Frontotemporal Dementia Cases Research Articles

TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis.

See Fratta and Isaacs (doi:10.1093/brain/awy091) for a scientific commentary on this article.The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.

Tau Filaments and the Development of Positron Emission Tomography Tracers.

A pathological pathway leading from soluble, monomeric to insoluble, filamentous Tau, is believed to underlie human Tauopathies. Cases of frontotemporal dementia are caused by dominantly inherited mutations in MAPT, the Tau gene. They show that dysfunction of Tau protein is sufficient to cause neurodegeneration and dementia. Extrapolation to the more common sporadic Tauopathies leads one to conclude that the pathological pathway is central to the development of all cases of disease, even if there are multiple reasons for Tau assembly. These findings are conceptually similar to those reported for beta-amyloid, alpha-synuclein and prion protein. Here, we provide an overview of Tau filaments and their positron emission tomography ligands.

The frequency of the C9orf72 expansion in a Brazilian population

G4C2 hexanucleotide repeat expansions in the C9orf72 gene seem to be the cause of numerous cases of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). In this study, we investigated the presence of the G4C2 repeat expansion in 463 Brazilian probands, of whom 404 had ALS/motor neuron disease and 67 FTD, and in 63 healthy controls in the southeastern region of Brazil. The highest frequencies of the C9orf72 mutation were in the ALS-FTD group (50% of familial and 17.6% of sporadic cases), although it was also present in 5% of pure ALS/motor neuron disease patients (11.8% of familial and 3.6% of sporadic cases) and in 7.1% of pure familial FTD. Among G4C2 repeat mutation carriers, 68.8% of the subjects who developed dementia symptoms were females. This frequency was significantly higher than the percentage reached by men with C9orf72 expansion who had this phenotype (p = 0.047). No abnormal repeat expansion was found in control groups. Inclusion of the C9orf72 genetic test in the molecular panels for Brazilian populations with these neurodegenerative diseases should be strongly considered.

Single-subject classification of presymptomatic frontotemporal dementia mutation carriers using multimodal MRI.

BackgroundClassification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification.MethodsAnatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC).ResultsThe bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005).ConclusionsFTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.

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.

A proteomic network approach across the ALS‐FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry‐based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD. Our systems‐level analysis of the brain proteome integrated both differential expression and co‐expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co‐expression network analysis revealed 15 modules of co‐expressed proteins, eight of which were significantly different across the ALS‐FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell‐type specificity that showed correlation with TDP‐43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP‐43 protein–protein interactions, revealing one module enriched with RNA‐binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems‐level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS‐FTD disease spectrum in human brain.

18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

Disulfide cross-linked multimers of TDP-43 and spinal motoneuron\xa0loss in a TDP-43A315T ALS/FTD mouse model

Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.

LSD1 protects against hippocampal and cortical neurodegeneration

To investigate the mechanisms that maintain differentiated cells, here we inducibly delete the histone demethylase LSD1/KDM1A in adult mice. Loss of LSD1 leads to paralysis, along with widespread hippocampus and cortex neurodegeneration, and learning and memory defects. We focus on the hippocampus neuronal cell death, as well as the potential link between LSD1 and human neurodegenerative disease and find that loss of LSD1 induces transcription changes in common neurodegeneration pathways, along with the re-activation of stem cell genes, in the degenerating hippocampus. These data implicate LSD1 in the prevention of neurodegeneration via the inhibition of inappropriate transcription. Surprisingly, we also find that transcriptional changes in the hippocampus are similar to Alzheimer’s disease (AD) and frontotemporal dementia (FTD) cases, and LSD1 is specifically mislocalized to pathological protein aggregates in these cases. These data raise the possibility that pathological aggregation could compromise the function of LSD1 in AD and FTD.

Atypical parkinsonian syndromes: a general neurologist's perspective.

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non-fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson-plus syndromes in the past, they are now classified as FTD-related disorders, reflecting that they pathologically differ from α-synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.

Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS.

ABSTRACTINTRODUCTION:TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features.METHODS:We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aβ, AT8, anti-α-synuclein and anti-phospho-TDP-43.RESULTS:Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aβ and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II).DISCUSSION:The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.

Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

HEAD-TO-HEAD COMPARISON OF [18F] AV-1451 AND [18F] THK5351 FOR TAU IMAGING IN ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEMENTIA

