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Fluid Biomarkers in Frontotemporal Dementia: Past, Present and Future

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Fluid Biomarkers in Frontotemporal Dementia: Past, Present and Future Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-323520 on 13 November 2020. Downloaded from Review Fluid biomarkers in frontotemporal dementia: past, present and future Imogen Joanna Swift ,1 Aitana Sogorb- Esteve,1,2 Carolin Heller ,1 Matthis Synofzik,3,4 Markus Otto ,5 Caroline Graff,6,7 Daniela Galimberti ,8,9 Emily Todd,2 Amanda J Heslegrave,1 Emma Louise van der Ende ,10 John Cornelis Van Swieten ,10 Henrik Zetterberg,1,11 Jonathan Daniel Rohrer 2 ► Additional material is ABSTRACT into a behavioural form (behavioural variant fron- published online only. To view, The frontotemporal dementia (FTD) spectrum of totemporal dementia (bvFTD)), a language variant please visit the journal online (primary progressive aphasia (PPA)) and a motor (http:// dx. doi. org/ 10. 1136/ neurodegenerative disorders includes a heterogeneous jnnp- 2020- 323520). group of conditions. However, following on from a series presentation (either FTD with amyotrophic lateral of important molecular studies in the early 2000s, major sclerosis (FTD- ALS) or an atypical parkinsonian For numbered affiliations see advances have now been made in the understanding disorder). Neuroanatomically, the FTD spectrum end of article. of the pathological and genetic underpinnings of the is characteristically associated with dysfunction and disease. In turn, alongside the development of novel neuronal loss in the frontal and temporal lobes, but Correspondence to more widespread cortical, subcortical, cerebellar Dr Jonathan Daniel Rohrer, methodologies for measuring proteins and other Dementia Research molecules in biological fluids, the last 10 years have and brainstem involvement is now recognised. Centre, Department of seen a huge increase in biomarker studies within FTD. Genetically, around a third of FTD is familial with Neurodegenerative Disease, This recent past has focused on attempting to develop autosomal dominant mutations in three genes UCL Queen Square Institute of markers that will help differentiate FTD from other accounting for most of the inheritance: progran- Neurology, London WC1N 3BG, UK; j. rohrer@ ucl. ac. uk dementias (particularly Alzheimer’s disease (AD)), as ulin (GRN), chromosome 9 open reading frame 72 well as from non- neurodegenerative conditions such (C9orf72) and microtubule- associated protein tau Received 5 August 2020 2 as primary psychiatric disorders. While cerebrospinal (MAPT). Lastly, pathologically, cellular inclusions copyright. Revised 3 October 2020 fluid, and more recently blood, markers of AD have containing abnormal forms of tau, TDP-43 or FET Accepted 3 October 2020 proteins are found in the majority of people with Published Online First 13 been successfully developed, specific markers identifying November 2020 primary tauopathies or TDP-43 proteinopathies are an FTD syndrome. The interaction between clinical still lacking. More focus at the moment has been phenotype, neuroanatomy, genotype and pathology on non- specific markers of neurodegeneration, and is complex (figure 1) and means that FTD can be in particular, multiple studies of neurofilament light hard to diagnose (particularly its specific patho- chain have highlighted its importance as a diagnostic, logical form during life) and difficult to track over prognostic and staging marker of FTD. As clinical time. trials get under way in specific genetic forms of FTD, One way that researchers have aimed to solve measures of progranulin and dipeptide repeat proteins some of these outstanding issues in the FTD field in biofluids have become important potential measures has been to develop fluid biomarkers, and there of therapeutic response. However, understanding has been a growing literature in recent years inves- http://jnnp.bmj.com/ of whether drugs restore cellular function will also tigating new cerebrospinal fluid (CSF) or blood be important, and studies of key pathophysiological measures in people with FTD. This review aimed processes, including neuroinflammation, lysosomal to set out what has been done so far, where we are function and synaptic health, are also now becoming at present and what we still need to achieve in the more common. There is much still to learn in the future within the FTD fluid biomarker research fluid biomarker field in FTD, but the creation of large world. This is particularly important in a time when multinational cohorts is facilitating better powered potential therapies have now been developed and on September 24, 2021 by guest. Protected studies and will pave the way for larger omics studies, clinical trials have started. including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other