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Article ; Online: Differential patterns of lysosomal dysfunction are seen in the clinicopathological forms of primary progressive aphasia.

Swift, Imogen J / Sjödin, Simon / Gobom, Johan / Brinkmalm, Ann / Blennow, Kaj / Zetterberg, Henrik / Rohrer, Jonathan D / Sogorb-Esteve, Aitana

Journal of neurology

2023 Volume 271, Issue 3, Page(s) 1277–1285

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Humans ; Aphasia, Primary Progressive ; Amyloid beta-Peptides ; Frontotemporal Dementia ; Language ; Lysosomes/pathology
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2023-11-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-12063-9
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Article ; Online: Variable clinical phenotype in TBK1 mutations: case report of a novel mutation causing primary progressive aphasia and review of the literature.

Swift, Imogen J / Bocchetta, Martina / Benotmane, Hanya / Woollacott, Ione Oc / Shafei, Rachelle / Rohrer, Jonathan D

Neurobiology of aging

2020 Volume 99, Page(s) 100.e9–100.e15

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Aged ; Amyotrophic Lateral Sclerosis/genetics ; Aphasia, Primary Progressive/diagnostic imaging ; Aphasia, Primary Progressive/genetics ; Brain/diagnostic imaging ; Female ; Frontotemporal Dementia/genetics ; Humans ; Magnetic Resonance Imaging ; Mutation ; Phenotype ; Protein-Serine-Threonine Kinases/genetics
Chemical Substances	Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; TBK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2020.08.014
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Article ; Online: Neurofilament light oligomers in neurodegenerative diseases: quantification by homogeneous immunoassay in cerebrospinal fluid.

Meda, Francisco J / Knowles, Kathryn / Swift, Imogen J / Sogorb-Esteve, Aitana / Rohrer, Jonathan D / Dittrich, Anna / Skoog, Ingmar / Kern, Silke / Becker, Bruno / Blennow, Kaj / Andreasson, Ulf / Kvartsberg, Hlin / Zetterberg, Henrik

BMJ neurology open

2023 Volume 5, Issue 1, Page(s) e000395

Abstract: Background: Neurofilament 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 ... ...

Abstract	Background: Neurofilament 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). Methods: A 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). Results: CSF 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. Conclusions: The 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.
Language	English
Publishing date	2023-02-27
Publishing country	England
Document type	Journal Article
ISSN	2632-6140
ISSN (online)	2632-6140
DOI	10.1136/bmjno-2022-000395
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Article ; Online: microRNA-based predictor for diagnosis of frontotemporal dementia.

Magen, Iddo / Yacovzada, Nancy-Sarah / Warren, Jason D / Heller, Carolin / Swift, Imogen / Bobeva, Yoana / Malaspina, Andrea / Rohrer, Jonathan D / Fratta, Pietro / Hornstein, Eran

Neuropathology and applied neurobiology

2023 Volume 49, Issue 4, Page(s) e12916

Abstract: Aims: This study aimed to explore the non-linear relationships between cell-free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers ... ...

Abstract	Aims: This study aimed to explore the non-linear relationships between cell-free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis. Methods: We initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls). Results: On the basis of cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non-linear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ~90% of cases. Conclusions: The fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.
MeSH term(s)	Humans ; MicroRNAs ; Frontotemporal Dementia/diagnosis ; Frontotemporal Dementia/genetics ; Machine Learning ; Biomarkers
Chemical Substances	MicroRNAs ; Biomarkers
Language	English
Publishing date	2023-06-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80371-6
ISSN	1365-2990 ; 0305-1846
ISSN (online)	1365-2990
ISSN	0305-1846
DOI	10.1111/nan.12916
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Article ; Online: Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation.

Sogorb-Esteve, Aitana / Swift, Imogen J / Woollacott, Ione O C / Warren, Jason D / Zetterberg, Henrik / Rohrer, Jonathan D

Journal of neuroinflammation

2021 Volume 18, Issue 1, Page(s) 224

Abstract: 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). ...

Abstract	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.
MeSH term(s)	Aged ; Aphasia, Primary Progressive ; Biomarkers/blood ; Biomarkers/cerebrospinal fluid ; Chemokines/blood ; Chemokines/cerebrospinal fluid ; Female ; Humans ; Male ; Middle Aged ; Neuroinflammatory Diseases
Chemical Substances	Biomarkers ; Chemokines
Language	English
Publishing date	2021-10-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02247-3
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Article ; Online: Altered plasma protein profiles in genetic FTD - a GENFI study.

Ullgren, Abbe / Öijerstedt, Linn / Olofsson, Jennie / Bergström, Sofia / Remnestål, Julia / van Swieten, John C / Jiskoot, Lize C / Seelaar, Harro / Borroni, Barbara / Sanchez-Valle, Raquel / Moreno, Fermin / Laforce, Robert / Synofzik, Matthis / Galimberti, Daniela / Rowe, James B / Masellis, Mario / Tartaglia, Maria Carmela / Finger, Elizabeth / Vandenberghe, Rik /

de Mendonça, Alexandre / Tirabosch, Pietro / Santana, Isabel / Ducharme, Simon / Butler, Chris R / Gerhard, Alexander / Otto, Markus / Bouzigues, Arabella / Russell, Lucy / Swift, Imogen J / Sogorb-Esteve, Aitana / Heller, Carolin / Rohrer, Jonathan D / Månberg, Anna / Nilsson, Peter / Graff, Caroline

Molecular neurodegeneration

2023 Volume 18, Issue 1, Page(s) 85

Abstract: 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 ... ...