Tau accumulation is known to be core pathologic changes in various neurodegenerative diseases including Alzheimer disease (AD) and frontotemporal dementia (FTD). Recently, [18F]AV-1451 (AV-1451) and [18F]THK5351 (THK5351) have been developed to detect tau deposition in vivo. We determined whether amount and distribution of THK5351 and AV-1451 cortical uptakes differed between AD and FTD cases. We also examined whether THK5351 and AV-1451 tracers exhibited different amounts and distribution of off-target bindings. Eight participants underwent magnetic resonance image, Florbetaben (FBB) and tau PET a using two tracers, THK5351 and AV-1451. Case 1 and 2 were clinically diagnosed as AD such as early onset AD and logopenic variant primary progressive aphasia (lvPPA). Case 3, 4, 5 and 6 were clinically diagnosed as FTD such as semantic variant primary progressive aphasia (svPPA), non-fluent/agrammatic variant PPA (nfvPPA) and behavioral variant FTD (bvFTD). Case 7 and 8 were normal control (NC). AV-1451 cortical uptakes were more prominent than THK5351 in Alzheimer disease, while, THK5351 cortical uptakes were more prominent in frontotemporal dementia, although THK5351 and AV-1451 tracers were highly correlated each other, (AD: r=0.63, p=0.009; FTD r=0.69, p<0.001). Off target bindings of THK5351 uptakes were more prominent than AV-1451 uptakes with cortical uptakes of AV-1451 were more striking in AD, while cortical uptakes of THK5351 were more prominent in FTD. Both THK5351 and AV-1451 tracers, regardless of type of dementia, showed off-target bindings in the midbrain, basal ganglia and thalamus, but THK5351 seemed more noticeable with high correlation (r= 0.61 to 0.98). AD cases showed higher cortical uptakes of AV-1451 than those of THK5351 while FTD cases showed higher cortical uptakes of THK5351 than those of AV-1451. Off target regions such as the midbrain, thalamus, and basal ganglia showed more prominent uptakes of THK5351than those of AV-1451 with wider variation of uptakes of THK5351. Our preliminary results suggested that AV-1451 seemed to be more sensitive and specific to Alzheimer disease type tau and less likely to present off-target binding.

GENETIC MUTATIONS IN EARLY-ONSET DEMENTIA: REPORT FROM THE MEMORY CLINIC FROM SERBIA

Monogenetic forms of early onset Alzheimer disease (EAOD) are very rare approximately 2.5 % of all dementia cases with three well known mutations in APP gene, Presenilin 1(PSEN1), and Presenilin 2 (PSEN2). Fronto-temporal dementia (FTD) is the second most common cause of early onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). The aim of this study was to assess the genetic mutations in a cohort of 322 Serbian patients with EOD and to report phenotypic features of identified carriers. PSEN1 was recorded in 2.42%, APP in 1.2 %, and PSEN2 in 1.21%. A family history of dementia is found in 30% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). There was no MAPT mutation in our cohort. Four patients have been diagnosed with mutation in progranulin gene (GRN). Three patients were classified in the FTD spectrum and one with possible Alzheimer disease. We identified 4 patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer's dementia. Mutations in valosin-containing protein (VCP) was found in 3 patients with isolated bvFTD, and no inclusion body myopathy or Paget disease. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation.

BEHAVIORAL VARIANT FTD CAUSED BY UBQLN2 P525S MUTATION, WITHOUT EVIDENCE OF MOTOR NEURON DISEASE

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) represent extremes of a spectrum with significant overlap. Numerous gene mutations are known to cause these diseases in isolation or combination. Ubiquilin 2 (UBQLN2) mutations have recently been described and have been shown to cause either pure ALS or combination ALS/FTD. Presentation of a well characterized case of FTD caused by a UBQLN2 mutation without clinical or familial evidence of ALS. A 69-year-old right-handed man with a 2-year history of personality changes, unwelcomed familiarity, and increased gregariousness and embellishments with growing grandeur, at times delusional. There was “lack of filtering” and more childishness, playing with grandchildren “at their level”. Appetitive changes included a diet of Frappuccino's, jelly beans, and devil dogs. Lost $20 000 in a scam. Unable to maintain gainful employment as an information technology consultant. Past medical and psychiatric history: non-contributory. Family history: father passed from liver cancer at 53, mother from dementia at 83, sister with hypochotdriasis, and “bipolar” brother who passed in his 60s from pancreatic cancer. Examination: mild diffuse extrapyramidal syndrome without evidence of pyramidal or lower motor neuron disease. MoCA was 20/30, moderate deficits in attention/concentration with impact on memory, which was fully recovered with cues. Neuropsychological assessment revealed tangentiallity, impulsivity, and impersistence. There were deficits in aspects of learning, attention, and executive functions, with intact contextual memory, language, and visual spatial functions. MRI and FDG-PET scans showed focal frontal and anterior temporal atrophy and hypometabolism. Whole exome sequencing failed to reveal the better known genetic causes of FTD (MAPT, GRN, and C9orf72), but did show a known pathologic P525S mutation of the UBQLN2 gene. In addition, known risk or modifyier genes variants were also absent. Remains without clinical evidence of motor neuron disease 5 years following initial symptoms. To our knowledge, this is the first documented case of an isolated presentation of behavioral variant FTD without ALS, caused by a mutation in UBQLN2. Although still rare, this case further expands the spectrum of diseases caused by this mutation.

Von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion.

The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls. Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9). von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

Age-related penetrance of the C9orf72 repeat expansion

A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.

Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive-compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia.

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.

Hodges’ Frontotemporal Dementia, Second Edition

Hodges’ Frontotemporal Dementia, Second Edition