The role of the vascular system in dementia James AR Nicoll Professor of Neuropathology, University of Southampton Consultant Neuropathologist, Southampton General Hospital
What does the vascular system do for the brain? Supplies nutrients (glucose, O 2 ) Removes waste products (CO 2 ) Blood flow tightly coupled to metabolic demand spatially (mms) and temporally (seconds) Basis of much functional brain imaging Grande Galerie de l Evolution, Musee d histoire naturelle, Paris fmri of the brain listening to sounds (blue) and seeing pictures (orange) http://www.ndcn.ox.ac.uk/research/introduction-to-fmri
Similar risk factors for vascular disease and Alzheimer s disease Risk factors Vascular disease (coronary & cerebrovascular atherosclerosis) Alzheimer s disease Age Genetics apoe polymorphism GWAS: lipids/inflammation Hyper/dyslipidaemia (esp. cholesterol) Local chronic inflammation Systemic inflammation Hypertension Diabetes mellitus Smoking Obesity Hyperhomocysteinaemia Physical inactivity apoe/aβ accumulation Prevention antihypertensives? statins? Beach et al 2007, Casserly & Topol 2004
Similar risk factors for vascular disease and Alzheimer s disease - what does this mean? 1. Coincidence? Separate processes in blood vessel walls and brain that happen to have the same risk factors? 2. In many studies of AD the diagnosis is clinical, without post mortem confirmation - may be contaminated with cases of vascular dementia? 3. Important direct role for cerebrovascular disease in AD?
Atherosclerosis Athero- (porridge) sclerosis (hardening) Fatty streak - Accumulation of lipids/cholesterol in vessel wall - 20 years onwards Fibrofatty plaque - Lipids/inflammation/scarring - Midlife onwards Complicated plaque - Calcification/surface lining damage/thrombus - Midlife onwards Aorta - Patrick Gallacher
Atherosclerosis Coronary artery - Patrick Gallacher Basilar artery - Shireen Padyachy
Consequences of atherosclerosis for the brain Stroke Infarct: local brain damage causing e.g. paralysis Vascular dementia i. Large vessel disease Multi-infarct dementia Vascular dementia ii. Small vessel disease Subcortical vascular dementia Diffuse degeneration of cerebral white matter Unbiased community based studies suggest vascular pathology contributes substantially to dementia CFAS
The brain in Alzheimer s disease Cerebral atrophy AD control Aβ Aβ: plaques/vascular amyloid (CAA) Tau: tangles Dysfunction/loss of nerve cells tau
CAA: Aβ accumulation causes vascular muscle cell damage Interferes with control of blood flow Consequences poorly understood Aβ Smooth muscle actin Aβ Roxana Carare, Abby Keable and colleagues (unpublished)
Aβ immunization in Alzheimer s disease The first clinical study started in 2000 Immunization with Aβ (Elan Pharmaceuticals) Mild to moderate AD Southampton, Bath, Swindon, Cardiff 80 patients Safety and immunogenicity study completed (Bayer et al, 2005, Neurology) Long term clinical and neuropathological follow up study performed Neuropathological assessments in 21 patients to date
102-15 102-2 102-7 102-10 AD: placebo AD: treated 102-3 102-8 102-11 102-1 102-6 102-9 102-16 non AD 102-5 (PSP) treated 102-12 (DLB) treated 102-13 (VaD) treated 102-14 (FTD) placebo
A load (%) Positive vessels / 10 fields Reduced plaques but increased CAA after Aβ immunization 7.5 *P = 0.02 1.80 ***P = 0.0008 **P = 0.006 1.20 5.0 A 42 2.5 0.60 A 40 0.0 AD iad 0.00 AD iad Aβ plaques Vascular Aβ (CAA) A 42 AD Case 1-4 months Case 3-20 months Case 8-64 months Boche et al (2008) Brain
Side effects of Aβ immunization (ARIA) due to increased CAA? Reduction of Aβ is associated with development of microbleeds and white matter abnormalities A B Sperling et al (2012) Lancet Neurol
Conclusions A well-functioning cardiovascular system is important in maintaining brain health - what s good for the heart is good for the mind Risk factors for age-related vascular disease similar to those for Alzheimer s - coincidence, cause and effect or overlapping effects? CAA - Aβ accumulation in blood vessel walls damages muscle cells, interfering with control of blood flow in the brain, likely contributing to cognitive impairment Immunization can remove Aβ from the brain but with consequences for the cerebral vasculature: - increased CAA - Amyloid-Related Imaging Abnormalities (limiting factor in current Aβ immunotherapy trials) Better understanding of blood vessel abnormalities will aid in understanding the development of dementia and inform ideas for the prevention and therapy We are what we eat the brain is built out of what we (and our mothers) have eaten so diet must be important for brain structure and function
Amyloid cascade hypothesis Aβ monomer Aβ amyloid plaque APP Aβ Aβ oligomers Aβ removal: Enzymes (neprilysin, IDE) Vascular (LRP, perivascular drainage) Phagocytosis Cerebral amyloid angiopathy Tau aggregation (tangle) Neuron synapse Microglial cell: inflammation