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P2‐022: Cerebral haemodynamics, cognitive decline and brain volume change in older patients with type 2 diabetes
Author(s) -
Berg Esther,
Brundel Ma,
Reijmer Yael,
Bresser Jeroen,
Kappelle Jaap,
Biessels GeertJan
Publication year - 2011
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.2011.05.912
Subject(s) - cognitive decline , cerebral blood flow , cardiology , medicine , hemodynamics , hyperintensity , dementia , psychology , magnetic resonance imaging , radiology , disease
were evaluated. Methods: Alzet osmotic pumps containing ELND006 or vehicle were implanted subcutaneously in FVB mice, followed by a subcutaneous loading dose. Animals were terminated, and tissues collected after 6 -72 hours of infusion. Microdialysis studies were performed by implanting FVB mice with hippocampal microdialysis probes to assess ISF As. As levels in brain, ISF, CSF and plasma were analyzed by ELISA. Compound levels in plasma and brain were determined by an LC-MS/MS assay. Results: After sustained administration of 2, 10 and 50 mg/kg/day, brain As was significantly reduced (26%, 59% and 72%, respectively). Plasma As was elevated 37% at 2 mg/kg/dose, and was reduced 17% (nonsignificantly, n.s.) and 62% at 10 and 50 mg/kg/day, respectively. CSFAswas elevated 34% (n.s.) at 2 mg/kg/day and significantly reduced 43% and 85% at 10 and 50 mg/kg/day, respectively. Plasma ELND006 concentrations of 35, 197, and 281 ng/mL were associated with 25% lowering of As in the brain, CSF and plasma respectively. Preliminary microdialysis experiments suggested that ISF As was reduced at doses as low as 0.5 mg/kg/day. Conclusions: Sustained infusion of ELND006 via Alzet subcutaneous minipumps in FVB mice demonstrated that therapeutically relevant lowering of As in the brain (25%) occurs at doses below those needed to effect similar responses in CSF and plasma. In addition, As reduction in the brain occurs at an exposure where CSF and plasma As is either unaffected or elevated. Understanding these relationships is important in interpreting As biomarkers in plasma and CSF in the clinic.