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@INPROCEEDINGS{Kasper:1005587,
      author       = {Kasper, Jan and Caspers, Svenja and Lotter, Leon and
                      Hoffstaedter, Felix and Eickhoff, Simon and Dukart, Jürgen},
      title        = {{B}rain function neurotransmitter co localization:
                      {E}ffects of aging and deviations in {P}arkinson’s
                      disease},
      reportid     = {FZJ-2023-01546},
      year         = {2023},
      abstract     = {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<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.},
      month         = {Apr},
      date          = {2023-04-04},
      organization  = {General Assembly of the Joint Lab
                       Supercomputing and Modeling for the
                       Human Brain, Jülich (Germany), 4 Apr
                       2023 - 5 Apr 2023},
      subtyp        = {After Call},
      cin          = {INM-7 / INM-1},
      cid          = {I:(DE-Juel1)INM-7-20090406 / I:(DE-Juel1)INM-1-20090406},
      pnm          = {5251 - Multilevel Brain Organization and Variability
                      (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5251},
      typ          = {PUB:(DE-HGF)6},
      doi          = {10.34734/FZJ-2023-01546},
      url          = {https://juser.fz-juelich.de/record/1005587},
}