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Increasing evidence implicates endo-lysosomal dysfunction in frontotemporal dementia (FTD). 18 proteins were quantified using a mass spectrometry assay panel in the cerebrospinal fluid of 36 people with the language variant of FTD, primary progressive aphasia (PPA) (including 13 with non-fluent variant (nfvPPA), 11 with semantic variant (svPPA), and 12 with logopenic variant (lvPPA)) and 19 healthy controls. The concentrations of the cathepsins (B, D, F, L1, and Z) as well as AP-2 complex subunit beta, ganglioside GM2 activator, beta-hexosaminidase subunit beta, tissue alpha l -fucosidase, and ubiquitin were decreased in nfvPPA compared with controls. In contrast, the concentrations of amyloid beta A4 protein, cathepsin Z, and dipeptidyl peptidase 2 were decreased in svPPA compared with controls. No proteins were abnormal in lvPPA. These results indicate a differential alteration of lysosomal proteins in the PPA variants, suggesting those with non-Alzheimer’s pathologies are more likely to show abnormal lysosomal function.

Although research has been prolific identifying proteomic changes in frontotemporal dementia (FTD), there are not strong evidence for the identification of biomarkers to help the understanding of the underlying pathologies. We explored proteomic profiles in genetic FTD associated to underlying pathologies. This is a follow up study from a proteomic database in the GENetic FTD cohort (GENFI) in which a total of 238 cerebrospinal fluid (CSF) samples were measured by untargeted mass spectrometry. We performed ANCOVA analyses to identify the best predictors to differentiate among pathologies and then studied the pathways where these proteins are indicated. Previous results from the study revealed individual proteomic changes in each genetic form of FTD. For the present work, we combined C9orf72 and GRN mutation carriers to conform the TDP-43 group and compared them against MAPT mutation carriers and controls. Among the proteins significantly altered in the disease groups compared to controls (155 in the TDP-43 group and 52 in the tau group), 14 proteins were specific of MAPT mutation carriers but not on the others and 43 were only significantly changed in the TDP-43 group. We identified DNASE2 and PLBD2 as potential predictors differentiating the underlying pathologies. Both proteins are significantly decreased in tau pathology, when compared to TDP-43 pathology (DNASE2 p-value<0.0001, PLBD2 p-value=0.006). These two proteins are also the ones driving the significant changes in the cluster identified as \"Lysosomal proteins\" in our network analysis. Our results suggest a proteomic difference related to the underlying pathologies of FTD that, combined with the proteomic signatures linked to the genetic mutations, could provide key insights in the search for potential biomarkers for this disorder.

Background The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) Methods Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. Results In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). Conclusion Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.

ObjectivesParacetamol is one of the most common drugs used in overdose.1 Current guidelines focus on early identification and management of liver toxicity. However, kidney toxicity may also occur after paracetamol overdose,2 but there is currently no guidance around how best to identify those at risk. The aim of this systematic review is to identify the evidence base for potential predictors of kidney toxicity which may be considered in the management of paracetamol overdose.MethodsA systemic search was conducted in December 2022 using Scopus, PubMed, and Web of Science. Included studies: conducted in human patients of any age and gender following paracetamol overdose, managed in a hospital setting; investigated serum phosphate, vomiting episodes, Kidney Injury Molecule-1, or urinalysis as predictors for nephrotoxicity; were available in full text English. Studies were excluded if they: included overdose of other drugs; investigated treatment with N-acetylcysteine; had an outcome of hepatotoxicity alone; were not conducted in humans; or used creatinine alone as a predictor of AKI.ResultsOf 567 articles identified, seven papers met the inclusion criteria.Abstract 6650 Table 1 Predictor Outcome Number of patients Result Type of study [Reference ] Serum phosphate Hypophosphatemia 273 Minimum serum phosphate concentration:• Patients with no treatment: 1.05mmol/l.• Patients with liver damage:0.45mmol/l Case series [3] Serum phosphate Hypophosphatemia 1 33-year-old woman. Plasma phosphate levels decreased to 0.10mmol/l on day 5. Case report [4] Vomiting episodes Serum creatinine levels increased with number of vomiting episodes. 291 Mean peak serum creatinine:• Patients with no episodes of vomiting: 66.74mmol/l.• Patients with >3 episodes of vomiting: 71.9mmol/l Observational retrospective case review [5] Kidney Injury Molecule-1 Increased KIM-1 concentration after paracetamol overdose. 74 Absolute KIM-1 concentration:• Healthy patients: 70.75pg/mg.• Patients with AKI: 16152.51pg/mg. Cohort study [6] Kidney Injury Molecule-1 Increased KIM-1 concentration after paracetamol overdose. 135 Mean KIM-1 concentration:• Patients who survived: 112.7pg/ml.• Patients who had a liver transplant and died: 1182.2pg/ml Cross-sectional cohort study [7] Urinalysis Renal impairment. 1 Protein 4+ on urinalysis of a 15-year-old girl. Case report [8] Urinalysis Renal impairment. 1 Protein 1+ on urinalysis of a 16-year-old girl, with decreased specific gravity and granular casts with erythrocytes and leukocytes on microscopic evaluation. Case report [9] ConclusionAnalysis of study results supports the monitoring of the suggested predictors in monitoring outcomes of paracetamol poisoning. Future research may include cohort studies to follow-up patients, and investigations into the pathophysiology of outcomes presented.ReferencesAgrawal S, Khazaenia B. StatPearls [Internet] Treasure Island (FL), 2023 Jan.Campbell NR, Baylis B. Postgrad Med J, 1992 Feb.Jones AF, et al. Lancet, 1989.Eckardt K, et al. Nephrology Dialysis Transplantation, 1999.Zyoud SH, et al. Basic & Clinical Pharmacology & Toxicology, 2010.Antoine DJ, et al. Hepatology, August 2015.Pavkovic M, et al. Toxicological Sciences, 2016.Ammenti A, et al. Paedaitric Nephrology, 1999.Ozkaya O. Renal Failure, 2010.