CLASSIFICATION AND USE OF BIOMARKERS IN domains. Here we provide an overview of the past, FTD present and future of fluid biomarkers within the FTD Fluid biomarkers, measured typically in CSF, serum or plasma (box 1) using a variety of different tech- © Author(s) (or their field. employer(s)) 2021. No niques (box 2), are objective indicators of normal commercial re-use . See rights or pathological biological processes or pharmaco- and permissions. Published logical responses to a therapeutic intervention. In by BMJ. INTRODUCTION FTD, biomarkers can be classified in a number of To cite: Swift IJ, Sogorb- The frontotemporal dementia (FTD) spectrum ways: Esteve A, Heller C, et al. J encompasses a group of conditions that overlap in ► Diagnostic, including distinguishing FTD Neurol Neurosurg Psychiatry their clinical, neuroanatomical, genetic and patho- versus non- neurodegenerative disorders and 2021;92:204–215. logical features.1 Clinically, FTD can be divided FTD versus Alzheimer’s disease (AD) or other 204 Swift IJ, et al. J Neurol Neurosurg Psychiatry 2021;92:204–215. doi:10.1136/jnnp-2020-323520 Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-323520 on 13 November 2020. Downloaded from KEY: Genetics TAU FTD-ALS Box 1 Biosamples TDP-43 Pathology FET UPS Cerebrospinal fluid (CSF) surrounds the brain and spinal bvFTD PPA-NOS svPPA nfvPPA cord, coming into direct contact with the extracellular space. lvPPA CBS PSP-RS Clinical Syndromes It is therefore the most effective biological fluid to measure FTD-ALS biochemical changes in brain tissue. However, in recent years, D nfvPPA FTD-ALS there has been an increasing focus on biomarkers in blood (plasma or serum), which forms a less invasive and more accessible alternative. Unfortunately, studies of blood-based biomarkers involve overcoming a number of challengesS1: first, the marker needs to be able to cross the blood–brain barrier (BBB), and if the marker is non-specific to the central FTD-ALS nervous system, there is a risk of peripheral contamination; Figure 1 Clinical–pathological–genetic correlations in the FTD second, numerous other blood- based proteins and heterophilic spectrum. The innermost part of the circle depicts the genetic causes antibodies, which are higher in blood than CSF, are likely to of FTD. The middle part depicts the different pathological forms: PiD, interfere with measurements; and finally, preanalytical factors, PSP, CBD, MAPT, GGT, UPS, BIBD, NIFID and aFTLDU. The outermost such as food intake or diurnal variation, need to be considered part of the circle represents the clinical diagnoses associated with each as these may be more relevant in blood. Fortunately, recent pathology—the largest font being the most common syndrome, the technological developments, such as Single molecule array medium font being syndromes less commonly seen and the smallest font (Simoa) technology (detailed further in box 2), allow for more being rare phenotypes. aFTLDU, atypical FTLD with ubiquitin inclusions; sensitive assays, eliminating many of these challenges. One ALS, amyotrophic lateral sclerosis; BIBD, basophilic inclusion body disease; other potential way of improving peripheral identification of bvFTD, behavioural variant FTD; CBD, corticobasal degeneration; CBS, neuronally derived biomarkers is through the measurement corticobasal syndrome; FTD, frontotemporal dementia; GGT, globular glial of proteins within exosomes.S2 These are small extracellular tauopathy; lv, logopenic variant; MAPT, pathology associated with MAPT vesicles, released by cells, including within the brain, and able mutations; nfv, nonfluent variant; NIFID, neuronal intermediate filament to cross the BBB, suggesting that measurement of their content inclusion disease; NOS, not otherwise specified; PiD, Pick’s disease; PPA, in blood (as well as in CSF) may well represent central nervous primary progressive aphasia; PSP, progressive supranuclear palsy; RS, system processes.S3 Technology is now available to extract Richardson’s syndrome; sv, semantic variant; UPS, ubiquitin–proteasome neuronal exosomes within blood,S4 making them an important system. prospect for future studies. Lastly, other body fluids poorly copyright. studied as potential sources of biomarkers in frontotemporal S5 S6 dementias, as well as identifying the particular pathological dementia are urine or saliva, and future studies would benefit form of FTD. from investigating these further. ► Prognostic, allowing prediction of likely disease course and survival. ► Staging, including particularly for the genetic forms of FTD, whether someone is presymptomatic, nearing symptom exclusionary diagnostic criterion) and PPA, where the logopenic onset (proximity markers) or phenoconverting. variant is usually
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