TY - JOUR
T1 - Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease
AU - Lin, Chen-Pei
AU - Knoop, Lydian E. J.
AU - Frigerio, Irene
AU - Bol, John G. J. M.
AU - Rozemuller, Annemieke J. M.
AU - Berendse, Henk W.
AU - Pouwels, Petra J. W.
AU - van de Berg, Wilma D. J.
AU - Jonkman, Laura E.
N1 - Funding Information: We thank all brain donors and their caregivers for donating their brain to scientific research, as well as the Netherlands Brain Bank (www.brainbank.nl) and the Normal Aging Brain Collection Amsterdam (www.nabca.eu) MRI and autopsy teams. Special thanks to Angela Ingrassia and Allert Jonker for helping in the lab with the immunohistochemical staining. Funding Information: This work was supported by The Micheal J. Fox Foundation (Grant ID: 17253). Funding Agency: Funding Information: No disclosures for C.P.L, L.E.J.K, I.F, J.G.J.M.B, A.J.M.R and P.J.W.P. H.W.B receives grants from The Michael J. Fox Foundation and The Netherlands Organization for Health Research (ZonMw 460001001). W.D.J.v.d.B receives grants from Amsterdam Neuroscience, The Netherlands Organization for Health Research (ZonMW 70‐73305‐98‐106; 70‐73305‐98‐102; 40‐46000‐98‐101), Stichting Parkinson Fonds (Insula 2014), Alzheimer association (AARF‐18‐566459), The Michael J. Fox Foundation (17253; 022468), and Parkinson Association (2020‐G01); and performed contract research and consultancy for Hoffmann‐La Roche, Roche Tissue Diagnostics, Crossbeta Sciences, Discoveric Bio, and received research consumables from Hoffmann‐La Roche and Prothena. L.E.J receives grant from Alzheimer's Association, Alzheimer Nederland, Dutch Research Council (NWO), The Michael J. Fox Foundation for Parkinson's research, Stichting Parkinson Fonds, Top Sector Life Sciences and Health, and The Netherlands Organization for Health Research (ZonMW). Publisher Copyright: © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PY - 2023/9
Y1 - 2023/9
N2 - Background: Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood. Objective: To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD. Methods: Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively. Results: Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load. Conclusions: In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology.
AB - Background: Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood. Objective: To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD. Methods: Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively. Results: Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load. Conclusions: In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology.
KW - Parkinson's disease
KW - diffusion MRI
KW - histopathology
KW - post-mortem
KW - substantia nigra
UR - http://www.scopus.com/inward/record.url?scp=85162733691&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/mds.29510
DO - https://doi.org/10.1002/mds.29510
M3 - Article
C2 - 37347552
SN - 0885-3185
VL - 38
SP - 1655
EP - 1667
JO - Movement disorders
JF - Movement disorders
IS - 9
ER -