Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression

Levit, Alexander; Regis, Aaron; Garabon, Jessica R.; Oh, Seung-Hun; Desai, Sumit; Rajakumar, Nagalingam; Hachinski, Vladimir; Ağca, Yüksel; Whitehead, Shawn N.; Allman, Brian L.

doi:10.1016/j.bbr.2017.07.006

Cited by 18 publications

(7 citation statements)

References 55 publications

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“…To study ischemic subcortical stroke, the same wild-type rats that received baseline in vivo imaging later received a stereotactic injection of 60 pmol endothelin-1 (ET1) dissolved in 3 μL sterile saline (n = 5) or sterile saline alone for control (n = 6) in the right dorsal striatum as previously described [ 17 ]. Whether a rat received ET1 or only saline was randomized.…”

Section: Methodsmentioning

confidence: 99%

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

Al-Khishman

Roseborough

et al. 2020

EJNMMI Res

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Background Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer’s disease and acute subcortical stroke. Methods Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. Results [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). Conclusion TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

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Section: Methodsmentioning

confidence: 99%

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

Al-Khishman

Roseborough

et al. 2020

EJNMMI Res

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“…More recent findings using a transgenic APP21 rat, with human Swedish/Indiana mutations of the APP [62], have revealed age-dependent increases in activated microglia, diffusely distributed within the white matter tracts [63] that correlate with executive dysfunction [64], both of which are exacerbated after a subcortical endothelin-1-induced stroke [65]. Using a positron emission tomography (PET) tracer for activated microglia, we also observed persistent expression of activated microglia in the comorbid AD/stroke transgenic rats [66].…”

Section: Inflammation Mediates Interaction Between Stroke and Ad In Pmentioning

confidence: 99%

Preventing dementia by preventing stroke: The Berlin Manifesto

Hachinski

Einhäupl²,

Ganten

et al. 2019

Alzheimer's & Dementia

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The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood Hachinski et al.

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“…Using a combination of behavioral testing, focused on executive dysfunction, live animal imaging with PET/ MRI, and brain histopathology, we make the case that white matter is a target for therapeutic intervention to preserve cognition during normal aging and early stages of disease progression. Our results using a transgenic APP21 rat, with human Swedish/Indiana mutations of the amyloid precursor protein (APP) (Agca et al 2008), have revealed age-dependent increases in activated microglia, diffusely distributed within the white matter tracts (Weishaupt et al 2018) that correlate with executive dysfunction (Levit et al 2019), both of which are exacerbated following a subcortical endothelin-1induced stroke (Levit et al 2017). Using a PET tracer for activated microglia, we also observed persistent expression of activated microglia in the co-morbid AD/stroke transgenic rats.…”

Section: Workhop Topic 5: Vcid Mechanisms and Modelsmentioning

confidence: 95%

Proceedings from the Albert Charitable Trust Inaugural Workshop on white matter and cognition in aging

et al. 2019

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This third in a series of vascular cognitive impairment (VCI) workshops, supported by "The Leo and Anne Albert Charitable Trust," was held from February 8 to 12 at the Omni Resort in Carlsbad, CA. This workshop followed the information gathered from the earlier two workshops suggesting that we focus more specifically on brain white matter in age-related cognitive impairment. The Scientific Program Committee (Frank Barone, Shawn Whitehead, Eric Smith, and Rod Corriveau) assembled translational, clinical, and basic scientists with unique expertise in acute and chronic white matter injury at the intersection of cerebrovascular and neurodegenerative etiologies. As in previous Albert Trust workshops, invited participants addressed key topics related to mechanisms of white matter injury, biomarkers of white matter injury, and interventions to prevent white matter injury and age-related cognitive decline. This report provides a synopsis of the presentations and discussions by the participants, including the existing knowledge gaps and the delineation of the next steps towards advancing our understanding of white matter injury and age-related cognitive decline. Workshop discussions and consensus resulted in action by The Albert Trust to (1) increase support from biannual to annual "White Matter and Cognition" workshops; (2) provide funding for two collaborative, novel research grants annually submitted by meeting participants; and(3) coordinate the formation of the "Albert Research Institute for White Matter and Cognition." This institute will fill a gap in white matter science, providing white matter and cognition communications, including annual updates from workshops and the literature and interconnecting with other Albert Trust scientific endeavors in cognition and dementia, and providing support for newly established collaborations between seasoned investigators and to the development of talented young investigators in the VCI-dementia (VCID) and white matter cognition arena.

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Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression

Cited by 18 publications

References 55 publications

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

Preventing dementia by preventing stroke: The Berlin Manifesto

Proceedings from the Albert Charitable Trust Inaugural Workshop on white matter and cognition in aging

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