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Cortical distribution of neurofilaments associates with pathological hallmarks and MRI measures of atrophy and diffusivity in Parkinson’s disease

View ORCID ProfileIrene Frigerio, View ORCID ProfileMax A Laansma, Chen-Pei Lin, Emma JM Hermans, Maud MA Bouwman, John GJM Bol, Yvon Galis-de Graaf, Dagmar H Hepp, Annemieke JM Rozemuller, View ORCID ProfileFrederik Barkhof, View ORCID ProfileWilma DJ van de Berg, View ORCID ProfileLaura E Jonkman
doi: https://doi.org/10.1101/2022.08.10.503440
Irene Frigerio
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
2Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands
3Amsterdam Neuroscience, Brain imaging, Amsterdam, The Netherlands
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  • For correspondence: i.frigerio@amsterdamumc.nl
Max A Laansma
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
3Amsterdam Neuroscience, Brain imaging, Amsterdam, The Netherlands
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Chen-Pei Lin
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
2Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands
3Amsterdam Neuroscience, Brain imaging, Amsterdam, The Netherlands
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Emma JM Hermans
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
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Maud MA Bouwman
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
2Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands
3Amsterdam Neuroscience, Brain imaging, Amsterdam, The Netherlands
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John GJM Bol
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
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Yvon Galis-de Graaf
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
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Dagmar H Hepp
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
4Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Neurology, De Boelelaan 1117, Amsterdam, Netherlands
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Annemieke JM Rozemuller
5Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pathology, De Boelelaan 1117, Amsterdam, Netherlands
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Frederik Barkhof
3Amsterdam Neuroscience, Brain imaging, Amsterdam, The Netherlands
6Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, De Boelelaan 1117, Amsterdam, Netherlands
7University College London, Institutes of Neurology and Healthcare Engineering, London, United Kingdom
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Wilma DJ van de Berg
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
2Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands
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Laura E Jonkman
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1118, Amsterdam, Netherlands
2Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands
3Amsterdam Neuroscience, Brain imaging, Amsterdam, The Netherlands
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Abstract

Increased neurofilament levels in biofluids, commonly used as a proxy for axonal degeneration in the brain, have been found in Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB), and correlate with MRI biomarkers. The aim of the current study was to unravel the regional distribution of cortical neurofilaments and their association with pathology load and MRI measures of atrophy and diffusivity in the post-mortem brain.

Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pSer129 alpha-synuclein (pSer129-αSyn), p-tau, and amyloid-beta, together with neurofilament light-chain (NfL) and phosphorylated neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in 7 cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models.

Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was mainly increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. Increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.

Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increasing pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Section "Pathology image processing" in Methods clarifies the segmentation of entorhinal, parahippocampal and fusiform cortex.

  • Abbreviations

    Aβ
    amyloid-beta
    AD
    Alzheimer’s disease
    CSF
    cerebrospinal fluid
    DLB
    dementia with Lewy bodies
    DTI
    diffusion tensor imaging
    FDR
    false discovery rate
    FWC-MD
    free-water corrected mean diffusivity
    IHC
    immunohistochemistry
    LB
    Lewy body
    MD
    mean diffusivity
    NfL
    neurofilament light chain
    NFT
    neurofibrillary tangles
    PD
    Parkinson’s disease
    PDD
    Parkinson’s disease dementia
    p-NfM/H
    phosphorylated neurofilament medium and heavy chain
    p-tau
    phosphorylated-tau
    pSer129-αSyn
    phosphorylated Ser129 alpha synuclein
  • Copyright 
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    Posted August 15, 2022.
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    Cortical distribution of neurofilaments associates with pathological hallmarks and MRI measures of atrophy and diffusivity in Parkinson’s disease
    Irene Frigerio, Max A Laansma, Chen-Pei Lin, Emma JM Hermans, Maud MA Bouwman, John GJM Bol, Yvon Galis-de Graaf, Dagmar H Hepp, Annemieke JM Rozemuller, Frederik Barkhof, Wilma DJ van de Berg, Laura E Jonkman
    bioRxiv 2022.08.10.503440; doi: https://doi.org/10.1101/2022.08.10.503440
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    Cortical distribution of neurofilaments associates with pathological hallmarks and MRI measures of atrophy and diffusivity in Parkinson’s disease
    Irene Frigerio, Max A Laansma, Chen-Pei Lin, Emma JM Hermans, Maud MA Bouwman, John GJM Bol, Yvon Galis-de Graaf, Dagmar H Hepp, Annemieke JM Rozemuller, Frederik Barkhof, Wilma DJ van de Berg, Laura E Jonkman
    bioRxiv 2022.08.10.503440; doi: https://doi.org/10.1101/2022.08.10.503440

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