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Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels.Maps of fractional amplitude of low frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 female) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 female). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Further, we evaluated if the strength of co-localization is associated with the observed clinical symptoms.Patients displayed significantly reduced fALFF in fronto-temporal and fronto-parietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b, 5-HT2a), dopamine (D2), and γ-aminobutyric acid (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with D2 and NET was associated with cognitive symptoms and disease severity of bvFTD.Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD.

A hexanucleotide (GGGGCC)n repeat expansion in the noncod-ing region of the C9orf72 gene is the most common pathogenicmutation in patients affected with frontotemporal dementia (FTD) oramyotrophic lateral sclerosis (ALS). The exact function of C9orf72remains largely unknown. We have identified two point mutations inthe C9orf72 gene. The first patient with clinical ALS carried (hg19)Chr9:27556694 C to A resulting in the following amino acid changeP319Q, and the second patient carrying Chr9:27566700 G to A(R140Q) presents with ataxia but not ALS/FTD. The mutations arehighly conserved and predicted to be damaging using insilicopredictions (PolyPhen-2 and MutationTaster) but definite evidencefor their pathogenicity is lacking. We therefore generated inducedpluripotent stem cells (iPS) from both patients and characterized thelines on a molecular level. The iPS cells from the point mutationsgrew normally with morphology similar to hES cells and can bedifferentiatied into neurons with similar potential to control linesand as expected do not show RNA foci characteristic hallmarks ofrepeat expansion carriers. To investigate global transcriptionalchanges we prepared Cap Analysis of Gene Expression (CAGE)libraries from RNA of iPS and iPS differentiated neurons, derivedfrom both point mutations, C9orf72 repeat expansion carriers andcontrols. CAGE libraries were, sequenced on Illumina HiSeq2500 atan average depth of 15 million reads. The resulting data wasprocessed through an in-house CAGE pipeline.We observed a general transcriptional downregulation in therepeat expansion carriers when compared to controls. We areintegrating the CAGE data from the repeat expansion carriers withthe point mutations carrier cells with the aim to build gene networkmodels using Ingenuity Pathway Analysis and will validate ourfindings of relevant pathways via perturbation of the key genes inour iPS lines.

Primary progressive aphasias (PPA), including the semanticvariant (svPPA), non-fluent variant (nfvPPA) and logopenic variant(lvPPA), are neurodegenerative diseases characterized by a pro-gressive decline in speach. Neuropathologically, svPPA and nfvPPAare assigned to frontotemporal dementia whereas lvPPA is mainlyassociated with Alzheimer0s disease (AD). Differential diagnosis ofPPAs is based on clinical symptoms and objective neurochemicalbiomarkers are highly appreciated to improve diagnostic accuracy.Here, we investigated a panel of biomarker candidates in cere-brospinal fluid (CSF) of PPA patients (n = 66) in a multicentercohort from the German FTLD consortium.There were no significant differences in CSF concentrations ofubiquitin (Kruskal-Wallis test, p = 0.50), progranulin (p = 0.12),Tau (p = 0.12) and pTau181 (p = 0.07) between PPAs. Ab42 wassignificantly reduced in lvPPA versus nfvPPA (p < 0.05) but notsvPPA and there was a great overlap between groups. The ratio ofthe AD biomarkers Ab42/pTau181 significantly differentiatedlvPPA from nfvPPA (p < 0.01) and svPPA (p < 0.05) and showeda sensitivity and specificity of 91.7% and 64.3% (lvPPA vs.nfv+svPPA). Neurofilament light chain (NfL) was significantlylower in lvPPA compared with nfvPPA (p < 0.01) and svPPA(p < 0.001) and sensitivity and specificity was 70.8% and 92.9%.Combination of NfL and AD biomarkers in the term Ab42*NfL/pTau181 improved diagnostic accuracy for the differentiation oflvPPA from nfvPPA and svPPA patients (sensitivity 87.5% andspecificity 85.7%). The phosphorylated neurofilament heavy chain(pNFH) was significantly increased in nfvPPA vs. svPPA (p < 0.05)and lvPPA (p < 0.01) and showed a sensitivity and specificity of80.0% and 64.3% to discriminate nfvPPA and svPPA.In conclusion, the combination of the AD biomarkers Ab42 andpTau181 with NfL is promising in the discrimination of lvPPApatients from nfvPPA and svPPA. CSF pNfH concentrations may assist in the differential diagnosis of nfvPPA and svPPA althoughadditional biomarkers are appreciated to increase sensitivity andspecificity of pNfH.

Both, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), and their combination (FTLD-U/MND) are principally sporadic diseases that are rarely familial. Cytoplasmic ubiquitinated proteinaceous inclusions in motor and extra-motor neurons are the pathological hallmark of all three forms. In 2006, the TAR DNA-binding protein of 43 kDa (TDP-43) was both identified as the key protein component of the ubiquitinated inclusions and recognised as the key protein of a spectrum of diseases that have since been consolidated as TDP-43 proteinopathies. TDP-43 as a nuclear protein contributes to the regulation of gene expression, and associated with neurodegeneration, it has been found to be truncated, hyperphosphorylated, and mislocalized. It is unclear whether the loss of the TDP-43's nuclear function or the gain of a toxic function outside its nucleus is disease causing. Since 2008, several TARDBP-mutations have been identified as leading to the autosomal-dominant familial ALS (ALS 10), although no TARDBP-mutations have yet to be linked to FTLD.

Objective: Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualized by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple magnetic resonance imaging scanners and patient cohorts. A multi-centre study was undertaken to assess structural connectivity in ALS at a large sample size. Methods: Four-hundred-and-forty-two DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study from eight international ALS-specialist international clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control subjects were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups. Results: Analysis of data pooled from all centres using whole-brain-based statistical analysis of FA maps confirmed the most significant alterations in the corticospinal tracts, and captured additionalsignificant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with post mortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings.Interpretation: This large-scale study overcomes the challenges associated with processing and analysis of multi-platform, multi-centre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multi-site disease-modifying studies in ALS.

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.