{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:55:54Z","timestamp":1793642154793,"version":"4.5.1"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Glaucoma is traditionally classified as an ocular disease characterized by progressive retinal ganglion cell (RGC) loss and optic nerve damage. However, emerging evidence suggests that its pathophysiology may extend beyond the eye, involving trans-synaptic neurodegeneration along the visual pathway and structural changes within central brain regions, including the lateral geniculate nucleus and visual cortex. In this narrative review, we have used the phrase \u2018brain involvement\u2019 to underscore central changes that accompany or follow retinal ganglion cell loss; we have not intended to redefine glaucoma as a primary cerebral disorder. Neuroimaging studies and neurocognitive assessments in adult glaucoma patients, primarily older individuals with primary open-angle glaucoma reveal that glaucoma patients may exhibit alterations in brain connectivity and cortical thinning, aligning it more closely with neurodegenerative disorders such as Alzheimer\u2019s and Parkinson\u2019s disease. This evolving neurocentric perspective raises important questions regarding shared mechanisms\u2014such as mitochondrial dysfunction, chronic inflammation, and impaired axonal transport\u2014that may link glaucomatous optic neuropathy to central nervous system (CNS) pathology. These insights open promising therapeutic avenues, including the repurposing of neuroprotective and neuroregenerative agents, targeting not only intraocular pressure (IOP) but also broader CNS pathways. Furthermore, neuroimaging biomarkers and brain-targeted interventions may play a future role in diagnosis, prognosis, and individualized treatment. This review synthesizes current evidence supporting glaucoma as a CNS disease, explores the mechanistic overlap with neurodegeneration, and discusses the potential clinical implications of glaucoma within a neuro-ophthalmologic paradigm.<\/jats:p>","DOI":"10.3390\/brainsci15090934","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T10:29:18Z","timestamp":1756376958000},"page":"934","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Beyond the Eye: Glaucoma and the Brain"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-5545","authenticated-orcid":false,"given":"Marco","family":"Zeppieri","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy"},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6710-2460","authenticated-orcid":false,"given":"Federico","family":"Visalli","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7486-8361","authenticated-orcid":false,"given":"Mutali","family":"Musa","sequence":"additional","affiliation":[{"name":"Department of Optometry, University of Benin, Benin 300283, Nigeria"},{"name":"Department of Ophthalmology, Africa Eye Laser Center Ltd., Benin 300211, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1051-876X","authenticated-orcid":false,"given":"Alessandro","family":"Avitabile","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9755-0786","authenticated-orcid":false,"given":"Rosa","family":"Giglio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Tognetto","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-0068","authenticated-orcid":false,"given":"Caterina","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"},{"name":"Eye Center \u201cG.B. Morgagni-DSV\u201d, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7938-876X","authenticated-orcid":false,"given":"Fabiana","family":"D\u2019Esposito","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"},{"name":"Imperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, 153-173 Marylebone Rd., London NW1 5QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6807-9455","authenticated-orcid":false,"given":"Francesco","family":"Cappellani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"},{"name":"Eye Center \u201cG.B. Morgagni-DSV\u201d, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1097\/ICU.0b013e3280895aea","article-title":"Glaucoma as a neurodegenerative disease","volume":"18","author":"Gupta","year":"2007","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Haykal, S., Jansonius, N.M., and Cornelissen, F.W. (2021). Progression of Visual Pathway Degeneration in Primary Open-Angle Glaucoma: A Longitudinal Study. Front. Hum. Neurosci., 15.","DOI":"10.3389\/fnhum.2021.630898"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s00401-016-1609-2","article-title":"Glaucoma: The retina and beyond","volume":"132","author":"Davis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wang, J., Li, T., Sabel, B.A., Chen, Z., Wen, H., Li, J., Xie, X., Yang, D., Chen, W., and Wang, N. (2016). Structural brain alterations in primary open angle glaucoma: A 3T MRI study. Sci. Rep., 6.","DOI":"10.1038\/srep18969"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1148\/radiol.2522081240","article-title":"Optic nerve and optic radiation neurodegeneration in patients with glaucoma: In vivo analysis with 3-T diffusion-tensor MR imaging","volume":"252","author":"Garaci","year":"2009","journal-title":"Radiology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.acra.2011.01.014","article-title":"Diffusion tensor imaging detects rarefaction of optic radiation in glaucoma patients","volume":"18","author":"Engelhorn","year":"2011","journal-title":"Acad. Radiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.ejrad.2014.05.014","article-title":"Glaucoma severity affects diffusion tensor imaging (DTI) parameters of the optic nerve and optic radiation","volume":"83","author":"Sidek","year":"2014","journal-title":"Eur. J. Radiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1002\/hbm.22079","article-title":"Resting-state functional MRI: Functional connectivity analysis of the visual cortex in primary open-angle glaucoma patients","volume":"34","author":"Dai","year":"2013","journal-title":"Hum. Brain Mapp."