Forms Of Frontotemporal Lobar Degeneration Research Articles

Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

Pick’s disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer’s Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

Putative Cellular Identity of Dystrophic Neurites in FTLD‐TDP Type C

AbstractBackgroundApproximately 90% of individuals diagnosed with the clinical syndrome of semantic variant of primary progressive aphasia (PPA‐S) will present at autopsy with the TDP‐43 type C pathologic form of frontotemporal lobar degeneration (FTLD‐TDP‐C). FTLD‐TDP‐C is primarily characterized by the presence of TDP‐43‐immunoreactive long, thick dystrophic neurites (DNs), which tend to be found in superficial cortical layers, perpendicular to the cortical surface. The cellular identity of long DNs is not yet known. This study aims to understand the neuronal origin of DNs via colocalization of pathologic TDP with axonal and dendritic markers.MethodTwo right‐handed cases with FTLD‐TDP‐C as the sole pathologic diagnosis and a clinical diagnosis of PPA‐S were identified from the Northwestern University Alzheimer’s Disease Research Center (NU‐ADRC) brain bank. Participants were co‐enrolled in the NU PPA program, a longitudinal study of individuals with this dementia syndrome. Paraffin‐embedded sections of right inferior frontal gyrus (IFG) were fluorescently double‐stained immunohistochemically with an antibody to TDP‐43 phosphorylated at Ser 409 / 410 (pTDP) and antibodies to either phosphorylated neurofilament (pNFH) or non‐phosphorylated neurofilament (npNFH) to visualize axons or proximal dendrites, respectively. A digital image of each slide was obtained at 20X magnification using the Olympus VS200 Slide Scanner and analyzed using QuPath software (v.0.4.3).ResultIn both cases, staining revealed that a small amount (∼2%) of total DNs per section colocalize with npNFH (see Figure 1). Both long and short DNs, the latter of which are commonly apparent in other pathologic TDP subtypes (e.g., type A), demonstrated colocalization. By observation, half of colocalized DNs were oriented vertically. No DNs were found to colocalize with pNFH.ConclusionPreliminary findings suggest that DNs in FTLD‐TDP‐C may be remnants of dystrophic dendrites. The vertical orientation of colocalized DNs could reflect the orientation of apical dendrites in superficial layers of cortex. It is possible that DNs that did not colocalize with dendritic or axonal protein may be of distal dendritic origin or may reflect loss of dendritic protein in affected neurons. While it is difficult to determine the pathogenic history of DNs, these observations are promising and warrant future in‐depth investigation.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration

BackgroundMeasuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).MethodsWe measured plasma concentrations of...

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome

ABSTRACT Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer’s neuropathologic changes. .

Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C.

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

Caspase inhibition mitigates tau cleavage and neurotoxicity in iPSC‐induced neurons with the V337M MAPT mutation

Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Proteolytic cleavage of tau by active caspases, including caspase-6, represents an underexplored tau PTM implicated in tau pathology by generating tau species with an enhanced propensity for self-aggregation and accumulation into neuronal cytoplasmic inclusions. To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two neoepitope monoclonal antibodies (mAbs) against caspase-6 tau proteolytic sites (D13 and D402) and cortical neurons (iNs) from induced pluripotent stem cells (iPSCs) with the frontotemporal dementia (FTD)-causing V337MMAPTmutation (tauV337M ). FTLD tauV337M and AD postmortem brains showed positivity for both cleaved tau mAbs as well as active caspase-6 (Fig. 1). Three month tauV337M iNs showed a three-fold increase in caspase-cleaved D402 and D13 tau protein levels and increased p-tau and oligomeric tau species compared to controls (Fig. 2). Three month tauV337M iNs also showed a significantly higher rate of neuronal death than the tauWT counterpart. Treatment with staurosporine (STS), a stress inducer, led to a 5-fold increase of cytotoxicity levels in STS-treated tauV337M iNs compared to vehicle-treated tauV337M iNs. Although STS-induced cytotoxicity was anticipated, the increase was significantly higher in STS-treated tauV337M iNs than in STS-treated control iNs. Similarly, we observed a 4-fold increase of caspase-6 activity in STS-treated tauV337M iNs compared to vehicle-treated tauV337M iNs that was reversed following co-treatment with the caspase-6 inhibitor z-VEID-fmk (Fig. 2). We propose a model in which time-dependent accumulation of caspase-cleaved tau in V337MMAPTneurons promotes neurotoxicity that is reversed by caspase-6 inhibition. Caspase-cleaved tau may be a biomarker of tauopathy, and caspases could be viable targets for therapeutic intervention against tau pathogenesis in FTLD and other tauopathies.

