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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.

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.

In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P, O’Connor et al. reveal significant differences in plasma Aβ ratios between PSEN1 and APP carriers, broadening understanding of the molecular drivers of Alzheimer’s disease. They also show associations between higher Aβ42:40 and Aβ42:38 ratios and earlier disease onset, supporting the pathogenicity of these peptide ratios.

In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutationsin-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios betweenPresenilin1 (PSEN1)andAmyloid Precursor Protein (APP)carriers. We examined the relationship between plasma andin-vitromodels of Aβ processing and, amongPSEN1carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28PSEN1and 11APP).Age- and sex-adjusted models showed marked differences in plasma Aβ betweenAPPandPSEN1: higher Aβ42:38 inPSEN1versusAPP(pAPPversusPSEN1(pAPPandPSEN1compared to non-carriers (both pPSEN1, sex-adjusted models demonstrated negative associations between (i)Aβ42:40 (ii)Aβ42:38 and parental AAO.In-vivodifferences in Aβ processing betweenAPPandPSEN1provide insights into ADAD pathophysiology which can inform therapy development.

Background\ud \ud Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end‐organ damage.\ud \ud \ud Objective\ud \ud To identify a biomarker for neurological involvement in WD.\ud \ud \ud Methods\ud \ud Neuronal and glial‐specific proteins were measured in plasma samples from 40 patients and 38 age‐matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non‐adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded.\ud \ud \ud Results\ud \ud Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients.\ud \ud \ud Conclusion\ud \ud NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by frontal and temporal lobe atrophy, typically manifesting with behavioural or language impairment. Because of its heterogeneity and lack of available diagnostic laboratory tests there can be a substantial delay in diagnosis. Cell-free, circulating, microRNAs are increasingly investigated as biomarkers for neurodegeneration, but their value in FTD is not yet established. In this study, we investigate microRNAs as biomarkers for FTD diagnosis. We performed next generation small RNA sequencing on cell-free plasma from 52 FTD cases and 21 controls. The analysis revealed the diagnostic importance of 20 circulating endogenous miRNAs in distinguishing FTD cases from controls. The study was repeated in an independent second cohort of 117 FTD cases and 35 controls. The combinatorial microRNA signature from the first cohort, precisely diagnosed FTD samples in a second cohort. To further increase the generalizability of the prediction, we implemented machine learning techniques in a merged dataset of the two cohorts, which resulted in a comparable or improved classification precision with a smaller panel of miRNA classifiers. In addition, there are intriguing molecular commonalities with cell free miRNA signature in ALS, a motor neuron disease that resides on a pathological continuum with FTD. However, the signature that describes the ALS-FTD spectrum is not shared with blood miRNA profiles of patients with multiple sclerosis. Thus, microRNAs are promising FTD biomarkers that might enable earlier detection of FTD and improve accurate identification of patients for clinical trials

TANK-binding kinase 1 (TBK1) mutations are a recently discovered cause of disorders in the frontotemporal dementia (FTD)–amyotrophic lateral sclerosis (ALS) spectrum. We describe a novel L683∗ mutation, predicted to cause a truncated protein and therefore be pathogenic, in a patient presenting with nonfluent variant primary progressive aphasia at the age of 65 years. Her disease progressed over the following years, leading to her being mute and wheelchair bound seven years into her illness. Brain imaging showed asymmetrical left-sided predominant atrophy affecting the frontal, insular, and temporal cortices as well as the striatum in particular. Review of the literature found 60 different nonsense, frameshift, deletion, or splice site mutations, including the newly described mutation, with data on clinical diagnosis available in 110 people: 58% of the cases presented with an ALS syndrome, 16% with an FTD-ALS overlap, 19% with a cognitive presentation (including behavioral variant FTD and primary progressive aphasia) and 4% with atypical parkinsonism. Age at onset (AAO) data were available in 75 people: mean (standard deviation) AAO was 57.5 (10.3) in those with ALS, which was significantly younger than those with a cognitive presentation (AAO = 65.1 (10.5), p = 0.008), or atypical parkinsonism (AAO = 68.3 (8.7), p = 0.021), with a trend compared with the FTD-ALS group (AAO = 61.9 (7.0), p=0.065); there was no significant difference in AAO between the other groups. In conclusion, clinical syndromes across the whole FTD-ALS-atypical parkinsonism spectrum have been reported in conjunction with mutations in TBK1. It is therefore important to include TBK1 on future gene panels for each of these disorders and to suspect such mutations particularly when there are multiple different phenotypes in the same family., Highlights • Novel TBK1 mutation, L683∗, is a probable pathogenic mutation in a case of FTD. • L683∗ lies in the optineurin-binding region, disrupting downstream pathways. • TBK1 mutations are found across the entire FTD-ALS-atypical parkinsonism spectrum. • TBK1 mutations cause differing ages of onset depending on clinical presentation.

Correlative vibrational spectroscopy and immunohistochemistry reveal astroglial processes co-localised with the lipid-rich shell of Aβ plaques., Recent work using micro-Fourier transform infrared (μFTIR) imaging has revealed that a lipid-rich layer surrounds many plaques in post-mortem Alzheimer's brain. However, the origin of this lipid layer is not known, nor is its role in the pathogenesis of Alzheimer's disease (AD). Here, we studied the biochemistry of plaques in situ using a model of AD. We combined FTIR, Raman and immunofluorescence images, showing that astrocyte processes co-localise with the lipid ring surrounding many plaques. We used μFTIR imaging to rapidly measure chemical signatures of plaques over large fields of view, and selected plaques for higher resolution analysis with Raman microscopy. Raman maps showed similar lipid rings and dense protein cores as in FTIR images, but also revealed cell bodies. We confirmed the presence of plaques using amylo-glo staining, and detected astrocytes using immunohistochemistry, revealing astrocyte co-localisation with lipid rings. This work is important because it correlates biochemical changes surrounding the plaque with the biological process of astrogliosis.