CSF pro-orexin and amyloid-β38 expression in Alzheimer's disease and frontotemporal dementia

Heywood, Wendy; Hällqvist, Jenny; Heslegrave, Amanda; Zetterberg, Henrik; Fenoglio, Chiara; Scarpini, Elio; Rohrer, Jonathan D.; Galimberti, Daniela; Mills, Kevin

doi:10.1016/j.neurobiolaging.2018.08.019

Cited by 27 publications

(15 citation statements)

References 37 publications

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“…Within the AD cohort, besides impairment of the neuronally produced forms, it is conceivable that production of secretory proteins by activated astrocytes increases as neuronal damage worsens [ 29 , 45 , 51 , 69 ]. Furthermore, the connection of secretory proteins with neurodegeneration, but not with amyloid plaque pathology, is consistent with recent proteomic studies in non-AD neurodegenerative diseases, such as frontotemporal dementia, where a decline of CgA, VGF and CysC occurs in the CSF of patients [ 84 – 86 ].…”

Section: Discussionsupporting

confidence: 86%

Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Barranco

Plá

Alcolea

et al. 2021

Transl Neurodegener

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Background New fluid biomarkers for Alzheimer's disease (AD) that reveal synaptic and neural network dysfunctions are needed for clinical practice and therapeutic trial design. Dense core vesicle (DCV) cargos are promising cerebrospinal fluid (CSF) indicators of synaptic failure in AD patients. However, their value as biomarkers has not yet been determined. Methods Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2, carboxypeptidase E (CPE), secretogranins SgIII and SgII, and Cystatin C in the cerebral cortex (n = 45, provided by Bellvitge University Hospital) and CSF samples (n = 66, provided by The Sant Pau Initiative on Neurodegeneration cohort) from AD patients (n = 56) and age-matched controls (n = 55). Results In AD tissues, most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astrocytes, whereas PC1/3, PC2 and CPE were also specifically accumulated in hippocampal granulovacuolar degeneration bodies. AD individuals displayed an overall decline of secretory proteins in the CSF. Interestingly, in AD patients, the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status. Conclusions These results demonstrate marked alterations of neuronal-specific prohormone convertases in CSF and cortical tissues of AD patients. The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.

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Section: Discussionsupporting

confidence: 86%

Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Barranco

Plá

Alcolea

et al. 2021

Transl Neurodegener

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“…The finding of abnormal proinflammatory eicosanoids in GRN mutation carriers is consistent with previous studies showing that inflammation plays a major role in this form of FTD [5,20]. In CSF, abnormalities have previously been shown in microglial activation markers [21][22][23][24], chemokines and cytokines [20,25], and complement proteins [26]. Here, we add to these findings, suggesting a further biomarker that may be useful in disease modifying trials -lowering of the concentrations of the proinflammatory eicosanoids may help to show a therapeutic effect in GRN-related FTD with improvement of chronic neuroinflammation, although more validation work would need to be done in the first instance.…”

Section: Discussionsupporting

confidence: 92%

Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation

Sogorb‐Esteve

Colas

Dalli

et al. 2021

JAD

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Background: The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective: We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods: 15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results: Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion: This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher).

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“…As an aside, one interesting point of note that has arisen from these studies has been the finding that A species including A38, A40 and sAPP are commonly lowered in FTD compared with controls [26][27][28][29][30][31][32] , with the reason for this remaining unclear at present.…”

Section: Differentiating Ftd From Other Dementias and From Non-degenementioning

confidence: 99%

Fluid biomarkers in frontotemporal dementia: past, present and future

Swift

Sogorb‐Esteve

Heller

et al. 2020

J Neurol Neurosurg Psychiatry

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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.

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CSF pro-orexin and amyloid-β38 expression in Alzheimer's disease and frontotemporal dementia

Cited by 27 publications

References 37 publications

Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation

Fluid biomarkers in frontotemporal dementia: past, present and future

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