A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

OBJECTIVES: The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers. METHODS: The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales. RESULTS: The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills. CONCLUSION: Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group

MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia

INTRODUCTION: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. METHODS: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation. RESULTS: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores. CONCLUSION: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database

Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia

BACKGROUND: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. METHODS: Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. RESULTS: Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. CONCLUSIONS: Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials

Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

INTRODUCTION: Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. METHODS: We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. RESULTS: Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301-872)) than presymptomatic carriers (1003 pg/mL (624-1358), p<0.001) and non-carriers (990 pg/mL (597-1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. DISCUSSION: We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD

FMRFamide-Like Peptides (FLPs) Enhance Voltage-Gated Calcium Currents to Elicit Muscle Contraction in the Human Parasite Schistosoma mansoni

Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca2+ influx through sarcolemmal voltage operated Ca2+ channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 µM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31–8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 µM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca2+ influx through VOCC currents using a PKC-dependent pathway

Molecular Evidence for a Functional Ecdysone Signaling System in Brugia malayi

Filarial parasites such as Brugia malayi and Onchocerca volvulus are the causative agents of the tropical diseases lymphatic filariasis and onchocerciasis, which infect 150 million people, mainly in Africa and Southeast Asia. Filarial nematodes have a complex life cycle that involves transmission and development within both mammalian and insect hosts. The successful completion of the life cycle includes four molts, two of which are triggered upon transmission from one host to the other, human and mosquito, respectively. Elucidation of the molecular mechanisms involved in the molting processes in filarial nematodes may yield a new set of targets for drug intervention. In insects and other arthropods molting transitions are regulated by the steroid hormone ecdysone that interacts with a specialized hormone receptor composed of two different proteins belonging to the family of nuclear receptors. We have cloned from B. malayi two members of the nuclear receptor family that show many sequence and biochemical properties consistent with the ecdysone receptor of insects. This finding represents the first report of a functional ecdysone receptor homolog in nematodes. We have also established a transgenic hormone induction assay in B. malayi that can be used to discover ecdysone responsive genes and potentially lead to screening assays for active compounds for pharmaceutical development

Discovery of Markers of Exposure Specific to Bites of Lutzomyia longipalpis, the Vector of Leishmania infantum chagasi in Latin America

Leishmania parasites are transmitted by the bite of an infected vector sand fly that injects salivary molecules into the host skin during feeding. Certain salivary molecules can produce antibodies and can be used as an indicator of exposure to a vector sand fly and potentially the disease it transmits. Here we identified potential markers of specific exposure to the sand fly Lutzomyia longipalpis, the vector of visceral leishmaniasis in Latin America. Initially, we determined which of the salivary proteins produce antibodies in humans, dogs, and foxes from areas endemic for the disease. To identify potential specific markers of vector exposure, we produced nine different recombinant salivary proteins from Lu. longipalpis and tested for their recognition by individuals exposed to another human-biting sand fly, Lu. intermedia, that transmits cutaneous leishmaniasis and commonly occurs in the same endemic areas as Lu. longipalpis. Two of the nine salivary proteins were recognized only by humans exposed to Lu. longipalpis, suggesting they are immunogenic proteins and may be useful in epidemiological studies. The identification of specific salivary proteins as potential markers of exposure to vector sand flies will increase our understanding of vector–human interaction, bring new insights to vector control, and in some instances act as an indicator for risk of acquiring disease