alzheimers disease and other dementia

Dementia

• the loss of mental processing ability, communication, abstract thinking, judgement and physical abilities such that it interferes with daily living

• Chronic progressive disorder

• Affects multiple parts of the brain

  • Higher cognitive function

  • Daily living activites

Alzheimer’s disease

• often present with memory lapse

• Physical abilities may be affected late stage

• 3-20 year duration

• Incidences of dementia increase with age

• Current treatment relatively poor- symptomatic

Alzheimer’s disease background

• broad clinical characteristic of AD

• Symptoms

  • Memory lapse of increasing frequency and extent

  • Language deficits

  • Distributed/ repetivite behaviour

  • Visuo spatial deficits

  • Impaired judgement and executive functions

  • Effects on social function

Microscopic pathology

• two types of key pathology

  • Extracellular

  • Intracellular

Extracellular

• amyloid plaques

• Contain amyloid beta

Intracellular

• neurofibrillary tangles

• Contain tau

Amyloid hypothesis

• build up of Ab is crucial event

• Normally monomeric and soluble

• Oligomerises

• Oligomers become insoluble

APP processing to generate a beta

• enzymes that cleave APP to produce Abeta

• Beta secretase

• Gamma secretase

• Group of enzymes including one called presenillin

Neurofibrillary tangles

• tau protein

• Naturally occuring axonal protein

  • Cross bridges with microtubules, promotes tubulin polymerization

  • Microtubules stability

• Abnormally phosphorylated in AD

  • Inhibits tau tau and tau tubulin

  • Produces cytoskeletal disruption

  • Altered protein transport from and to dendrites

  • NFT contributes to neuronal cell death

• Good correlation between severity of dementia and NFT

Alzheimer’s disease ‘typical’ progression

• mild cognitive impairment

• AD early phase

• Forgetfulness, anxiety. Agitation

• Middle phase

  • Withdrawal, loss of insight

• Late phase

  • Aphasiam affected comprehensive

Disease progression

• pathology appears sequentially

• Early shrinkage- temporal lobes, then frontal cortex

• Progressive spread to whole cortex and subcorticla structure

Causes of AD - genetic s

• two presentation

  • Early onset/ familial strong genetic component

  • Late onset - sporadic

• Genetic implicated in familial disease

  • Rare, autosomal dominant

• Mutation in APP

  • Copy number

  • Other clusters around cleavage sites

  • Alter APP processing

• Mutation in resembling

• Genetic implicated sporadic disease

• Age

• Lancet modifiable factor

Treatment

• all symptomatic

  • Do not affect underlying diseases process

• Treat cognitive symptoms

  • Acetyl cholinesterase inhbitor

  • NMDA receptor antagonist

• Non cognitive symptoms

  • Behaviour and psychological symptoms of dementia

Acetylcholinesterase inhbitors

• loss pf cholinergic neurones

• Substantial contribution to cognitive and non cognitive symptoms

• Counteract cholinergic deficits by inhibiting the b/d of acetylcholine

Acetylcholinesterase inhbitors examples

• donepezil- selective AChE inhibition

• Galantamine- selective AChE inhibition

• Rivastigmine- AChE/ BuChE inhibition

Excitotoxicity- NMDA receptor antagonist

• excessive glutamate release

  • Activate NMDA receptor

• Calcium influx results

  • Leads to the formation of reactive oxygen species and mitochondrial damage

  • This oxidation stress and the activation of protease and endonuclease break down cells protein and nucleic acids and contribute too neuronal death

Current treatment- NMDA receptor antagonist

• NMDA receptor antagonist

  • Memantine- uncompetitive antagonist appears not to affect normal NMDA receptor activity

  • Moderate to advanced AD

    • No/ little delay in disease progression

  • No change in Ab

New drugs

• Aducanumab

• Lecanemab

  • Recieved accelerated approval as treatment for Alzheimer’s disease form the US food and drug administration

  • Monoclonal antibody- target and aims to reduce Abeta

  • First new class of drugs appproved for approx. 20 years

Dementia with Lewy bodies

• alpha syncleinopathy

  • Round inclusion bodies in cytoplasm of neurons

  • Substantia nigra and cortex

• Loss of dopamine and acetylation choline

• Symptoms

  • Fluctuating cognitive function

    • Hallucination

  • May respond better to cholinesterase inhibition than AD

  • Movement disorder treated in similar ways to PD

Frontotemporal dementia

• younger onset

  • Frontal/ temporal lobe affected

  • Behaviour variant

    • Early decline in social interpersonal and personal conduct

    • Disinhibition and executive functioning

• Semantic variant

• Recent memory typically preserved

• Pathology

  • Pick cell/ bodies

  • Protein inclusion

    • Tau/ TDP-43

    • No Abeta

    • Little benefit of cholinersterase inhibitors