Neuropathological Substrates of Dementia after Stroke

Dementia is a major health problem which is increasing with the rising numbers of older people. Research effort in this field has focused largely on mechanisms that damage nerve-cells in disorders such as Alzheimer?s disease. Recent evidence suggests that impairments in blood supply to the brain may cause or accelerate these so-called ?neurodegenerative changes?. We have shown that 10% of patients who survive a stroke without severe memory problems, develop dementia in the following year. We have also highlighted possible risk associated with rapid changes in blood supply to the brain caused by disorders of cardiovascular regulation. The relationships between impaired blood supply, neurodegeneration and dementia are poorly understood. We propose to elucidate these, and identify the underlying mechanisms in older people who (a) have had a stroke and experience reduced blood supply to key subcortical regions of the brain. We will perform repeated clinical, psychological, cardiovascular and brain imaging assessments in these patients, to enable us to relate changes in memory and attention to structural damage to the brain. Most patients in our studies consent to brain donation at death, and we will compare pathological features with changes seen on brain imaging, and identify the molecular substrates of this damage. Our studies will advance understanding of the importance of how impariment occurs in stroke patients and in blood supply to the brain in dementia, and how this is affected by age. They will enable us to make more accurate, early diagnoses and identify those at risk of cognitive decline, and inform the development of therapies to slow or prevent such changes.
Our findings will be disseminated in many different ways, including: (i) publication in scientific journals; (ii) development of professional guidelines for the diagnosis and treatment of dementia and related medical conditions; (iii) inclusion in lay information bulletins and ?fact sheets? produced by bodies such as the Alzheimer?s Society, and US Alzheimer Association ;(iv) presentation at public lectures, workshops and carers support groups run by such organisations; and (v) through collaboration with Newcastle University?s Institute for Policy and Ethics in the Life Sciences (PEALS) whose main mission is to promote public engagement. Older people and representative voluntary organisations are involved in the strategic direction of research within the IAH and the management of facilities such as the brain tissue bank.

Recent advances highlight the importance of vascular factors in the aetiopathogenesis of dementia but the relationships between vascular damage, cerebral hypoperfusion, neurodegenerative changes and cognitive decline remain unclear. We have previously shown (i) considerable overlap between Alzheimer?s disease and cerebrovascular disease, which is most pronounced in those aged over 80; (ii) 10% of older patients who survive a stroke without severe cognitive impairment at 3 months develop incident dementia in the first year; (iii) 30% of older stroke survivors show improvement in cognition over the first year; and (iv) a high proportion of patients with dementia have carotid sinus hypersensitivity (CSH) which correlates with the severity of small vessel disease.
Understanding the mechanisms for delayed dementia following stroke and the contribution of cerebral hypoperfusion to dementia, and the clinical characteristics which predict cognitive decline (or improvement) are essential if effective preventative strategies are to be developed. We will build upon our recent findings in post stroke dementia to address two key problems in a unique post-stroke cohort recruited and prospectively assessed during the last 5 years. Using pathological investigation of post-mortem specimens combined with in vivo imaging in post-stroke survivors, we will elucidate (i) whether cerebrovascular injury leads to increased burden of AD type changes in stroke survivors who become demented and (ii) whether increased burden of microvascular pathology in the subcortical structures (basal ganglia and thalamus) is a substrate for dementia in post-stroke survivors. Thus autopsy cases of post-stroke survivors will be examined for neuronal and microvascular pathology including Alzheimer lesions, cerebral amyloid angiopathy and hippocampal sclerosis and atrophy and subcortical WM pathology. To differentiate between post-stroke patients who decline and remain intact (improvers) we will also assess the expression of oxidative stress mechanisms in temporal lobe. Repeated assessments of clinical and neuropsychological measures prior to death will inform on the physical and cognitive status and be used to correlate with pathological findings and apolipoprotein E genotype. We believe the proposed research project will not only disclose the neuropathological substrates of post-stroke dementia but impact significantly on common dementing disorders in later life and underpin development of novel preventative and treatment strategies based on vascular protection.