Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Yousef

et al. 2021

Ann Clin Transl Neurol

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Objective: Decreased amyloid beta (Ab) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer's disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages. Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETI-ONOMY consortium. Two additional cohorts from Sweden were used for biological verification. Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Ab42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations. Interpretation: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.

Section: Discussionmentioning

confidence: 88%

“… 63 In addition, a previously in‐house developed NEFM sandwich assay showed a strong correlation to the single binder data (rho > 0.82). 52 …”

Section: Discussionmentioning

confidence: 99%

Multi‐cohort profiling reveals elevated CSF levels of brain‐enriched proteins in Alzheimer’s disease

Yousef

et al. 2021

Ann Clin Transl Neurol

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“…The transmembrane protein TMEM132D is highly expressed in the brain (60) and has been proposed to serve as an oligodendric cell surface marker (61) with cell-adhesion functions (62), although its main function still remains unknown. To our knowledge TMEM132D has not been studied in the context of AD but we previously observed altered levels in patients with frontotemporal dementia (32). Other membrane bound proteins that showed strong associations to tau were CEND1, myelin oligodendrocyte glycoprotein (MOG), PIK3IP1 and VASN, which have various functions relevant to cell-cycle regulation, cell-adhesion and T-cell activation (63)(64)(65)(66).…”

Section: Discussionmentioning

confidence: 97%

“…Read-out was done in a FlexMap3D instrument (Luminex Corporation) and results reported as median uorescence intensities per bead identity and sample, calculated from at least 30 measured beads. More detailed explanations on experimental procedures can be found elsewhere (25,32).…”

Section: Protein Pro Lingmentioning

confidence: 99%

Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds

Olofsson

et al. 2021

Preprint

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BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

“…The transmembrane protein TMEM132D is highly expressed in the brain (57) and has been proposed to serve as an oligodendric cell surface marker (58) with cell-adhesion functions (59), although its main function still remains unknown. To our knowledge TMEM132D has not been studied in the context of AD but we previously observed altered levels in patients with frontotemporal dementia (32). Other membrane bound proteins that showed strong associations to tau were CEND1, myelin oligodendrocyte glycoprotein (MOG), PIK3IP1 and VASN, which have various functions relevant to cell-cycle regulation, cell-adhesion and T-cell activation (60)(61)(62)(63).…”

Section: Discussionmentioning

confidence: 97%

Association of CSF Proteins With Tau and Amyloid β Levels in Asymptomatic 70-year-olds 

Olofsson

et al. 2020

Preprint

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BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and Aβ42 in all individuals. Sixty-three proteins showed significant correlations with either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins to CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated to or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport that were associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore their role in AD pathophysiology.