Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles

Jessica A. Noche; Hamsanandini Radhakrishnan; Margo F. Ubele; Kathy Boaz; Jennifer L. Mefford; Erin D. Jones; Hollie Y. van Rooyen; Jessica A. Perpich; Katie McCarty; Beverly Meacham; Jeffrey Smiley; Stasia A. Bembenek Bailey; László G. Puskás; David K. Powell; Lorena Sordo; Michael J. Phelan; Christopher M. Norris; Elizabeth Head; Craig E.L. Stark

doi:10.1523/JNEUROSCI.2366-23.2024

Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles

Jessica A. Noche
, Hamsanandini Radhakrishnan
, Margo F. Ubele
, Kathy Boaz
, Jennifer L. Mefford
, Erin D. Jones
, Hollie Y. van Rooyen
, Jessica A. Perpich
, Katie McCarty
, Beverly Meacham
, Jeffrey Smiley
, Stasia A. Bembenek Bailey
, László G. Puskás
, David K. Powell
, Lorena Sordo
, Michael J. Phelan
, Christopher M. Norris
, Elizabeth Head
, Craig E.L. Stark

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Aging dogs serve as a valuable preclinical model for Alzheimer’s disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

Original language	English
Article number	e2366232024
Journal	Journal of Neuroscience
Volume	44
Issue number	20
DOIs	https://doi.org/10.1523/JNEUROSCI.2366-23.2024
State	Published - May 15 2024

Bibliographical note

Publisher Copyright:
© 2024 the authors.

Funding

The study was supported by National Institutes of Health/National Institute on Aging (NIH/NIA) R01AG056998 (EH/CN/CELS). J.A.N. is supported by NIH/NIA T32AG073088. We thank Christine Lee and Elena Singh for their assistance in quality control of the imaging data. Received Dec. 15, 2023; revised Feb. 8, 2024; accepted Feb. 28, 2024. Author contributions: J.A.N., H.R., M.J.P., and C.E.L.S. analyzed data; M.F.U., K.B., J.L.M., E.D.J., J.A.P., K.M., B.M., J.S., S.A.B.B., D.K.P., and L.S. performed research; L.G.P., C.M.N., and E.H. designed research; E.H. and C.E.L.S. contributed unpublished reagents/analytic tools; J.A.N. wrote the paper. The study was supported by National Institutes of Health/National Institute on Aging (NIH/NIA) R01AG056998 (EH/CN/CELS). J.A.N. is supported by NIH/NIA T32AG073088. We thank Christine Lee and Elena Singh for their assistance in quality control of the imaging data. L.G.P.: personal financial interests, as he is the main shareholder of one of Aperus Pharma’s company shares. Correspondence should be addressed to Jessica A. Noche at [email protected]. https://doi.org/10.1523/JNEUROSCI.2366-23.2024 Copyright © 2024 the authors

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Aging	R01AG056998, T32AG073088
National Institute on Aging

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Alzheimer’s disease
Q134R
amyloid
beagle
calcineurin
neurodegeneration
prevention
tacrolimus

ASJC Scopus subject areas

General Neuroscience

Access to Document

10.1523/JNEUROSCI.2366-23.2024

Cite this

Noche, J. A., Radhakrishnan, H., Ubele, M. F., Boaz, K., Mefford, J. L., Jones, E. D., van Rooyen, H. Y., Perpich, J. A., McCarty, K., Meacham, B., Smiley, J., Bembenek Bailey, S. A., Puskás, L. G., Powell, D. K., Sordo, L., Phelan, M. J., Norris, C. M., Head, E., & Stark, C. E. L. (2024). Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles. Journal of Neuroscience, 44(20), Article e2366232024. https://doi.org/10.1523/JNEUROSCI.2366-23.2024

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title = "Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles",

abstract = "Aging dogs serve as a valuable preclinical model for Alzheimer{\textquoteright}s disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.",

keywords = "Alzheimer{\textquoteright}s disease, Q134R, amyloid, beagle, calcineurin, neurodegeneration, prevention, tacrolimus",

author = "Noche, \{Jessica A.\} and Hamsanandini Radhakrishnan and Ubele, \{Margo F.\} and Kathy Boaz and Mefford, \{Jennifer L.\} and Jones, \{Erin D.\} and \{van Rooyen\}, \{Hollie Y.\} and Perpich, \{Jessica A.\} and Katie McCarty and Beverly Meacham and Jeffrey Smiley and \{Bembenek Bailey\}, \{Stasia A.\} and Pusk{\'a}s, \{L{\'a}szl{\'o} G.\} and Powell, \{David K.\} and Lorena Sordo and Phelan, \{Michael J.\} and Norris, \{Christopher M.\} and Elizabeth Head and Stark, \{Craig E.L.\}",

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Noche, JA, Radhakrishnan, H, Ubele, MF, Boaz, K, Mefford, JL, Jones, ED, van Rooyen, HY, Perpich, JA, McCarty, K, Meacham, B, Smiley, J, Bembenek Bailey, SA, Puskás, LG, Powell, DK, Sordo, L, Phelan, MJ, Norris, CM, Head, E & Stark, CEL 2024, 'Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles', Journal of Neuroscience, vol. 44, no. 20, e2366232024. https://doi.org/10.1523/JNEUROSCI.2366-23.2024

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AU - Radhakrishnan, Hamsanandini

AU - Ubele, Margo F.

AU - Boaz, Kathy

AU - Mefford, Jennifer L.

AU - Jones, Erin D.

AU - van Rooyen, Hollie Y.

AU - Perpich, Jessica A.

AU - McCarty, Katie

AU - Meacham, Beverly

AU - Smiley, Jeffrey

AU - Bembenek Bailey, Stasia A.

AU - Puskás, László G.

AU - Powell, David K.

AU - Sordo, Lorena

AU - Phelan, Michael J.

AU - Norris, Christopher M.

AU - Head, Elizabeth

AU - Stark, Craig E.L.

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N2 - Aging dogs serve as a valuable preclinical model for Alzheimer’s disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

AB - Aging dogs serve as a valuable preclinical model for Alzheimer’s disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

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KW - Q134R

KW - amyloid

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KW - calcineurin

KW - neurodegeneration

KW - prevention

KW - tacrolimus

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SN - 0270-6474

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JO - Journal of Neuroscience

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ER -

Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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