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nuzzi, R., Dallorto, L., and Rolle, T. (2018). Changes of visual pathway and brain connectivity in glaucoma: A systematic review. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00363"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"You, M., Rong, R., Zeng, Z., Xia, X., and Ji, D. (2021). Transneuronal Degeneration in the Brain During Glaucoma. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.643685"},{"key":"ref_11","first-page":"3216","article-title":"Atrophy of relay neurons in magno- and parvocellular layers in the lateral geniculate nucleus in experimental glaucoma","volume":"42","author":"Zhang","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"638","DOI":"10.18240\/ijo.2023.04.19","article-title":"Magnetic resonance imaging assessment of the lateral geniculate nucleus volume and height in patients with glaucoma: A Meta-analysis","volume":"16","author":"Hu","year":"2023","journal-title":"Int. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1167\/iovs.62.10.21","article-title":"Diffusion Tensor Imaging of Visual Pathway Abnormalities in Five Glaucoma Animal Models","volume":"62","author":"Colbert","year":"2021","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Li, K., Lu, C., Huang, Y., Yuan, L., Zeng, D., and Wu, K. (2014). Alteration of fractional anisotropy and mean diffusivity in glaucoma: Novel results of a meta-analysis of diffusion tensor imaging studies. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097445"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yu, L., Xie, L., Dai, C., Xie, B., Liang, M., Zhao, L., Yin, X., and Wang, J. (2015). Progressive thinning of visual cortex in primary open-angle glaucoma of varying severity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121960"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1093\/brain\/awp119","article-title":"Changes in cortical grey matter density associated with long-standing retinal visual field defects","volume":"132","author":"Boucard","year":"2009","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Frezzotti, P., Giorgio, A., Motolese, I., De Leucio, A., Iester, M., Motolese, E., Federico, A., and De Stefano, N. (2014). Structural and functional brain changes beyond visual system in patients with advanced glaucoma. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105931"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/bjo.2008.138172","article-title":"Atrophy of the lateral geniculate nucleus in human glaucoma detected by magnetic resonance imaging","volume":"93","author":"Gupta","year":"2009","journal-title":"Br. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.survophthal.2021.06.001","article-title":"Trans-synaptic degeneration in the visual pathway: Neural connectivity, pathophysiology, and clinical implications in neurodegenerative disorders","volume":"66","author":"Sharma","year":"2022","journal-title":"Surv. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/IJG.0000000000000558","article-title":"MRI Study of the Posterior Visual Pathways in Primary Open Angle Glaucoma","volume":"26","author":"Zhou","year":"2017","journal-title":"J. Glaucoma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.21037\/qims-21-790","article-title":"Application of advanced magnetic resonance imaging in glaucoma: A narrative review","volume":"12","author":"Kang","year":"2022","journal-title":"Quant. Imaging Med. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yu, L., Xie, B., Yin, X., Liang, M., Evans, A.C., Wang, J., and Dai, C. (2013). Reduced cortical thickness in primary open-angle glaucoma and its relationship to the retinal nerve fiber layer thickness. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073208"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s11682-023-00800-7","article-title":"Altered stability of dynamic brain functional architecture in primary open-angle glaucoma: A surface-based resting-state fMRI study","volume":"18","author":"Yang","year":"2024","journal-title":"Brain Imaging Behav."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, Y., Lu, W., Xie, Y., Zhou, J., Yan, T., Han, W., and Qiu, J. (2020). Functional Alterations in Resting-State Visual Networks in High-Tension Glaucoma: An Independent Component Analysis. Front. Hum. Neurosci., 14.","DOI":"10.3389\/fnhum.2020.00330"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1002\/hbm.23862","article-title":"Diffuse brain damage in normal tension glaucoma","volume":"39","author":"Giorgio","year":"2018","journal-title":"Hum. Brain Mapp."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s10548-024-01060-4","article-title":"Topological Organization of the Brain Network in Patients with Primary Angle-closure Glaucoma Through Graph Theory Analysis","volume":"37","author":"Chen","year":"2024","journal-title":"Brain Topogr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"971","DOI":"10.2174\/1570159X16666171206144045","article-title":"Glaucoma and Alzheimer Disease: One Age-Related Neurodegenerative Disease of the Brain","volume":"16","author":"Mancino","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, D.J., Huang, B.L., Peng, Y., Liang, L.Y., and Liu, H. (2023). Altered dynamic functional connectivity in the primary visual cortex in patients with primary angle-closure glaucoma. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1131247"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s00062-018-0728-7","article-title":"Magnetic Resonance Spectroscopy Features of the Visual Pathways in Patients with Glaucoma","volume":"29","author":"Aksoy","year":"2019","journal-title":"Clin. Neuroradiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1097\/IJG.0000000000001098","article-title":"Metabolic Alterations Within the Primary Visual Cortex in Early Open-angle Glaucoma Patients: A Proton Magnetic Resonance Spectroscopy Study","volume":"27","author":"Guo","year":"2018","journal-title":"J. Glaucoma"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4404","DOI":"10.1007\/s00330-016-4279-5","article-title":"In vivo proton magnetic resonance spectroscopy (1H-MRS) evaluation of the metabolite concentration of optic radiation in primary open angle glaucoma","volume":"26","author":"Sidek","year":"2016","journal-title":"Eur. Radiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Jassim, A.H., Inman, D.M., and Mitchell, C.H. (2021). Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.699623"},{"key":"ref_33","first-page":"1000118","article-title":"Tumor Necrosis Factor-\u03b1 and Interleukin-6 Levels in Patients with Primary Open-Angle Glaucoma","volume":"2","author":"Ghanem","year":"2010","journal-title":"J. Clin. Exp. Ophthalmol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, L., and Mao, X. (2021). Role of Retinal Amyloid-\u03b2 in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052360"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.1523\/JNEUROSCI.3986-15.2016","article-title":"Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma","volume":"36","author":"Chiasseu","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Venkatesan, A., and Bernstein, A.M. (2025). Protein misfolding and mitochondrial dysfunction in glaucoma. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1595121"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chakravorty, A., Jetto, C.T., and Manjithaya, R. (2019). Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer\u2019s Disease Pathogenesis. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00311"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100159","DOI":"10.1016\/j.xops.2022.100159","article-title":"The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma","volume":"2","author":"Mullany","year":"2022","journal-title":"Ophthalmol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zheng, C., Liu, S., Zhang, X., Hu, Y., Shang, X., Zhu, Z., Huang, Y., Wu, G., Xiao, Y., and Du, Z. (2022). Shared genetic architecture between the two neurodegenerative diseases: Alzheimer\u2019s disease and glaucoma. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.880576"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1097\/IJG.0000000000001017","article-title":"Reduced Cerebral Blood Flow in the Visual Cortex and Its Correlation With Glaucomatous Structural Damage to the Retina in Patients With Mild to Moderate Primary Open-angle Glaucoma","volume":"27","author":"Wang","year":"2018","journal-title":"J. Glaucoma"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kim, K.E., Oh, S., Baek, S.U., Ahn, S.J., Park, K.H., and Jeoung, J.W. (2020). Ocular Perfusion Pressure and the Risk of Open-Angle Glaucoma: Systematic Review and Meta-analysis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-66914-w"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1177\/0271678X20935274","article-title":"Altered coupling of cerebral blood flow and functional connectivity strength in visual and higher order cognitive cortices in primary open angle glaucoma","volume":"41","author":"Wang","year":"2020","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Velkov, N., Kandilarova, S., and Stoyanov, D. (2025). The Connectivity of the Resting Brain in Primary Open-Angle Glaucoma: A Systematic Review. Biomedicines, 13.","DOI":"10.3390\/biomedicines13061402"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/ceo.13390","article-title":"Optic nerve head perfusion changes preceding peripapillary retinal nerve fibre layer thinning in preclinical diabetic retinopathy","volume":"47","author":"Cao","year":"2019","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1007\/s00417-019-04553-2","article-title":"Optical coherence tomography angiography-derived flow density: A review of the influencing factors","volume":"258","author":"Storp","year":"2020","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.4103\/1673-5374.259600","article-title":"Normal tension glaucoma: From the brain to the eye or the eye to the brain","volume":"14","author":"Zhang","year":"2019","journal-title":"Neural Regen Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1038\/s41433-023-02481-4","article-title":"Frequency of coexistent eye diseases and cognitive impairment or dementia: A systematic review and meta-analysis","volume":"37","author":"Xu","year":"2023","journal-title":"Eye"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/9\/934\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:10Z","timestamp":1760034850000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/9\/934"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["brainsci15090934"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15090934","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]}}}