressive aphasia. The neuropathology underlying the clinical syndromes is also heterogeneous. A common feature is the accumulation of certain neuronal proteins. Of these, the microtubule-associated protein tau (MAPT), the transactive response DNA-binding protein, and the fused in sarcoma protein are most important. Approximately 10% to 30% of FTLD shows an autosomal dominant pattern of inheritance, with mutations in the genes for MAPT, progranulin (GRN), and in the chromosome 9 open reading frame 72 (C9orf72) accounting for more than 80% of familial cases. Although significant advances have been made in recent years regarding diagnostic criteria, clinical assessment instruments, neuropsychological tests, cerebrospinal fluid biomarkers, and brain imaging techniques, the clinical diagnosis remains a challenge. To date, there is no specific pharmacological treatment for FTLD. Some evidence has been provided for serotonin reuptake inhibitors to reduce behavioral disturbances. No large-scale or high-quality studies have been conducted to determine the efficacy of non-pharmacological treatment approaches in FTLD. In view of the limited treatment options, caregiver education and support is currently the most important component of the clinical management.

The ubiquilin-2 gene (UBQLN-2) is the only amyotrophic lateral sclerosis (ALS)-related gene mapping on the X chromosome. Mutations in the PXX domain of UBQLN-2 have been first described in ALS patients with a mutational frequency of 2.6% in familial ALS cases with no evidence of male-to-male transmission. Different populations have been further tested with mutations largely distributed in the gene and lower frequency of positive cases. To determine the genetic contribution of UBQLN-2 in frontotemporal lobar degeneration (FTLD) and FTLD-ALS, we screened a cohort of 136 French patients, identifying a missense variant (c.1006A>G; p.T336A) in 1 FTLD patient whose biological relevance to disease is questionable. We conclude that UBQLN-2 mutations related to ALS/FTLD are extremely rare in French FTLD and FTLD-ALS patients and should not be analyzed systematically.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.

Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration.

Stereotypies are common in frontotemporal lobar degeneration (FTLD) however the anatomical correlates of stereotypies are unknown. We therefore set out to compare patterns of grey matter volume loss in FTLD subjects with and without stereotypies. Subjects with a diagnosis of FTLD that met international consensus criteria were prospectively recruited and separated into those with and without stereotypies. MRI and cognitive measures were obtained and voxel-based morphometry was used to assess the patterns of grey matter volume loss in those with and without stereotypies, compared to a group of age- and gender-matched controls. Demographic and clinical features were similar between subjects with and without stereotypies. FTLD subjects with stereotypies had greater volume loss in the striatum compared to those without stereotypies. Those without stereotypies showed a more widespread and typical pattern of cortical frontotemporal loss. Stereotypies in FTLD are therefore associated with a greater proportion of striatal to cortical volume loss than those without stereotypies.

Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.

art may signal emotions independently of a biological or social carrier: it might therefore constitute a test case for defining brain mechanisms of generic emotion decoding and the impact of disease states on those mechanisms. This is potentially of particular relevance to diseases in the frontotemporal lobar degeneration (FTLD) spectrum. These diseases are often led by emotional impairment despite retained or enhanced artistic interest in at least some patients. However, the processing of emotion from art has not been studied systematically in FTLD. Here we addressed this issue using a novel emotional valence matching task on abstract paintings in patients representing major syndromes of FTLD (behavioural variant frontotemporal dementia, n=11; sematic variant primary progressive aphasia (svPPA), n=7; nonfluent variant primary progressive aphasia (nfvPPA), n=6) relative to healthy older individuals (n=39). Performance on art emotion valence matching was compared between groups taking account of perceptual matching performance and assessed in relation to facial emotion matching using customised control tasks. Neuroanatomical correlates of art emotion processing were assessed using voxel-based morphometry of patients' brain MR images. All patient groups had a deficit of art emotion processing relative to healthy controls; there were no significant interactions between syndromic group and emotion modality. Poorer art emotion valence matching performance was associated with reduced grey matter volume in right lateral occopitotemporal cortex in proximity to regions previously implicated in the processing of dynamic visual signals. Our findings suggest that abstract art may be a useful model system for investigating mechanisms of generic emotion decoding and aesthetic processing in neurodegenerative diseases.

The neurobiological basis of personality is poorly understood. Frontotemporal lobar degeneration (FTLD) frequently presents with complex behavioural changes, and therefore potentially provides a disease model in which to investigate brain substrates of personality.

Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P<0.001) main effect of diagnosis, and significant interactions for diagnosis and region, and diagnosis and hemisphere. Post-hoc comparisons with HC showed bilateral GM atrophy in the caudate, putamen and thalamus, in bvFTD; a left-confined GM reduction in the amygdala in SD; and bilateral GM atrophy in the caudate and thalamus, and left-sided GM reduction in the putamen and amygdala in PNFA. Correlation analyses suggested an association between GM volumes and language, psychomotor speed and behavioral disturbances. This study showed a widespread involvement of subcortical and deep cortical GM in early FTLD with patterns specific for clinical entity.

Impairments of face processing occur frequently in frontotemporal lobar degeneration (FTLD) but the neuroanatomical basis for these deficits has seldom been studied systematically. Here a prospective voxel based morphometry study is described addressing the neuroanatomy of two key dimensions of face processing--face identification and facial emotion recognition--in a single cohort of 32 patients with FTLD (19 with frontal variant and 13 with temporal variant FTLD). For the FTLD group as a whole, face identification was positively associated with grey matter in the right anterior fusiform gyrus while recognition of angry expressions was positively associated with grey matter in the bilateral insula cortex. FTLD provides a perspective on the neuroanatomy of face processing that is complementary to focal lesion and normal functional imaging work.

Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer's disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls.

Detergent-insoluble protein accumulation and aggregation in the brain is one of the pathological hallmarks of neurodegenerative diseases. Here, we describe the identification of septin 11 (SEPT11), an enriched component of detergent-resistant fractions in frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U), using large-scale unbiased proteomics approaches.

There is an urgent need for a better understanding of the pathophysiology of cognitive impairment in syndromes associated with frontotemporal lobar degeneration. Here, we used magnetic resonance spectroscopy to quantify metabolite deficits in sixty patients with a clinical syndrome associated with frontotemporal lobar degeneration (behavioral variant frontotemporal dementia n = 11, progressive supranuclear palsy n = 26, corticobasal syndrome n = 11, primary progressive aphasias n = 12), and 38 age- and sex-matched healthy controls. We measured nine metabolites in the right inferior frontal gyrus, superior temporal gyrus and right primary visual cortex. Metabolite concentrations were corrected for age, sex, and partial volume then compared with cognitive and behavioral measures using canonical correlation analysis. Metabolite concentrations varied significantly by brain region and diagnosis (region x metabolite x diagnosis interaction F(64) = 1.73, p < 0.001, corrected for age, sex, and atrophy within the voxel). N-acetyl aspartate and glutamate concentrations were reduced in the right prefrontal cortex in behavioral variant frontotemporal dementia and progressive supranuclear palsy, even after partial volume correction. The reduction of these metabolites was associated with executive dysfunction and behavioral impairment (canonical correlation analysis R = 0.85, p < 0.001).

Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD).

The brain bases of specific human behaviours in health and disease are not well established. In this voxel-based morphometric (VBM) study we demonstrate neuroanatomical signatures of different abnormalities of eating behaviour (pathological sweet tooth and increased food consumption, or hyperphagia) in individuals with frontotemporal lobar degeneration (FTLD). Sixteen male patients with FTLD were assessed using the Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia and classified according to the presence or absence of abnormal eating behaviours. Volumetric brain magnetic resonance imaging was performed in all patients and in a group of nine healthy age-matched male controls and grey matter changes were assessed using an optimised VBM protocol. Compared with healthy controls, the FTLD group had a typical pattern of extensive bilateral grey matter loss predominantly involving the frontal and temporal lobes. Within the FTLD group, grey matter changes associated with different abnormal behaviours were assessed independently using a covariate-only model. The development of pathological sweet tooth was associated with grey matter loss in a distributed brain network including bilateral posterolateral orbitofrontal cortex (Brodmann areas 12/47) and right anterior insula. Hyperphagia was associated with more focal grey matter loss in anterolateral OFC bilaterally (Brodmann area 11). In accord with emerging evidence in humans and other species, our findings implicate distinct components of a multi-component brain network in the control of specific aspects of eating behaviour.

The diagnosis of frontotemporal lobar degeneration (FTLD) is based on neuropsychological examination in addition to clinical symptoms and brain imaging. There is no simple, validated, cognitive tool available in screening for FTLD. The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NB) was originally devised to identify the early cognitive changes related to Alzheimer's disease (AD). Our aim was to investigate the utility of the CERAD-NB in FTLD.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aβ pathway, the plasmin system may affect cognition through synaptic activity.

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.