Consensus Paper: Cerebellum and Ageing

doi:10.1007/s12311-023-01577-7

Review

. 2024 Apr;23(2):802-832.

doi: 10.1007/s12311-023-01577-7. Epub 2023 Jul 10.

Consensus Paper: Cerebellum and Ageing

Angelo Arleo¹, Martin Bareš^{2

3}, Jessica A Bernard^{4

5}, Hannah R Bogoian⁶, Muriel M K Bruchhage^{7

8

9

10}, Patrick Bryant¹¹, Erik S Carlson^{12

13}, Chetwyn C H Chan¹⁴, Liang-Kung Chen^{15

16

17}, Chih-Ping Chung^{15

18}, Vonetta M Dotson^{6

19}, Pavel Filip^{20

21}, Xavier Guell^{22

23}, Christophe Habas^{24

25}, Heidi I L Jacobs^{26

27

28}, Shinji Kakei²⁹, Tatia M C Lee^{30

31}, Maria Leggio^{32

33}, Maria Misiura⁶, Hiroshi Mitoma³⁴, Giusy Olivito^{32

33}, Stephen Ramanoël^{1

35}, Zeynab Rezaee³⁶, Colby L Samstag^{12

13}, Jeremy D Schmahmann^{22

23

37}, Kaoru Sekiyama³⁸, Clive H Y Wong¹⁴, Masatoshi Yamashita^{39

40}, Mario Manto^{41

42}

Affiliations

¹ Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.
² First Department of Neurology, Faculty of Medicine, Masaryk University and St. Anne's Teaching Hospital, Brno, Czech Republic.
³ Department of Neurology, School of Medicine, University of Minnesota, Minneapolis, USA.
⁴ Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX, 77843, USA.
⁵ Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, USA.
⁶ Department of Psychology, Georgia State University, Atlanta, GA, USA.
⁷ Department of Psychology, Stavanger University, Institute of Social Sciences, Kjell Arholms Gate 41, 4021, Stavanger, Norway.
⁸ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Centre for Neuroimaging Sciences, Box 89, De Crespigny Park, London, PO, SE5 8AF, UK.
⁹ Rhode Island Hospital, Department for Diagnostic Imaging, 1 Hoppin St, Providence, RI, 02903, USA.
¹⁰ Department of Paediatrics, Warren Alpert Medical School of Brown University, 222 Richmond St, Providence, RI, 02903, USA.
¹¹ Freie Universität Berlin, Fachbereich Mathematik und Informatik, Arnimallee 12, 14195, Berlin, Germany.
¹² Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, WA, USA.
¹³ Geriatric Research, Education and Clinical Center, Veteran's Affairs Medical Center, Puget Sound, Seattle, WA, USA.
¹⁴ Department of Psychology, The Education University of Hong Kong, New Territories, Tai Po, Hong Kong, China.
¹⁵ Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan.
¹⁶ Center for Geriatric and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁷ Taipei Municipal Gan-Dau Hospital (managed by Taipei Veterans General Hospital), Taipei, Taiwan.
¹⁸ Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁹ Gerontology Institute, Georgia State University, Atlanta, GA, USA.
²⁰ Department of Neurology, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
²¹ Center for Magnetic Resonance Research (CMRR), University of Minnesota, Minneapolis, MN, USA.
²² Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²³ Laboratory for Neuroanatomy and Cerebellar Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁴ CHNO Des Quinze-Vingts, INSERM-DGOS CIC 1423, 28 rue de Charenton, 75012, Paris, France.
²⁵ Université Versailles St Quentin en Yvelines, Paris, France.
²⁶ School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, PO BOX 616, 6200, MD, Maastricht, The Netherlands.
²⁷ Faculty of Psychology and Neuroscience, Department of Cognitive Neuroscience, Maastricht University, PO BOX 616, 6200, MD, Maastricht, The Netherlands.
²⁸ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁹ Jissen Women's University, Tokyo, Japan.
³⁰ State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
³¹ Laboratory of Neuropsychology and Human Neuroscience, Department of Psychology, The University of Hong Kong, Hong Kong, China.
³² Department of Psychology, Sapienza University of Rome, Rome, Italy.
³³ Ataxia Laboratory, I.R.C.C.S. Santa Lucia Foundation, Rome, Italy.
³⁴ Department of Medical Education, Tokyo Medical University, Tokyo, Japan.
³⁵ Université Côte d'Azur, LAMHESS, Nice, France.
³⁶ Noninvasive Neuromodulation Unit, Experimental Therapeutics & Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, USA.
³⁷ Ataxia Center, Cognitive Behavioural neurology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³⁸ Graduate School of Advanced Integrated Studies in Human Survivability, Kyoto University, Kyoto, Japan.
³⁹ Research Center for Child Mental Development, University of Fukui, Fukui, Japan.
⁴⁰ United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, Japan.
⁴¹ Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, Charleroi, Belgium. mario.manto@ulb.be.
⁴² Service des Neurosciences, University of Mons, Mons, Belgium. mario.manto@ulb.be.

