{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T23:16:49Z","timestamp":1784675809899,"version":"3.55.0"},"reference-count":104,"publisher":"SAGE Publications","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2024,1,30]]},"abstract":"<jats:p>This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer\u2019s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.<\/jats:p>","DOI":"10.3233\/jad-231202","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T12:09:32Z","timestamp":1704802172000},"page":"1069-1081","source":"Crossref","is-referenced-by-count":4,"title":["The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"97","author":[{"given":"Jonathan","family":"Stone","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health, University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Mitrofanis","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, Fonds de Dotation, Clinatec, Grenoble, France"},{"name":"Institute of Ophthalmology, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia"},{"name":"School of Medical Sciences, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Robinson","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Bundoora, Australia"},{"name":"Institute for Breathing and Sleep, Austin Health, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-231202_ref1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3233\/JAD-230429","article-title":"Best medicine for dementia: The life-long defense of the brain","volume":"94","author":"Andersson","year":"2023","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-231202_ref2","doi-asserted-by":"crossref","first-page":"1141568","DOI":"10.3389\/fnins.2023.1141568","article-title":"The brain\u2019s weakness in the face of trauma: How head trauma causes the destruction of the brain","volume":"17","author":"Johnstone","year":"2023","journal-title":"Front Neurosci"},{"key":"10.3233\/JAD-231202_ref3","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/BF02866241","article-title":"\u00dcber eigenartige Krankheitsf\u00e4lle des sp\u00e4teren Alters.356 -","volume":"4","author":"Alzheimer","year":"1911","journal-title":"Z Neurol Psychiatrie"},{"key":"10.3233\/JAD-231202_ref4","first-page":"533","article-title":"Senile and pre-senile dementias. 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