Stem cell models of primary tauopathies reveal defects in synaptic function.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). To begin to identify the genes and pathways that are dysregulated in primary tauopathies, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)-derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed between MAPT p.R406W carriers and control brains. Twelve of these genes are also differentially expressed between PSP and control brains. Together, these genes are enriched for pathways involved in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies. Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants

Several clinical trials are planned for familial forms of frontotemporal lobar degeneration (f-FTLD). Precise modeling of brain atrophy in f-FTLD could improve the power to detect a treatment effect. To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia. This investigation was a case-control study of participants enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration or Longitudinal Evaluation of Familial Frontotemporal Dementia studies. The study took place at 18 North American academic medical centers between January 2009 and September 2018. Participants with f-FTLD (n = 100) with a known pathogenic variant (MAPT [n = 28], GRN [n = 33], or C9orf72 [n = 39]) were grouped according to disease stage (ie, Clinical Dementia Rating [CDR] plus National Alzheimer's Coordinating Center [NACC] FTLD module). Included were participants with at least 2 structural magnetic resonance images at presymptomatic (CDR + NACC FTLD = 0 [n = 57]), mild or questionable (CDR + NACC FTLD = 0.5 [n = 15]), or symptomatic (CDR + NACC FTLD = ≥1 [n = 28]) disease stages. The control group included family members of known pathogenic variant carriers who did not carry the pathogenic variant (n = 60). This study fitted bayesian linear mixed-effects models in each voxel of the brain to quantify the rate of atrophy in each of the 3 genes, at each of the 3 disease stages, compared with controls. The study also analyzed rates of clinical decline in each of these groups, as measured by the CDR + NACC FTLD box score. The sample included 100 participants with f-FTLD with a known pathogenic variant (mean [SD] age, 50.48 [13.78] years; 53 [53%] female) and 60 family members of known pathogenic variant carriers who did not carry the pathogenic variant (mean [SD] age, 47.51 [12.43] years; 36 [60%] female). MAPT and GRN pathogenic variants were associated with increased rates of volume loss compared with controls at all stages of disease. In MAPT pathogenic variant carriers, statistically significant regions of accelerated volume loss compared with controls were identified in temporal regions bilaterally in the presymptomatic stage, with global spread in the symptomatic stage. For example, mean [SD] rates of atrophy in the left temporal were -231 [47] mm3 per year during the presymptomatic stage, -381 [208] mm3 per year during the mild stage, and -1485 [1025] mm3 per year during the symptomatic stage (P < .05). GRN pathogenic variant carriers generally had minimal increases in atrophy rates between the presymptomatic and mild stages, with rapid increases in atrophy rates in the symptomatic stages. For example, in the right frontal lobes, annualized volume loss was -267 [81] mm3 per year in the presymptomatic stage and -182 [90] mm3 per year in the mild stage, but -1169 [555] mm3 per year in the symptomatic stage. Compared with the other groups, C9orf72 expansion carriers showed minimal increases in rate of volume loss with disease progression. For example, the mean (SD) annualized rates of atrophy in the right frontal lobe in C9orf72 expansion carriers was -272 (118) mm3 per year in presymptomatic stages, -310 (189) mm3 per year in mildly symptomatic stages, and -251 (145) mm3 per year in symptomatic stages. These findings are relevant to clinical trial planning and suggest that the mechanism by which C9orf72 pathogenic variants lead to symptoms may be fundamentally different from the mechanisms associated with other pathogenic variants.

