Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease

Chen-Pei Lin; Irene Frigerio; John G J M Bol; Maud M A Bouwman; Alex J Wesseling; Martin J Dahl; Annemieke J M Rozemuller; Ysbrand D van der Werf; Petra J W Pouwels; Wilma D J van de Berg; Laura E Jonkman

doi:10.1186/s40035-024-00400-5

Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease

Chen-Pei Lin, Irene Frigerio, John G J M Bol, Maud M A Bouwman, Alex J Wesseling, Martin J Dahl, Annemieke J M Rozemuller, Ysbrand D van der Werf, Petra J W Pouwels, Wilma D J van de Berg, Laura E Jonkman

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Abstract

BACKGROUND: Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer's disease (AD) and Parkinson's disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.

METHODS: Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.

RESULTS: The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity.

CONCLUSIONS: In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.

Original language	English
Article number	9
Pages (from-to)	9
Journal	Translational Neurodegeneration
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s40035-024-00400-5
Publication status	Published - Dec 2024

Keywords

Alzheimer’s disease
Diffusion MRI
Histopathology
Locus coeruleus
Noradrenergic degeneration
Parkinson’s disease
Post-mortem

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10.1186/s40035-024-00400-5

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Lin, C.-P., Frigerio, I., Bol, J. G. J. M., Bouwman, M. M. A., Wesseling, A. J., Dahl, M. J., Rozemuller, A. J. M., van der Werf, Y. D., Pouwels, P. J. W., van de Berg, W. D. J., & Jonkman, L. E. (2024). Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease. Translational Neurodegeneration, 13(1), 9. Article 9. https://doi.org/10.1186/s40035-024-00400-5

@article{08b4042a7f354b079e733f128156104e,

title = "Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease",

abstract = "BACKGROUND: Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer's disease (AD) and Parkinson's disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.METHODS: Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.RESULTS: The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity.CONCLUSIONS: In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.",

keywords = "Alzheimer{\textquoteright}s disease, Diffusion MRI, Histopathology, Locus coeruleus, Noradrenergic degeneration, Parkinson{\textquoteright}s disease, Post-mortem",

author = "Chen-Pei Lin and Irene Frigerio and Bol, {John G J M} and Bouwman, {Maud M A} and Wesseling, {Alex J} and Dahl, {Martin J} and Rozemuller, {Annemieke J M} and {van der Werf}, {Ysbrand D} and Pouwels, {Petra J W} and {van de Berg}, {Wilma D J} and Jonkman, {Laura E}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s40035-024-00400-5",

language = "English",

volume = "13",

pages = "9",

journal = "Translational Neurodegeneration",

issn = "2047-9158",

publisher = "BioMed Central",

number = "1",

}

Lin, C-P , Frigerio, I , Bol, JGJM , Bouwman, MMA , Wesseling, AJ, Dahl, MJ, Rozemuller, AJM , van der Werf, YD , Pouwels, PJW , van de Berg, WDJ & Jonkman, LE 2024, 'Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease', Translational Neurodegeneration, vol. 13, no. 1, 9, pp. 9. https://doi.org/10.1186/s40035-024-00400-5

TY - JOUR

T1 - Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease

AU - Lin, Chen-Pei

AU - Frigerio, Irene

AU - Bol, John G J M

AU - Bouwman, Maud M A

AU - Wesseling, Alex J

AU - Dahl, Martin J

AU - Rozemuller, Annemieke J M

AU - van der Werf, Ysbrand D

AU - Pouwels, Petra J W

AU - van de Berg, Wilma D J

AU - Jonkman, Laura E

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/12

Y1 - 2024/12

N2 - BACKGROUND: Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer's disease (AD) and Parkinson's disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.METHODS: Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.RESULTS: The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity.CONCLUSIONS: In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.

AB - BACKGROUND: Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer's disease (AD) and Parkinson's disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.METHODS: Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.RESULTS: The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity.CONCLUSIONS: In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.

KW - Alzheimer’s disease

KW - Diffusion MRI

KW - Histopathology

KW - Locus coeruleus

KW - Noradrenergic degeneration

KW - Parkinson’s disease

KW - Post-mortem

UR - http://www.scopus.com/inward/record.url?scp=85185132073&partnerID=8YFLogxK

U2 - 10.1186/s40035-024-00400-5

DO - 10.1186/s40035-024-00400-5

M3 - Article

C2 - 38336865

SN - 2047-9158

VL - 13

SP - 9

JO - Translational Neurodegeneration

JF - Translational Neurodegeneration

IS - 1

M1 - 9

ER -

Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease

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