PBL - Dementia Flashcards
Delirium is diagnosed by what criteria?
Acute onset Fluctuating consciousness levels Is secondary to an underlying medical problem Disordered thinking Visual/tactile hallucinations Illusions
What are the most common causes of delirium?
Infection of the bladder, chest or brain Fever Medication side effect Dehydration Liver or kidney problem Cessation of drug or alcohol use Epilepsy Terminal illness
What are the signs and symptoms of delirium?
Reduced awareness of surroundings - inability to concentrate on one topic - being concerned with one idea and avoiding conversation or questions Cognitive impairment - reduced memory - poor understanding of speech, difficulty speaking Changes in behaviour - hallucinations - sleep disturbances - being agitated, irritable or restless
Describe the main differences between dementia and delirium.
Attention span
- people with delirium can’t focus on anything
Onset
- delirium is rapid onset, within a few hours or days, while dementia is a slowly progressing disease
Fluctuation in symptoms
- delirium symptoms fluctuate, coming and going throughout the day, while in dementia thinking skill and memory remain fairly constant
What is the differentia diagnosis for delirium?
A - Alzheimer's V - vascular disease D - drugs, depression, delirium E - ethanol M - metabolic E - endocrine N - neurological (other primary degenerations) T - tumour, toxins, trauma I - infection A - autoimmune
What are the four main types of dementia?
Alzheimer’s
Vascular
Lewy body
Fronto-temporal
What are the risk factors for Alzheimer’s disease?
Genetics
- a mutation in the APP gene found on chromosome 21
- a mutation in the gene for apoplipoprotein E4 on chromosome 19
Down’s syndrome
- 50% extra APP production due to the 3rd chromosome 21
What are the clinical features of Alzheimer’s?
Failing memory Cognition decline - language - writing - reading - calculation - attention and problem solving Psychiatric - personality and mood changes Neurological - primitive reflexes, postural abnormalities Mute, bed ridden, death
What are the main pathologies seen in Alzheimer’s?
Neuritic plaque
Neurofibrillary tangles
Describe neuritic plaques.
A complex extracellular lesion
Aggregates of filaments with a central core of beta-amyloid protein
Found in the hippocampus and parietal lobes
Describe neurofibrilliary tangles
An intracellular lesion
Paired helical strands of protein close to the nuclei of affected neurons - derived from micro tubule-associated protein tau
- in a hyperphosphorylated state
Mainly affects the temporal and parietal lobes
Where are signs of Alzheimer’s first seen in the brain?
Entorhinal cortex, and then the hippocampus
- atrophy with associated neuron loss
- atrophy most evident in the temporal gyri
Describe what symptoms are seen in mild Alzheimer’s?
Memory loss Confusion Trouble handling money Poor judgment Mood changes Anxiety
Describe the symptoms seen in moderate Alzheimer’s.
Increased memory loss and confusion Problems recognising people Difficulty with languages and thoughts Restlessness Agitation Wandering Repetitive statements
Describe the symptoms of severe Alzheimer’s.
Severe cortical atrophy Completely dependent on the care of others Weight loss Seizures Increases sleeping Loss of bladder and bowl disease Death - usually from pneumonia
How is Alzheimer’ diagnosed?
A typical case history with progressive dementia and negative findings in routine tests
CT scans show non-specific cerebral atrophy with enlarged ventricles
What are the risk factors of vascular dementia?
Hypertension
Atherosclerosis
What is small and large vessel disease?
Small - subcortical
- ministries slowly block off the areas of the brain
Large - cortical multi-infarcts
- brain lesions may affect specific cognitive functions
- multiple infarcts are caused by an accumulations of bilateral multi focal ischaemic events
- dementia progresses in a step wise fashion
How is vascular dementia diagnosed?
History base
Presence of multiple-infarcts on CT and MRI scanning
- also look for presence of beta-amyloid plaques and neurofibrillary tangles
- just because the patient has had a stroke, it doesn’t mean that is the cause of dementia
What are the signs and symptoms of dementia with Lewy bodies?
Progressive cognitive decline Fluctuating consciousness Visual hallucinations Parkinsonism - no resting tremor, no response to L-DOPA treatment
What are the pathological findings of dementia with Lewy bodies?
Similar to Alzheimer’s and Parkinson’s disease
Cortical Lewy bodies form form, often instead of tangles
- present in basal ganglia
- little pink balls
Plaques and tangles can be present as well
Cholinergic deficit
Describe the aetiology of frontotemporal dementia.
Sporadic and inherited
Affects a younger group of patients (aged 45-65 typically)
Frontal lobe dysfunction
- behavioural and personality changes, disinhibition, depression and agitation are common
Cognitive and memory impairment
Describe the pathology of frontotemporal dementia.
Tau accumulations causes plaques called Pick’s bodies
- these contain tau and argyrophilic bodies
Significant fronto-temporal atrophy can be seen
How is frontotemporal dementia diagnosed?
Functional MRI scans show the frontotemporal lobes of the brain to be less active than other areas .
What are the possible treatments for dementia?
Acetylcholinesterase inhibitors
Memantine hydrochloride
Antipsychotics
Antidepressants
Describe the mechanism of acetylcholinesterase inhibitors (e.g. Rivastigmine and Donepezil)
It prevents the breakdown of ACh that crosses the synapses, allowing more action potentials to be passed between neurons #.
Doesn’t treat, merely manages the effect
What are acetylcholinesterase inhibitors used to treat?
Alzheimer’s disease
Dementia with Lewy bodies
Parkinson’s dementia
What are the side-effects of acetylcholinesterase inhibitors?
Nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue, anorexian cardiac adverse events and peptic ulcers/GI bleeding
Describe the mechanism of action of Memantine hydrochloride.
Uncompetitive NMDA receptor agonists (NMDA being a major glutamate receptor)
- Alzheimers causes increased gutamate in the brain
- increased levels of glutamate counters the voltage-dependent block of the receptor by magnesium ions
- constant calcium influx
- neuron degeneration
Memantine blocks these channels more effectively than the magnesium ions to allow normal action of glutamate
What are the risks of using antipsychotics to treat someone with dementia?
CV problems
Drowsiness
Dementia with Lewy bodies
- causes rigidity, immobility and inability to communicate
What cleaves amyloid protein?
Alpha/bet/gamma - secretase
Mutations in what gene is the cause of familial AD?
Presenilins 1 or 2
How do plaques form in dementia?
Mutation in gamm-secretase causes abnormal cleaving of the amyloid precursor protein. Sticky, hydrophobic beta-amyloid plaques form and aggregate together.
What is apoplipo-protein?
A lipoprotein produced by astrocytes, thought to be involved in lipid metbaolism.
Normal function promotes breakdown of A-beta
What happens in an apolipo-protein mutations?
E4 mutation = 20x higher risk of Alzheimers
Inhibits breakdown of amyloid-beta, and this aggregates more easily
What are the four main mutations that can cause Alzheimer’s?
Beta-APP mutations
ApoE4 polymorphisms
Presenilin 1 mutations
Preenilin 2 mutations
What causes neurofibrilliary tangles?
Hyper-phosphorylation of tau protein
Causes soluble tau aggreagtes
Causes tau deposition
- more common in fronto-temporal dementias
How can people maintain cognitive function during aging?
Higher levels of physical activity
Mental activity
Social interaction
Cognitive training intervention
What is the organic pathology of vascular dementia?
Mainly atherosclerotic blood vessels, emboli or other vascular problems.
Can see some cerebral atrophy, beta-amyloid plaques and neurofibrillary tangles, because they are normal in ageing
What are Lewy bodies made from?
Alpha synuclin
Define a molecular chaperone.
Any protein that interacts with, stabilises or helps another protein to acquire its functionally active formation, without being a part of its final structure
What is the name of the enzyme which determines whether a protein has been misfolded or not?
Glucosyltransferase
Briefly describe a proteasome
A hollow cylindrical structure that consists of
- a cap
- alpha subunits (non-enzymatic)
- beta subunits (proteolytic activity)
Describe the formation of Lewy bodies?
Misfoldin into beta-pleated sheet structure of alpha-synuclein that further aggregate into high-order insoluble structures (fibrils)
What is the affected protein in prion disease?
PrPc - becomes PrPsc