Antibody against TDP-43 phosphorylated at serine 375 suggests conformational differences of TDP-43 aggregates among FTLD\u2013TDP subtypes

Aggregation of hyperphosphorylated TDP-43 is the hallmark pathological feature of the most common molecular form of frontotemporal lobar degeneration (FTLD–TDP) and in the vast majority of cases with amyotrophic lateral sclerosis (ALS–TDP). However, most of the specific phosphorylation sites remain to be determined, and their relevance regarding pathogenicity and clinical and pathological phenotypic diversity in FTLD–TDP and ALS–TDP remains to be identified. Here, we generated a novel antibody raised against TDP-43 phosphorylated at serine 375 (pTDP-43S375) located in the low-complexity domain, and used it to investigate the presence of S375 phosphorylation in a series (n = 44) of FTLD–TDP and ALS–TDP cases. Immunoblot analysis demonstrated phosphorylation of S375 to be a consistent feature of pathological TDP-43 species, including full-length and C-terminal fragments, in all FTLD–TDP subtypes examined (A–C) and in ALS–TDP. Of particular interest, however, detailed immunohistochemical analysis showed striking differences in the immunoreactivity profile of inclusions with the pTDP-43S375 antiserum among pathological subtypes. TDP-43 pathology of ALS–TDP, FTLD–TDP type B (including cases with the C9orf72 mutation), and FTLD–TDP type C all showed strong pTDP-43S375 immunoreactivity that was similar in amount and morphology to that seen with an antibody against TDP-43 phosphorylated at S409/410 used as the gold standard. In stark contrast, TDP-43 pathology in sporadic and genetic forms of FTLD–TDP type A (including cases with GRN and C9orf72 mutations) was found to be almost completely negative by pTDP-43S375 immunohistochemistry. These data suggest a subtype-specific, conformation-dependent binding of pTDP-43S375 antiserum to TDP-43 aggregates, consistent with the idea of distinct structural TDP-43 conformers (i.e., TDP-43 strains) as the molecular basis for the phenotypic diversity in TDP-43 proteinopathies.

Molecular and behavioural abnormalities in the FUS-tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti-inflammatory therapies.

Genetic mutations in FUS, a DNA/RNA‐binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1‐359]‐tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1‐359]‐tg mouse displays behavioural and brain pro‐inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre‐symptomatic FUS[1‐359]‐tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD‐like syndrome. FTLD‐related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre‐symptomatic FUS[1‐359]‐tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS‐like syndrome in the mutants. We used anti‐ALS drug riluzole (8 mg/kg/d), or anti‐inflammatory drug, a selective blocker of cyclooxygenase‐2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro‐Cells, 500 000‐CD34+), which showed anti‐inflammatory properties. Signs of elevated anxiety, depressive‐like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS‐tg–treated animals. Applied treatments have normalized protein expression of interleukin‐1β (IL‐1β) in the prefrontal cortex and the hippocampus, and of Iba‐1 and GSK‐3β in the hippocampus. Thus, the pre‐symptomatic FUS[1‐359]‐tg mice demonstrate FTLD‐like abnormalities that are attenuated by standard and new ALS treatments, including Neuro‐Cell preparation.

In vivo staging of frontotemporal lobar degeneration TDP-43 type C pathology

BackgroundTDP-43 type C is one of the pathological forms of frontotemporal lobar degeneration (FTLD) and mainly associated clinically with the semantic variant of primary progressive aphasia (svPPA). We aimed to define in vivo the sequential pattern of neuroanatomical involvement in a cohort of patients with FTLD-TDP type C pathology.MethodsWe extracted the volumes of a set of cortical and subcortical regions from MRI scans of 19 patients with post mortem confirmed TDP-43 type C pathology (all with left hemisphere-predominant atrophy at baseline). In the initial development phase, we used w-scores computed from 81 cognitively normal controls to define a set of sequential stages of neuroanatomical involvement within the FTLD-TDP type C cohort where a w-score of < − 1.65 was considered abnormal. In a subsequent validation phase, we used 31 follow-up scans from 14 of the 19 patients in the same cohort to confirm the staging model.ResultsFour sequential stages were identified in the initial development phase. Stage 1 was defined by atrophy in the left amygdala, medial temporal cortex, temporal pole, lateral temporal cortex and right medial temporal cortex; Stage 2 by atrophy in the left supratemporal cortex; Stage 3 by atrophy in the right anterior insula; and Stage 4 by atrophy in the right accumbens. In the validation phase, calculation of w-scores in the longitudinal scans confirmed the staging system, with all patients either staying in the same stage or progressing to a later stage at follow-up.ConclusionIn vivo imaging is able to detect distinct stages of neuroanatomical involvement in FTLD-TDP type C pathology. Using an imaging-derived staging system allows a more refined stratification of patients with svPPA during life.

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

SummaryPrimary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

Burden of caregivers of patients with frontotemporal lobar degeneration - a scoping review.

