2025-11-06

101_ Proteomic blood biomarker signature for prediction of poor clinical outcome in affective and non-affective Psychosis: Pilot Study (Amendment to 063)

Research Question and Aims

The aim of the proposed analysis is to measure proven blood biomarkers of neuronal damage and microglial activation (neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)) using 4th-generation immunoassays (single-molecule array, Simoa) [Khalil 2018] in a longitudinal and transdiagnostic approach within the PsyCourse Study. NfL levels in blood plasma and cerebrospinal fluid (CSF) are highly correlated [Mielke 2019]. Elevated plasma NfL is a prognostic marker of short-term cognitive decline and associated with decline in hippocampal volume, cortical thickness, fractional anisotropy (FA) in the corpus callosum and global cognition in healthy older adults [Mielke 2019]. GFAP is a component of the astrocyte cytoskeleton and relevant for the structural and functional integrity of astrocytes and may be even better detectable in in the peripheral blood than in cerebrospinal fluid and reflect changes of the central nervous system. It is involved in many processes in the central nervous system like cell communication and functioning of the blood brain barrier, which have been described as impaired in neuropsychiatric disorders [Garden 2016][Kealy 2020]. Glial-mediated processes of inflammation are also coming increasingly to the fore in psychiatric disorders such as, in particular, schizophrenia and affective psychoses [Watkins 2014][Jeppesen 2022]. Increasingly, glial-mediated pathways of inflammation are becoming the focus of the development of new innovative drugs. For this reason, it is important to identify which patients suffer from glial-mediated neuroinflammation as well as which patients might respond to glial-mediated therapy. Since it is currently not possible to measure all PsyCourse participants without research funding, we have decided on the following approach for our pilot study:
We have identified 40 patients in the PsyCourse Study whose performance in Verbal Learning (cognitive test: VLMT) declined over a one-year observation period (comparing visit 2 and visit 4). We then matched a comparison group of patients who improved in Verbal Learning over the same one-year period with respect to age, sex, diagnosis and medication (number of antidepressant and number of antipsychotics). These two subsamples will be compared cross-sectionally and, even more important, longitudinally where are each patient can act as his or her own control. Secondary analyses will compare other cognitive tests in this subsample, and analyze possible relations to NfL and GFAP levels.
ADDENDUM:
Longitudinal NfL- and GFAP-Analysis of the selected patients revealed a subgroup of schizophrenia patients with a worse outcome and significant elevated products of fold changes of NfL and GFAP. However, outliers with a high product occurred also in single patients who suffer from schizoaffective or bipolar disorder. Our aim is to perform additional exploratory analyses to analyze available phenotypic information of this (transdiagnostic) subgroup more precisely. Specifically, we are interested to examine the following types of variables:
• Demographic information
• Illness history
• Medication (both cross-sectional and longitudinal)
• Physical measures and somatic diseases (both cross-sectional and longitudinal, where available)
• Substance abuse (both cross-sectional and longitudinal)
• Illness episodes between study visits
Please also see the added analysis report of the company “MicroDiscovery” we collaborated with for these analyses.

Analytic Plan

We will perform inhouse measurement of two plasma blood biomarkers (NfL and GFAP) with ultra-sensitive SIMOA® technology using the “Human Neurology 2-Plex” assay. Measurements will be twofold on the same Duplex plates.

The hypotheses of the primary analyses would be:
a) both groups differ significantly in cross-sectional blood concentrations of NfL and GFAP, and
b) in the group with a decrease in cognitive performance there is also an increase (NfL) or decrease (GFAP) in the measured parameters associated with cognitive performance.

In secondary analyses it will be tested if the plasma blood biomarkers are associated with the magnitude of cognitive decline.

ADDENDUM:
in addition to the detailed examination of the phenotype of the schizophrenia subgroup with a high product we will focus on the product itself as a continuous variable. Especially we will look into the extent to which there is a confounder of the product (e.g. kidney dysfunction, diabetes mellitus, and substance abuse (especially alcohol use disorder)) or which cognitive functions correlate most closely with the level of the product. Because dividing the data into quartiles or quantiles tends to lead to unclear statements, the decision was taken to treat the product of NfL and GFAP as a continuous variable.

Resources needed

v1_seas_birth
v1_age_m_birth
v1_age_f_birth
v1_cntr_brth
v1_outpat_psy_trm
v1_age_1st_out_trm
v1_daypat_inpat_trm
v1_age_1st_inpat_trm
v1_1st_ep
v1_cat_daypat_outpat_trm
v1_medchange
v1_lith
v1_lith_prd
v1_height
v1_weight
v1_waist
v1_bmi
v1_chol_trig
v1_hyperten
v1_ang_pec
v1_heart_att
v1_stroke
v1_diabetes
v1_hyperthy
v1_hypothy
v1_osteopor
v1_asthma
v1_copd
v1_allerg
v1_neuroder
v1_psoriasis
v1_autoimm
v1_cancer
v1_stom_ulc
v1_kid_fail
v1_stone
v1_epilepsy
v1_migraine
v1_parkinson
v1_liv_cir_inf
v1_tbi
v1_beh
v1_eyear
v1_inf
v1_ever_smkd
v1_age_smk
v1_no_cig
v1_alc_pst12_mths
v1_alc_5orm
v1_lftm_alc_dep
v1_evr_ill_drg
v1_sti_cat_evr
v1_can_cat_evr
v1_opi_cat_evr
v1_kok_cat_evr
v1_hal_cat_evr
v1_inh_cat_evr
v1_tra_cat_evr
v1_var_cat_evr
v1_evr_hvy_usr
v1_pst6_ill_drg
v2_interv_date
v2_clin_ill_ep_snc_lst
v2_clin_no_ep
v2_weight
v2_waist
v2_bmi
v2_medchange
v2_lith
v2_lith_prd
v2_smk_strt_stp
v2_no_cig
v2_alc_pst6_mths
v2_alc_5orm
v2_pst6_ill_drg
v4_interv_date
v4_clin_ill_ep_snc_lst
v4_clin_no_ep
v4_weight
v4_bmi
v4_waist
v4_medchange
v4_lith
v4_lith_prd
v4_smk_strt_stp
v4_no_cig
v4_alc_pst6_mths
v4_alc_5orm
v4_pst6_ill_drg