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P2‐112: PATTERNS OF STRUCTURAL COVARIANCE ASSOCIATED WITH ALZHEIMER'S DISEASE: A NOVEL VOXEL‐WISE GRAPH THEORETIC APPROACH
Author(s) -
Whitlow Christopher T.,
Hughes Timothy M.,
Jung Youngkyoo,
Kim Jeongchul,
Lockhart Samuel N.,
Solingapuram Sai Kiran Kumar
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.2519
Subject(s) - voxel , voxel based morphometry , pattern recognition (psychology) , hippocampal formation , hippocampus , correlation , neuroscience , artificial intelligence , psychology , computer science , mathematics , white matter , medicine , magnetic resonance imaging , geometry , radiology
Background: The multiplicity of systems affected in Alzheimer’s disease (AD) brains strongly encourages the development of multi-target therapies. Mesenchymal stem cells (MSC) represent a promising candidate being endowed with neuro-regenerative/ reparative, immunomodulatory and anti-amyloidogenic abilities, but their clinical application is still limited by several risks related to their direct implantation inside the host. We herein want to exploit the paracrine action theory, which states that MSC repair damaged environments by releasing multiple bioactive molecules in their “secretome”, rather than through their physical engraftment. Methods: Mouse bone-marrow-derived MSC and APP/ PS1dE9 brain homogenates were used for secretome preparation. APP/PS1dE9 mice were used to test MSC-CS efficacy. 6E10 antiAb, A11 anti-oligomer, anti-GFAP, anti-Iba1 and anti-CD68 antibodies were used to assess amyloidosis and neuroinflammation. NISSL staining was used for neuronal counts. MSC were preexposed in vitro to AD mouse brain extracts to stimulate the production of a neuroreparative conditioned secretome. Twelve and 22-month-old APP/PS1dE9 mice were intravenously (IV) or intranasally (IN) injected with MSC-CS following different treatment regimens. At several time points post-treatment mouse memory was investigated in the novel object recognition test (NORT) as well as changes in neuropathology: amyloidosis, neuroinflammation, phagocytosis, neuronal density. Results: One single IV injection of MSC-CS fully restored memory in 12and 22month-old APP/PS1 mice tested in the NORT 7-day post-injection. In younger mice plaques were rapidly reduced of 30% and microglia activation was significantly decreased. In older mice brain repair was achieved at many levels under a repeated IN treatment. We found a huge plaque reduction in both the cortex and the hippocampus; most remaining plaques lacked their nucleation core and looked smaller in size with a lower concentration of surrounding oligomers. Gliosis was significantly decreased, as well as the expression of the phagocytic microglial marker CD68. Neuro-regeneration was observed in both the cortex and the hippocampus. Life span of APP/PS1dE9-treated mice reached a significant increase compared to untreated ones. Conclusions: These data are compelling, since provide an alternative use of stem cellbased therapy, with the great opportunity of circumventing their implantation and those risks related to their unknown fate once inside the host.