Frontotemporal lobar degeneration (FTLD) is the second-most common cause of young-onset dementia. Personality and behavior changes lead to high caregiver stress and burden, but little support is available. Our aim is to present the evidence on the characteristics, challenges and unmet needs of caregivers as well as on possible interventions. We conducted a scoping review on caregiver burden using PubMed, Web of Science and ScienceDirect. A total of 69 articles were considered eligible and were analyzed in the present study. Through the analysis of 69 empirical articles, our results show that caregivers of patients with FTLD are often younger in age, have children and find behavioral disturbances to be the most burdensome. Nine studies assessed the needs of and support for caregivers. Ten studies compared the burden in different forms of FTLD, 19 compared FTLD to other types of dementia, and one compared the caregiver burden between two countries. Eight studies reported on interventions for caregivers or interventions taking burden into account. One study assessed the support structure for caregivers of FTLD patients. Five case reports, eight research overviews and three reviews addressed specific needs and challenges. Further research should reproduce and validate efficacious interventions and focus on underage children of FTLD patients and findings from non-Western countries. Additionally, support structures for FTLD caregivers should be assessed and extended. Awareness both in the wider population and among healthcare professionals is an urgent need for the future.

The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau.

Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3β pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3β pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.

Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology

Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Administration of a PKC inhibitor, B-Raf inhibitor, or knockdown of molecules in the Gas6-Tyro3-tau axis rescues spine loss and cognitive impairment of PGRN-KI mice. Collectively, these results suggest that targeting of early-stage and aggregation-independent tau signaling represents a promising therapeutic strategy for this disease.

Heterogeneous ribonuclear protein E2 (hnRNP E2) is associated with TDP-43-immunoreactive neurites in Semantic Dementia but not with other TDP-43 pathological subtypes of Frontotemporal Lobar Degeneration

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi-quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP-43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD.

Neuropathologic Associations of Learning and Memory in Primary Progressive Aphasia.

The dementia syndrome of primary progressive aphasia (PPA) can be caused by 1 of several neuropathologic entities, including forms of frontotemporal lobar degeneration (FTLD) or Alzheimer disease (AD). Although episodic memory is initially spared in this syndrome, the subtle learning and memory features of PPA and their neuropathologic associations have not been characterized. To detect subtle memory differences on the basis of autopsy-confirmed neuropathologic diagnoses in PPA. Retrospective analysis was conducted at the Northwestern Cognitive Neurology and Alzheimer's Disease Center in August 2015 using clinical and postmortem autopsy data that had been collected between August 1983 and June 2012. Thirteen patients who had the primary clinical diagnosis of PPA and an autopsy-confirmed diagnosis of either AD (PPA-AD) or a tau variant of FTLD (PPA-FTLD) and 6 patients who had the clinical diagnosis of amnestic dementia and autopsy-confirmed AD (AMN-AD) were included. Scores on the effortless learning, delayed retrieval, and retention conditions of the Three Words Three Shapes test, a specialized measure of verbal and nonverbal episodic memory. The PPA-FTLD (n = 6), PPA-AD (n = 7), and AMN-AD (n = 6) groups did not differ by demographic composition (all P > .05). The sample mean (SD) age was 64.1 (10.3) years at symptom onset and 67.9 (9.9) years at Three Words Three Shapes test administration. The PPA-FTLD group had normal (ie, near-ceiling) scores on all verbal and nonverbal test conditions. Both the PPA-AD and AMN-AD groups had deficits in verbal effortless learning (mean [SD] number of errors, 9.9 [4.6] and 14.2 [2.0], respectively) and verbal delayed retrieval (mean [SD] number of errors, 6.1 [5.9] and 12.0 [4.4], respectively). The AMN-AD group had additional deficits in nonverbal effortless learning (mean [SD] number of errors, 10.3 [4.0]) and verbal retention (mean [SD] number of errors, 8.33 [5.2]), which were not observed in the PPA-FTLD or PPA-AD groups (all P < .005). This study identified neuropathologic associations of learning and memory in autopsy-confirmed cases of PPA. Among patients with clinical PPA syndrome, AD neuropathology appeared to interfere with effortless learning and delayed retrieval of verbal information, whereas FTLD-tau pathology did not. The results provide directions for future research on the interactions between limbic and language networks.

A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques

IntroductionAlthough TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.ResultsWe describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance.ConclusionsTARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users.