PMID: 37428408
PMCID: PMC10776824
DOI: 10.1007/s12311-023-01577-7

Review

Consensus Paper: Cerebellum and Ageing

Angelo Arleo et al. Cerebellum. 2024 Apr.

. 2024 Apr;23(2):802-832.

doi: 10.1007/s12311-023-01577-7. Epub 2023 Jul 10.

Authors

Affiliations

¹ Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.
² First Department of Neurology, Faculty of Medicine, Masaryk University and St. Anne's Teaching Hospital, Brno, Czech Republic.
³ Department of Neurology, School of Medicine, University of Minnesota, Minneapolis, USA.
⁴ Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX, 77843, USA.
⁵ Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, USA.
⁶ Department of Psychology, Georgia State University, Atlanta, GA, USA.
⁷ Department of Psychology, Stavanger University, Institute of Social Sciences, Kjell Arholms Gate 41, 4021, Stavanger, Norway.
⁸ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Centre for Neuroimaging Sciences, Box 89, De Crespigny Park, London, PO, SE5 8AF, UK.
⁹ Rhode Island Hospital, Department for Diagnostic Imaging, 1 Hoppin St, Providence, RI, 02903, USA.
¹⁰ Department of Paediatrics, Warren Alpert Medical School of Brown University, 222 Richmond St, Providence, RI, 02903, USA.
¹¹ Freie Universität Berlin, Fachbereich Mathematik und Informatik, Arnimallee 12, 14195, Berlin, Germany.
¹² Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, WA, USA.
¹³ Geriatric Research, Education and Clinical Center, Veteran's Affairs Medical Center, Puget Sound, Seattle, WA, USA.
¹⁴ Department of Psychology, The Education University of Hong Kong, New Territories, Tai Po, Hong Kong, China.
¹⁵ Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan.
¹⁶ Center for Geriatric and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁷ Taipei Municipal Gan-Dau Hospital (managed by Taipei Veterans General Hospital), Taipei, Taiwan.
¹⁸ Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁹ Gerontology Institute, Georgia State University, Atlanta, GA, USA.
²⁰ Department of Neurology, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
²¹ Center for Magnetic Resonance Research (CMRR), University of Minnesota, Minneapolis, MN, USA.
²² Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²³ Laboratory for Neuroanatomy and Cerebellar Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁴ CHNO Des Quinze-Vingts, INSERM-DGOS CIC 1423, 28 rue de Charenton, 75012, Paris, France.
²⁵ Université Versailles St Quentin en Yvelines, Paris, France.
²⁶ School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, PO BOX 616, 6200, MD, Maastricht, The Netherlands.
²⁷ Faculty of Psychology and Neuroscience, Department of Cognitive Neuroscience, Maastricht University, PO BOX 616, 6200, MD, Maastricht, The Netherlands.
²⁸ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁹ Jissen Women's University, Tokyo, Japan.
³⁰ State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
³¹ Laboratory of Neuropsychology and Human Neuroscience, Department of Psychology, The University of Hong Kong, Hong Kong, China.
³² Department of Psychology, Sapienza University of Rome, Rome, Italy.
³³ Ataxia Laboratory, I.R.C.C.S. Santa Lucia Foundation, Rome, Italy.
³⁴ Department of Medical Education, Tokyo Medical University, Tokyo, Japan.
³⁵ Université Côte d'Azur, LAMHESS, Nice, France.
³⁶ Noninvasive Neuromodulation Unit, Experimental Therapeutics & Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, USA.
³⁷ Ataxia Center, Cognitive Behavioural neurology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³⁸ Graduate School of Advanced Integrated Studies in Human Survivability, Kyoto University, Kyoto, Japan.
³⁹ Research Center for Child Mental Development, University of Fukui, Fukui, Japan.
⁴⁰ United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, Japan.
⁴¹ Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, Charleroi, Belgium. mario.manto@ulb.be.
⁴² Service des Neurosciences, University of Mons, Mons, Belgium. mario.manto@ulb.be.

PMID: 37428408
PMCID: PMC10776824
DOI: 10.1007/s12311-023-01577-7

Abstract

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Keywords: Affective; Aging; Alzheimer’s Disease; Cerebellum; Cognitive; Motor.

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Conflict of interest statement

Conflicts of interest

The authors declare no conflict of interest.

Figures

**Figure 1.. Group-wise probabilistic connections between cerebellar and bilateral amygdala/hippocampus areas.**
VBM = voxel-based morphometry.

**Figure 2.**
Cerebellar changes related to musical instrument experience [partial modification from [179]. (a) Older musicians had higher bilateral GMVs in the cerebellum than non-musicians. (b) For the cerebellar ROIs, the non-musicians demonstrated a negative correlation between their GMV and age, whereas such correlation was not significant. ** P < 0.01, *** P < 0.001. CB-L, left cerebellum; CB-R, right cerebellum; GMV, gray matter volume; ROI, region of interest; a.u., arbitrary units

See this image and copyright information in PMC

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References

1. Manto M, Gruol DL, Schmahmann JD, Koibuchi N, Sillitoe RV. Handbook of Cerebellum and Cerebellar Disorders. Springer, 2022
1. Van Overwalle F, Manto M, Cattaneo Z, Clausi S, Ferrari C, Gabrieli JDE, Guell X, Heleven E, Lupo M, Ma Q, Michelutti M, Olivito G, Pu M, Rice LC, Schmahmann JD, Siciliano L, Sokolov AA, Stoodley CJ, van Dun K, Vandervert L, Leggio M. Consensus Paper: cerebellum and social cognition. Cerebellum 2020;19(6):833–868 - PMC - PubMed
1. Bareš M, Apps R, Avanzino L, Breska A, D’Angelo E, Filip P, Gerwig M, Ivry RB, Lawrenson CL, Louis ED, Lusk NA, Manto M, Meck WH, Mitoma H, Petter EA. Consensus paper: decoding the contributions of the cerebellum as a time machine. from neurons to clinical applications. Cerebellum 2019;18(2):266–286 - PubMed
1. Bostan AC, Strick PL. The basal ganglia and the cerebellum: nodes in an integrated network. Nat Rev Neurosci 2018;19(6):338–350 - PMC - PubMed
1. D’Angelo E. Physiology of the cerebellum. Handb Clin Neurol 2018;154:85–108 - PubMed

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[1] Manto M, Gruol DL, Schmahmann JD, Koibuchi N, Sillitoe RV. Handbook of Cerebellum and Cerebellar Disorders. Springer, 2022

[2] Manto M, Gruol DL, Schmahmann JD, Koibuchi N, Sillitoe RV. Handbook of Cerebellum and Cerebellar Disorders. Springer, 2022

[3] Van Overwalle F, Manto M, Cattaneo Z, Clausi S, Ferrari C, Gabrieli JDE, Guell X, Heleven E, Lupo M, Ma Q, Michelutti M, Olivito G, Pu M, Rice LC, Schmahmann JD, Siciliano L, Sokolov AA, Stoodley CJ, van Dun K, Vandervert L, Leggio M. Consensus Paper: cerebellum and social cognition. Cerebellum 2020;19(6):833–868 - PMC - PubMed

[4] Van Overwalle F, Manto M, Cattaneo Z, Clausi S, Ferrari C, Gabrieli JDE, Guell X, Heleven E, Lupo M, Ma Q, Michelutti M, Olivito G, Pu M, Rice LC, Schmahmann JD, Siciliano L, Sokolov AA, Stoodley CJ, van Dun K, Vandervert L, Leggio M. Consensus Paper: cerebellum and social cognition. Cerebellum 2020;19(6):833–868 - PMC - PubMed

[5] Bareš M, Apps R, Avanzino L, Breska A, D’Angelo E, Filip P, Gerwig M, Ivry RB, Lawrenson CL, Louis ED, Lusk NA, Manto M, Meck WH, Mitoma H, Petter EA. Consensus paper: decoding the contributions of the cerebellum as a time machine. from neurons to clinical applications. Cerebellum 2019;18(2):266–286 - PubMed

[6] Bareš M, Apps R, Avanzino L, Breska A, D’Angelo E, Filip P, Gerwig M, Ivry RB, Lawrenson CL, Louis ED, Lusk NA, Manto M, Meck WH, Mitoma H, Petter EA. Consensus paper: decoding the contributions of the cerebellum as a time machine. from neurons to clinical applications. Cerebellum 2019;18(2):266–286 - PubMed

[7] Bostan AC, Strick PL. The basal ganglia and the cerebellum: nodes in an integrated network. Nat Rev Neurosci 2018;19(6):338–350 - PMC - PubMed

[8] Bostan AC, Strick PL. The basal ganglia and the cerebellum: nodes in an integrated network. Nat Rev Neurosci 2018;19(6):338–350 - PMC - PubMed

[9] D’Angelo E. Physiology of the cerebellum. Handb Clin Neurol 2018;154:85–108 - PubMed

[10] D’Angelo E. Physiology of the cerebellum. Handb Clin Neurol 2018;154:85–108 - PubMed

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Consensus Paper: Cerebellum and Ageing

Affiliations

Consensus Paper: Cerebellum and Ageing

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