Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A &amp;gt; G patients

Roy A. M. Haast; Irenaeus F. M. De Coo; Dimo Ivanov; Ali R. Khan; Jacobus F. A. Jansen; Hubert J. M. Smeets; Kamil Uludag

doi:10.1093/braincomms/fcac024

journal article Open Access Jan 04, 2022

Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A &gt; G patients

Roy A. M. Haast

Irenaeus F. M. De Coo

Dimo Ivanov

Ali R. Khan

Jacobus F. A. Jansen Hubert J. M. Smeets Kamil Uludag

Brain Communications Vol. 4 No. 1 · Oxford University Press (OUP)

View at Publisher Save 10.1093/braincomms/fcac024

Abstract

Abstract
Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissue’s homeostasis and integrity. The m.3243A &gt; G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A &gt; G’s negative impact on neuronal energy production and integrity, m.3243A &gt; G patients show cerebral grey matter tissue changes. However, its impact on the most neuron dense, and therefore energy-consuming brain structure—the cerebellum—remains elusive. In this work, we used high-resolution structural and functional data acquired using 7 T MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A &gt; G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared with healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state functional MRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information-processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.

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Published: Jan 04, 2022
Vol/Issue: 4(1)
License: View

Authors

R

Roy A. M. Haast

Centre for Functional and Metabolic Mapping, Robarts Research Institute, Western University, London, ON, Canada, N6A 5B7

I

Irenaeus F. M. De Coo

Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, the Netherlands

D

Dimo Ivanov

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands

A

Ali R. Khan

Centre for Functional and Metabolic Mapping, Robarts Research Institute, Western University, London, ON, Canada, N6A 5B7; Brain and Mind Institute, Western University, London, ON, Canada, N6A 3K7; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5B7

J

Jacobus F. A. Jansen

Department of Radiology & Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; School for Mental Health & Neuroscience, Maastricht University, Maastricht, the Netherlands

H

Hubert J. M. Smeets

Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, the Netherlands; School for Mental Health & Neuroscience, Maastricht University, Maastricht, the Netherlands

K

Kamil Uludag

IBS Center for Neuroscience Imaging Research, Sungkyunkwan University, Seobu-ro, 2066, Jangan-gu, Suwon, South Korea; Department of Biomedical Engineering, N Center, Sungkyunkwan University, Seobu-ro, 2066, Jangan-gu, Suwon, South Korea; Techna Institute and Koerner Scientist in MR Imaging, University Health Network, Toronto, ON, Canada, M5G 1L5

Funding

The Netherlands Organization for Scientific Research Award: 452-11-002

Maastricht University, Technology Foundation STW

Institute for Basic Science, Suwon, Republic of Korea Award: NeMo

Cite This Article

Roy A. M. Haast, Irenaeus F. M. De Coo, Dimo Ivanov, et al. (2022). Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A &gt; G patients. Brain Communications, 4(1). https://doi.org/10.1093/braincomms/fcac024

Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A &amp;gt; G patients

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