MECHANISMS OF NEURODEGENERATION AND REGENERATION IN POST-STROKE SURVIVORS

Summary

Principal Investigator: Raj N Kalaria
Abstract: [unreadable] DESCRIPTION (provided by applicant): Stroke is the third major cause of morbidity and mortality in older people, with a prevalence of approximately 10% in those over 75 years, and has similarly high costs for society. Prospective assessments of our post-stroke cohort (n=400) suggests 25% of stroke survivors develop dementia as an immediate consequence of infarction or haemorrhage. However, in those stroke survivors who do not develop immediate cognitive impairment, the risk of developing dementia at 3 years or longer after the stroke is almost 10-fold greater than for age- matched controls. Cognitive function also continues to improve for up to 15 months after a stroke in over a third of the survivors. Understanding the risk factors and mechanisms for the delayed dementia and cognitive improvement are critical for selective recruitment to clinical trials, and has important implications for the prognosis and rehabilitation of stroke patients. We have collected post-mortem brains from these prospectively assessed stroke survivors and propose i) histopathological and immunocytochemical analyses to examine markers of angiogenesis and neurogenesis (neurovascular unit) against the burden of sclerosis, oxidative damage and Alzheimer type of lesions in the medial temporal lobe of post-stroke improvers and decliners, and ii) the application of large-scale fluorescence-difference (DiGE) proteomics and mass spectrometry to define protein changes in the brains from post-stroke survivors who declined and improved in cognition. Brain tissue will be available from at least 60 prospectively assessed survivors. The proteomic profiles will be explored in the hippocampal CA1 and dentate gyrus cells, which will be bulk isolated and for further scrutiny by Laser Capture Microdissection. These investigations are based on the hypotheses that improvers will express growth promoting or signalling markers of neurogenesis (neural stem cells) and angiogenseis (vascular/ progenitor cells). The proposed research will uncover neuronal-vascular interactions that may relate to cognitive improvement and functional recovery in the post-stroke survivors. This work relates to delayed dementia after stroke but also neurodegenerative dementia which affects nearly 10% of elderly over age 75 years. This will impact on neurodegenerative mechanisms associated with common dementing disorders including Alzheimer's disease and dementia with Lewy bodies besides vascular dementia, leading towards rational preventative or treatment strategies based on vascular protection. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-07-01 - 2008-05-31
more information: NIH RePORT

Top Publications

  1. pmc Vascular basis for brain degeneration: faltering controls and risk factors for dementia
    Raj N Kalaria
    Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK
    Nutr Rev 68:S74-87. 2010
  2. ncbi Does vascular pathology contribute to Alzheimer changes?
    Raj N Kalaria
    Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom
    J Neurol Sci 322:141-7. 2012
  3. ncbi Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia
    Rufus O Akinyemi
    Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, United Kingdom
    Curr Alzheimer Res 10:642-53. 2013
  4. pmc Neuropathological correlates of temporal pole white matter hyperintensities in CADASIL
    Yumi Yamamoto
    Institute for Ageing and Health, WRc, Campus for Ageing and Vitality, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, United Kingdom
    Stroke 40:2004-11. 2009
  5. ncbi Review: molecular genetics and pathology of hereditary small vessel diseases of the brain
    Y Yamamoto
    Institute for Ageing and Health, Wolfson Research Centre, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
    Neuropathol Appl Neurobiol 37:94-113. 2011

Detail Information

Publications5

  1. pmc Vascular basis for brain degeneration: faltering controls and risk factors for dementia
    Raj N Kalaria
    Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK
    Nutr Rev 68:S74-87. 2010
    ..Lifestyle measures that maintain or improve cardiovascular health, including consumption of healthy diets, moderate use of alcohol, and implementation of regular physical exercise are important factors for brain protection...
  2. ncbi Does vascular pathology contribute to Alzheimer changes?
    Raj N Kalaria
    Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom
    J Neurol Sci 322:141-7. 2012
    ....
  3. ncbi Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia
    Rufus O Akinyemi
    Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, United Kingdom
    Curr Alzheimer Res 10:642-53. 2013
    ....
  4. pmc Neuropathological correlates of temporal pole white matter hyperintensities in CADASIL
    Yumi Yamamoto
    Institute for Ageing and Health, WRc, Campus for Ageing and Vitality, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, United Kingdom
    Stroke 40:2004-11. 2009
    ..We assessed pathological changes in postmortem tissue from the temporal pole to reveal the cause of CADASIL-specific WM hyperintensities...
  5. ncbi Review: molecular genetics and pathology of hereditary small vessel diseases of the brain
    Y Yamamoto
    Institute for Ageing and Health, Wolfson Research Centre, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
    Neuropathol Appl Neurobiol 37:94-113. 2011
    ..The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment...