Common Neurological Conditions Flashcards
What is alzeimers disease?
Cognitive impairment leading to dementia
Most common cause of dementia
Distinct pathological signature emerging
Huge social and economic burden
- Mainly happening after 65 years old
- Early onset – 5% - under 65 years old – some genetic linking
State some deficients of alzeimers disease
Sensation – speed processing – perception – motor skills – executive functioning – language – memory
What are the key anatomical features of Alzheimers disease?
Cortical atrophy - tissue loss
- Loss of parenchyma
- Hydrocephalus ex vacuo – tissue loss – increased size of ventricles
- Narrow gyri
- Widened Sulci
- Atrophy of parahippocampal cortex – base of brain – memory forming loss
State the two sections of the pathological signature of Alzheimers disease
- Senile plaques – AKA neurotic plaques/ amyloid plaques
- Neurofibrillary tangles
What are two other names for amyloid plaques?
Senile or neurotic plaques
What are amyloid plaques?
1.Extracellular deposits of beta amyloid (inflammatory cells and deposits build up)
2. Recruitment of activated astrocytes (removed inflammatory build up) and microglia (local inflammatory response)
3. Dystrophic neuritis locally (spouting/ expansion of proteins/ other cells)
(Number and distribution not scientifically correlated)
How is beta amyloid formed?
- Amyloid precursor protein APP
- Alpha and gamma secretes enzymes
- Other peptides losses
- Beta amyloid formed
- Secreted from neurone into tissue around nerve cells - stack up of molecules (oligomer then protofibril then fibril) – if this is miss-folded which enhances accumulation of protein around the cell
- Amyloid plaque develops from this accumulation
Whats the hypothesis for how amyloid leads to Alzheimers?
Amyloid cascade hypothesis
What is the amyloid cascade hypothesis?
- Amyloid accumulation may be the initial step in alzheimer’s dementia pathogenesis
- Leading to deposition of Tau protein (neurofibrillary tangles)
- Taupathy is linked to neuronal decline and synaptic loss
- These in turn result in classical cognitive decline (tissue loss)
How has Tau protein production effect alheimers?
Important link in causing the loss of neurons and synapses.
with link to inflammatory mechanisms
What are Tau proteins?
- Usually very soluble protein that encoded by MAPT gene
- Stabilising the cytoskeleton of neuron networks in axons (inside the neuron cells)
- Important for axonal transport – movement of transport vesicles – forming deposits
What are MAPT gene?
- Microtubule associated protein Tau
- Stabilising microtubule (cytoskeleton) network in axons
- Abundant in neurons of CNS
- Microtubules important for axonal transport – movement of transport vesicles and important molecules
What are neurofibillary tangles?
- Formed from Tau protein
- Tau becomes insoluble when its highly phosphorylated
- Hyperphosphorylaed Tau – insoluble
- Accumulated in cytoplasm
- Fine filaments observable
What is the Tau hypothesis of Alzheimers disease?
Correlation for profession of disease and increase in amyloid plaque
- Tau pathology
- Primary driver of neurodegeneration
- Insoluble and goes inside the neuron to phosphorylate
Distribution of tangles correlates with clinical dementia rating
Spread of Tau pathology correlated with cognitive decline and neuron loss
Pathology spreads from neuron to neuron
How are Tau proteins spread to cause degeneration in neurons?
- NF tangle inside neurone
- Goes towards synapse by diffusion
- Filament fragments transferred trasnsynaptically (across the synaptic cleft)
- Second neuron seeded and new tangles develop
What does Tauopathy do to neurons?
1.Disruption to functioning of cytoskeleton
2. Disruption to receptor protein trafficking inside cell
3. Disruption to synapse function and formation
IN the end these issues lead to neuronal death
Whats the overall effect of tauopathy?
IN the end these issues lead to neuronal death
What is the role of inflammtion in Alzheimers dementia?
Amyloid deposition turns microglia cells to activated microglia cells (cells in brain regulate brain development, maintain neuronal pathways and injury repaire)
- Activated microglia/astrocytes prominent feature in AD pathology
- Genetic linkage with regulators of microglia function
Correlation between activation of microglia and AD pathology
As symptomatic Alzheimers disease develops what does pathology show?
- Reduction in synaptic and neuronal function and density
- Increase in amyloid beta deposition, microglia and astrocytes activation, Tau pathology
What does activated microglia do?
- Inhibits seeding of amyloid beta and remove amyloid beta by endocytosis
- Inhibits seeding of Tau
But Amyloid beta endocytosis activates release of damaging inflammatory mediators
How is the ageing brain effected by Alzheimers disease?
By 20 years old neuronal deficit has begun.
(linked to deposition of amyloid plaque) and neuromelanin pigments of neural tissue as we age
How is age related to issues with the brain?
- Hippocampus loses mass - Short term memory problems
- Motor cortex increased neuronal atrophy – gate and movement deficit
- Autonomic centres respond less rapidly – postural hypertension – dizziness as sitting or standing
- Reducing integrity of blood brain barrier – pathogens and harmful substances ins to brain tissue (inflammatory)
- Neurotransmitter production reduced
- Mitochondrial dysregulation – reduction of production of brain cells
Whats the gross anatomy of meninges?
- Dura mater (thick) - periostea’s and meningeal layers
- Arachnoid mater – sub arachnoid space containing cerebrospinal fluid
- Pia mater – nutritive layer hugging surface of the brain
Why associated brain and microbiome?
Brain inclosed, edged space (little room for expansion)
Close to areas containing wet mucosa (associated with complex microbiome)
Microbiome may contain – commensal, parasitic and/or pathogenic organisms