Abstract	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. Conclusion: 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.
MeSH term(s)	Humans ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/pathology ; Mutation/genetics ; C9orf72 Protein/genetics ; Progranulins/genetics ; tau Proteins/genetics ; Biomarkers
Chemical Substances	C9orf72 Protein ; Progranulins ; tau Proteins ; Biomarkers
Language	English
Publishing date	2023-11-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-023-00677-6
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Article ; Online: Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.

Mok, Tze How / Nihat, Akin / Majbour, Nour / Sequeira, Danielle / Holm-Mercer, Leah / Coysh, Thomas / Darwent, Lee / Batchelor, Mark / Groveman, Bradley R / Orr, Christina D / Hughson, Andrew G / Heslegrave, Amanda / Laban, Rhiannon / Veleva, Elena / Paterson, Ross W / Keshavan, Ashvini / Schott, Jonathan M / Swift, Imogen J / Heller, Carolin /

Rohrer, Jonathan D / Gerhard, Alexander / Butler, Christopher / Rowe, James B / Masellis, Mario / Chapman, Miles / Lunn, Michael P / Bieschke, Jan / Jackson, Graham S / Zetterberg, Henrik / Caughey, Byron / Rudge, Peter / Collinge, John / Mead, Simon

Brain : a journal of neurology

2023 Volume 146, Issue 6, Page(s) 2570–2583

Abstract: Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict ... ...

Abstract	Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.
MeSH term(s)	Humans ; tau Proteins/metabolism ; Prion Diseases ; Creutzfeldt-Jakob Syndrome ; Prions ; Biomarkers
Chemical Substances	tau Proteins ; Prions ; Biomarkers
Language	English
Publishing date	2023-03-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awad101
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Article ; Online: Diagnostic accuracy of research criteria for prodromal frontotemporal dementia.

Benussi, Alberto / Premi, Enrico / Grassi, Mario / Alberici, Antonella / Cantoni, Valentina / Gazzina, Stefano / Archetti, Silvana / Gasparotti, Roberto / Fumagalli, Giorgio G / Bouzigues, Arabella / Russell, Lucy L / Samra, Kiran / Cash, David M / Bocchetta, Martina / Todd, Emily G / Convery, Rhian S / Swift, Imogen / Sogorb-Esteve, Aitana / Heller, Carolin /

van Swieten, John C / Jiskoot, Lize C / Seelaar, Harro / Sanchez-Valle, Raquel / Moreno, Fermin / Laforce, Robert Jr / Graff, Caroline / Synofzik, Matthis / Galimberti, Daniela / Rowe, James B / Masellis, Mario / Tartaglia, Maria Carmela / Finger, Elizabeth / Vandenberghe, Rik / Mendonça, Alexandre / Tiraboschi, Pietro / Butler, Chris R / Santana, Isabel / Gerhard, Alexander / Le Ber, Isabelle / Pasquier, Florence / Ducharme, Simon / Levin, Johannes / Sorbi, Sandro / Otto, Markus / Padovani, Alessandro / Rohrer, Jonathan D / Borroni, Barbara

Alzheimer's research & therapy

2024 Volume 16, Issue 1, Page(s) 10

Abstract: Background: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the ... ...

Abstract	Background: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. Methods: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. Results: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). Conclusions: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.
MeSH term(s)	Humans ; Frontotemporal Dementia/diagnosis ; Frontotemporal Dementia/genetics ; Neurofilament Proteins ; Biomarkers ; Atrophy
Chemical Substances	Neurofilament Proteins ; Biomarkers
Language	English
Publishing date	2024-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-024-01383-1
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Article ; Online: Fluid biomarkers in frontotemporal dementia: past, present and future.

Swift, Imogen Joanna / Sogorb-Esteve, Aitana / Heller, Carolin / Synofzik, Matthis / Otto, Markus / Graff, Caroline / Galimberti, Daniela / Todd, Emily / Heslegrave, Amanda J / van der Ende, Emma Louise / Van Swieten, John Cornelis / Zetterberg, Henrik / Rohrer, Jonathan Daniel

Journal of neurology, neurosurgery, and psychiatry

2020 Volume 92, Issue 2, Page(s) 204–215

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Biomarkers/blood ; Biomarkers/cerebrospinal fluid ; Diagnosis, Differential ; Forecasting ; Frontotemporal Dementia/blood ; Frontotemporal Dementia/cerebrospinal fluid ; Frontotemporal Dementia/diagnosis ; Humans
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-11-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3087-9
ISSN	1468-330X ; 0022-3050
ISSN (online)	1468-330X
ISSN	0022-3050
DOI	10.1136/jnnp-2020-323520
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Article ; Online: Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

Brain : a journal of neurology

2021 Volume 144, Issue 10, Page(s) 2964–2970

Abstract: 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 ... ...

Abstract	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 < 0.001) and non-carriers (P < 0.001); higher Aβ38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P < 0.001). Amyloid-β profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aβ42:38, Aβ42:40 and Aβ38:40 ratios and parental age at onset. In vivo differences in amyloid-β processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.
MeSH term(s)	Adult ; Alzheimer Disease/blood ; Alzheimer Disease/diagnosis ; Alzheimer Disease/genetics ; Amyloid beta-Peptides/blood ; Amyloid beta-Peptides/genetics ; Biomarkers/blood ; Cohort Studies ; Cross-Sectional Studies ; Female ; Genotype ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Presenilin-1/blood ; Presenilin-1/genetics
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; PSEN1 protein, human ; Presenilin-1
Language	English
Publishing date	2021-04-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awab166
Database	MEDical Literature Analysis and Retrieval System OnLINE

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