UNASSIGNED: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood.
UNASSIGNED: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI).
UNASSIGNED: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72, MAPT, and GRN, including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC).
UNASSIGNED: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression.
UNASSIGNED: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs\' relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications.

BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.
METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.
RESULTS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.
CONCLUSIONS: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.
BACKGROUND: Biogen.

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

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic Amyotrophic lateral sclerosis cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of 7 publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested 3 previously characterized disease-modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application.

BACKGROUND: Blood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.
METHODS: Comparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)-(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRN or MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.
RESULTS: NfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12±1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.
CONCLUSIONS: Our results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.

BACKGROUND: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia.
METHODS: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins.
RESULTS: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers.
CONCLUSIONS: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.

One goal of the Longitudinal Early-onset Alzheimer\'s Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.
LEADS amyloid-positive early-onset Alzheimer\'s disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson\'s Progression Markers Initiative (PPMI) study.
Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.
Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.
Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer\'s Disease Study (LEADS) is a key resource for early-onset Alzheimer\'s genetic research.

ALS patients with hexanucleotide expansion in C9orf72 are characterized by a specific clinical phenotype, including more aggressive disease course and cognitive decline. Computerized multiparametric MRI with gray matter volumetry and diffusion tensor imaging (DTI) to analyze white matter structural connectivity is a potential in vivo biomarker.
The objective of this study was to develop a multiparametric MRI signature in a large cohort of ALS patients with C9orf72 mutations. The aim was to investigate how morphological features of C9orf72-associated ALS differ in structural MRI and DTI compared to healthy controls and ALS patients without C9orf72 mutations.
Atlas-based volumetry (ABV) and whole brain-based DTI-based analyses were performed in a cohort of n = 51 ALS patients with C9orf72 mutations and compared with both n = 51 matched healthy controls and n = 51 C9orf72 negative ALS patients, respectively. Subsequently, Spearman correlation analysis of C9orf72 ALS patients\' data with clinical parameters (age of onset, sex, ALS-FRS-R, progression rate, survival) as well as ECAS and p-NfH in CSF was performed.
The whole brain voxel-by-voxel comparison of fractional anisotropy (FA) maps between C9orf72 ALS patients and controls showed significant bilateral alterations in axonal structures of the white matter at group level, primarily along the corticospinal tracts and in fibers projecting to the frontal lobes. For the frontal lobes, these alterations were also significant between C9orf72 positive and C9orf72 negative ALS patients. In ABV, patients with C9orf72 mutations showed lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus, but also in hippocampi and amygdala. Compared to C9orf72 negative ALS, the differences were shown to be significant for cerebral gray matter (p = 0.04), especially in the frontal (p = 0.01) and parietal lobe (p = 0.01), and in the thalamus (p = 0.004). A correlation analysis between ECAS and averaged regional FA values revealed significant correlations between cognitive performance in ECAS and frontal association fibers. Lower FA values in the frontal lobes were associated with worse performance in all cognitive domains measured (language, verbal fluency, executive functions, memory and spatial perception). In addition, there were significant negative correlations between age of onset and atlas-based volumetry results for gray matter.
This study demonstrates a distinct pattern of DTI alterations of the white matter and ubiquitous volume reductions of the gray matter early in the disease course of C9orf72-associated ALS. Alterations were closely linked to a more aggressive cognitive phenotype. These results are in line with an expected pTDP43 propagation pattern of cortical affection and thus strengthen the hypothesis that an underlying developmental disorder is present in ALS with C9orf72 expansions. Thus, multiparametric MRI could contribute to the assessment of the disease as an in vivo biomarker even in the early phase of the disease.

BACKGROUND: The characterisation of presymptomatic disease-burden patterns in asymptomatic mutation carriers has a dual academic and clinical relevance. The understanding of disease propagation mechanisms is of considerable conceptual interests, and defining the optimal time of pharmacological intervention is essential for improved clinical trial outcomes.
METHODS: In a prospective, multimodal neuroimaging study, 22 asymptomatic C9orf72 GGGGCC hexanucleotide repeat carriers, 13 asymptomatic subjects with SOD1, and 54 \"gene-negative\" ALS kindreds were enrolled. Cortical and subcortical grey matter alterations were systematically appraised using volumetric, morphometric, vertex, and cortical thickness analyses. Using a Bayesian approach, the thalamus and amygdala were further parcellated into specific nuclei and the hippocampus was segmented into anatomically defined subfields.
RESULTS: Asymptomatic GGGGCC hexanucleotide repeat carriers in C9orf72 exhibited early subcortical changes with the preferential involvement of the pulvinar and mediodorsal regions of the thalamus, as well as the lateral aspect of the hippocampus. Volumetric approaches, morphometric methods, and vertex analyses were anatomically consistent in capturing focal subcortical changes in asymptomatic C9orf72 hexanucleotide repeat expansion carriers. SOD1 mutation carriers did not exhibit significant subcortical grey matter alterations. In our study, none of the two asymptomatic cohorts exhibited cortical grey matter alterations on either cortical thickness or morphometric analyses.
CONCLUSIONS: The presymptomatic radiological signature of C9orf72 is associated with selective thalamic and focal hippocampal degeneration which may be readily detectable before cortical grey matter changes ensue. Our findings confirm selective subcortical grey matter involvement early in the course of C9orf72-associated neurodegeneration.