Brain function neurotransmitter co localization: Effects of aging and deviations in Parkinson’s disease
Creators: name: Kasper, Jan
name: Caspers, Svenja
name: Lotter, Leon
name: Hoffstaedter, Felix
name: Eickhoff, Simon
name: Dukart, Jürgen
Publisher: name: Forschungzentrum Jülich
Year: 2023

description: General Assembly of the Joint Lab Supercomputing and Modeling for the Human Brain, Jülich, Germany, 4 Apr 2023 - 5 Apr 2023
description: Neurodegenerative diseases exhibit a specific spatial pattern of altered brain activity as capturedby resting-state fMRI[1]. In Parkinson’s disease (PD), areas with the most severe alterations inbrain activity co-localize with higher density of specific neurotransmitter systems[2], indicatingincreased vulnerability of respective neural cell populations. Such vulnerability may also be reflectedin a deviation from normal associations between brain activity and specific neurotransmittersystems. Here, we test this hypothesis by computing normative models of co-localization ofneurotransmitter systems and brain activity in a large cohort of healthy subjects. We then examinedeviations from these models in PD.We computed individual maps of voxel-wise (3 mm^3) brain activity at rest (fractional amplitudeof low-frequency fluctuations, fALFF; local correlation, LCOR) and connectivity measures (globalcorrelation, GCOR) of 25,917 healthy subjects (age: mean ± SD, range: 64 ± 7.5, [44 – 82]; 46% male)from the UK-Biobank. Individual levels of co-localization (Fisher’s z(Spearman ρ)) of all threemeasures and 19 neurotransmitter systems (dopamine, serotonin, norepinephrine, acetylcholine,glutamate, cannabinoid, opioid, and GABA) were obtained by spatial correlation analyses. Effectsof aging and sex differences in these levels were identified via linear regression and two-samplet-tests. We modeled the level of co-localization with age and sex as covariates using Bayesianlinear regression implemented in the PCNtoolkit[3]. Deviations (z-scores) from these models werecalculated for patients with PD (n=58, age[yr]: 68 ± 6.5, [52-80]; male:55%, from UKBiobank) andexamined for correlations with disease duration. For interpretation of aging effects, voxel-wiselinear effects of aging in all three measures were also examined for associations with specificneurotransmitter systems. All analyses were corrected for multiple comparisons (pcorr&lt;0.05).The spatial distribution of serotonergic, dopaminergic, glutamatergic, opioid, and GABAergic systemsexplained more than 5 % in fALFF, LCOR, and GCOR variance. Co-localization levels of allthree measures changed significantly with age (maximum explained variance: 4.6%) and showedsex differences (maximum Cohen’s d: 0.38) in most of the systems. Patients with PD exhibitedsignificantly lower co-localizations (z-range:-0.26 to -0.64) regarding all measures with 5-HT1b,5-HT6, D1, D2, GABAa, H3, M1, mGluR5, NMDA, and transporters of dopamine, serotonin, norepinephrineand acetylcholine. Deviation from LCOR-GABAa association was correlated with diseaseduration (pFDR=0.027, r=-0.38). Figure 1 shows representative models. Wide-spread agerelatedalteration in all three measures were found in the healthy population. For fALFF, thevoxel-wise age-effects were associated with the availability of norepinephrine transporters, 5-HT4,5-HT6, D2, GABAa, and NMDA. For LCOR, associations were found with NMDA and transportersof norepinephrine, dopamine, serotonin, and acetylcholine availability, and for GCOR with thetransporter of norepinephrine.Here, we find that the co-localization of resting-state activity estimates with neurotransmitter systemsfollows sex-specific patterns during healthy aging and that patients with PD deviate from thisnormative development in dopaminergic, serotonergic, norepinephrine, GABAergic, histaminergic,acetylcholinergic, and glutamatergic systems. Given that all of the indicated transmitter systemsare affected in PD[4–16], these findings suggest that rs-fMRI-neurotransmitter co-localizationmay indeed reflect individual and neurotransmitter specific neuropathology, necessitating furtherresearch into the value of cross-modal brain-wide co-localization estimates as PD biomarkers.