BackgroundNeurofilament light (NfL) is a widely used biomarker for neurodegeneration. NfL is prone to oligomerisation, but available assays do not reveal the exact molecular nature of the protein variant measured. The objective of this study was to develop a homogeneous ELISA capable of quantifying oligomeric NfL (oNfL) in cerebrospinal fluid (CSF).MethodsA homogeneous ELISA, based on the same capture and detection antibody (NfL21), was developed and used to quantify oNfL in samples from patients with behavioural variant frontotemporal dementia (bvFTD, n=28), non-fluent variant primary progressive aphasia (nfvPPA, n=23), semantic variant PPA (svPPA, n=10), Alzheimer’s disease (AD, n=20) and healthy controls (n=20). The nature of NfL in CSF, and the recombinant protein calibrator, was also characterised by size exclusion chromatography (SEC).ResultsCSF concentration of oNfL was significantly higher in nfvPPA (p<0.0001) and svPPA patients (p<0.05) compared with controls. CSF oNfL concentration was also significantly higher in nfvPPA compared with bvFTD (p<0.001) and AD (p<0.01) patients. SEC data showed a peak fraction compatible with a full-length dimer (~135 kDa) in the in-house calibrator. For CSF, the peak was found in a fraction of lower molecular weight (~53 kDa), suggesting dimerisation of NfL fragments.ConclusionsThe homogeneous ELISA and SEC data suggest that most of the NfL in both the calibrator and human CSF is present as a dimer. In CSF, the dimer appears to be truncated. Further studies are needed to determine its precise molecular composition.

The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer’s disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.

Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72 , GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects. Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs

Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer’s disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO −9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85–0.98]) and presymptomatic (EYO ≥ −7 years) (AUC 0.86 [95% CI 0.72–0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.

Background GRN mutations are a common cause of frontotemporal dementia (FTD), with previous studies linking granulin deficiency to reduced bis(monoacylglycerol)phosphate (BMP) levels, which ultimately impairs ganglioside degradation. BMP is involved in the lysosomal functions within cells, as it facilitates the adhesion of hydrolases and activator proteins where the lysosomal membranes meet, therefore a lack of BMP could impact lysosome function and integrity. We hypothesised that urine levels of BMP isoforms will be lower in FTD patients with GRN haploinsufficiency, as a reflection of reduced BMP in neural tissues, when compared to those with FTD caused by C9orf72 expansions and MAPT mutations, or healthy controls. The objective of this study was to investigate changes to urinary phospholipids as potential biomarkers of GRN mutations in FTD. Method A panel of 3 different di‐22:6 BMP, and 3 di‐18:1 BMP isoforms, as well as total di‐22:6 and di‐18:1 BMP, were measured in urine collected from the UCL GENFI cohort consisting of 36 controls, 11 symptomatic GRN mutation carriers, 11 symptomatic C9orf72 carriers and 12 symptomatic MAPT mutation carriers. A mass spectrometric method was used to quantitate molecular species of BMPs in urine, with results normalised to creatinine. Data analysis was performed in Stata, using an age and sex‐adjusted bootstrapped regression to compare the different symptomatic groups to the controls, with P<0.05 considered statistically significant. Result GRN mutation carriers showed reduced levels of the 2:2 di‐22:6 BMP isoform (mean=11.9 (standard deviation=7.5)) when compared to controls (17.9 (13.5); p=0.015), with a trend for reduced levels of the 2:2 di‐18:1 BMP isoform also (3.5 (2.1)) for GRN mutation carriers compared with (4.6 (4.2)) for controls, consistent with the idea that mutations in GRN lower levels of BMP. Concentrations of the 2:3 and 3:3 isoforms as well as the total amount were not significantly different between control and mutation groups. Conclusion Our results indicate that GRN mutations cause a reduction in the levels of certain isoforms of BMP in urine. Future studies will be helpful to see if urinary BMP concentrations increase with treatments that restore progranulin levels.

Background Although research has been prolific identifying proteomic changes in frontotemporal dementia (FTD), there are not strong evidence for the identification of biomarkers to help the understanding of the underlying pathologies. We explored proteomic profiles in genetic FTD associated to underlying pathologies. Method This is a follow up study from a proteomic database in the GENetic FTD cohort (GENFI) in which a total of 238 cerebrospinal fluid (CSF) samples were measured by untargeted mass spectrometry. We performed ANCOVA analyses to identify the best predictors to differentiate among pathologies and then studied the pathways where these proteins are indicated. Result Previous results from the study revealed individual proteomic changes in each genetic form of FTD. For the present work, we combined C9orf72 and GRN mutation carriers to conform the TDP‐43 group and compared them against MAPT mutation carriers and controls. Among the proteins significantly altered in the disease groups compared to controls (155 in the TDP‐43 group and 52 in the tau group), 14 proteins were specific of MAPT mutation carriers but not on the others and 43 were only significantly changed in the TDP‐43 group. We identified DNASE2 and PLBD2 as potential predictors differentiating the underlying pathologies. Both proteins are significantly decreased in tau pathology, when compared to TDP‐43 pathology (DNASE2 p‐value<0.0001, PLBD2 p‐value=0.006). These two proteins are also the ones driving the significant changes in the cluster identified as “Lysosomal proteins” in our network analysis. Conclusion Our results suggest a proteomic difference related to the underlying pathologies of FTD that, combined with the proteomic signatures linked to the genetic mutations, could provide key insights in the search for potential biomarkers for this disorder.