Dementia

What is dementia?

An umbrella term for neurological conditions causing deterioration in multiple cognitive abilities severe enough to impair daily function.

What are the two broad classifications of dementia?

Primary degenerative dementia: Selective neuronal loss in specific connected brain regions.

Secondar/symptomatic dementia: Disorders that damage brain tissue (brain injury), increase intracranial pressure (build up of CSF, hemorrhagic strokes (blood in brain) if pressure mitigates can reverse dementia), or cause cellular malfunction (includes disorders that change how cells metabolize things like glucose).

Name examples of primary degenerative dementias.

Alzheimer’s disease, Parkinson’s disease dementia, Huntington’s disease, frontotemporal dementia.

Name examples of secondary dementias.

Traumatic brain injury, vascular dementia, infections, toxic/drug-induced dementia.

What is young-onset dementia?

Why is young-onset dementia difficult to diagnose early?

Dementia occurring before 65 years of age.

Symptoms and diagnostic criteria may take time to fully appear.

Dementia pathology

caused by what, what are the 2 hallmark lesions

Nerve and synpase loss

Amyloid-β plaques and neurofibrillary tangles (aggregates of protein tau formed intercellulalry within neurons).

What pathology is characteristic of frontotemporal dementia?

Tau pathology without amyloid-β pathology.

Which gene mutations are associated with some forms of Alzheimer’s disease?

amyloid precursor protein (APP), microtubule-associated protein tau (MAPT), presenilin-1 or 2 (PS1 or PS2)

MAPT crucial for microtubules needed for general cell structure so when degraded there is disintegration of cells so they breakdown and die

What is brain atrophy?

What macroscopic brain changes occur in dementia?

Which ventricles enlarge in dementia?

Loss of brain tissue causing shrinkage of the brain.

Widening of sulci, enlarged ventricles, and loss of pigmented neurons in locus coeruleus which is needed for mediating attention, focus and memory

Frontal and temporal horns of the lateral ventricles.

How is amyloid-β formed?

What are normal functions of amyloid-β?

Why is amyloid-β toxic in Alzheimer’s disease?

Cleavage of amyloid precursor protein (APP). from gamma secretase

Synaptic function, synaptic plasticity, and protection against oxidative stress.

Aggregated amyloid-β damages synapses and alters synaptic plasticity.

Which receptors are especially sensitive to amyloid-β toxicity?

What structures are lost due to amyloid-β toxicity?

mGluRs and NMDA receptors.

Synapses and dendritic spines.

Tau

found where, normal function, what happens in dementia and accumulates where

Predominantly in axons.

Stabilises microtubules and regulates axonal transport.

Tau becomes hyperphosphorylated and aggregates from Neurofibrillary tangles.

accumulates in somas and dendrites

What are the 3 possible modes of interaction for Amyloid B and tau

A: AB produced and accumulates inducing tau to hyperphosphorylated leading to toxic environment and cell death

b: AB exist in brain as dormant then something happens and hyperphosphorylated tay and combination of both causes toxic environment and cell death

C: AB and phosphorylated tau form tangles and this combo acts on mitochondria causing dysfunction leading to more ROSS and thus cell death

What is the amyloid hypothesis?

Why has the amyloid hypothesis been questioned?

Can neurofibrillary tangles occur without plaques?

The theory that amyloid-β accumulation causes Alzheimer’s disease.

Plaques can exist in cognitively normal adults and many clinical trials failed.

Yes.

What does acetylcholinesterase (AChE) do?

Why are AChE inhibitors used in Alzheimer’s disease?

Name common AChE inhibitors used in dementia.

Breaks down acetylcholine into choline.

To increase acetylcholine signalling due to cholinergic neuron loss.

Donepezil, rivastigmine

Donepezil

what is it, what it does and a downside

A reversible AChE inhibitor.

Improves memory and cognition relative to placebo.

Delays amyloid B plaque deposition.

lots of side effects because it is not local

Rivastigmine

what is it, what it does and a downside

A reversible AChE and butyrylchonlinesterase inhibitor.

Slows cognitive decline and reduces dementia severity.

Parkinson’s disease dementia.

lots of side effecrs

Memantine

how it works, what it does it dementia and given with what

NMDA receptor antagonist.

Excitotoxicity: Neuronal damage caused by excessive NMDA receptor activation. (quick off rate so binds and blocks only for a short while because we don’t want to block glutamatergic signaling for long time)

Improves cognition in Alzheimer’s disease and vascular dementia.

Given in combination with AChe inhibitors

What is the goal of amyloid-β antibody therapy?

Removal of amyloid-β aggregates.

Aducanumab

Use and why is it controversial

Removes amyloid B plaques

Phase 3 trials showed inconsistent effectiveness and side effects. (enlarged lateral ventricles)

What is scanning ultrasound stimulation (SUS)?

how does it work and what it does

A non-pharmacological therapy using low intensity ultrasound to breakdown amyloid B plaques to a point where they can be broken down by other cells eg microglia

Removed amyloid-β and restored memory performance.