Alzheimer's and other Dementias (Yvonne Mbaki)

Question 1

Outline Vascular Dementia

Answer 1

Blood supply to the brain is blocked or interrupted by a blocked or diseased vascular system

Question 2

What are the features/causes of VD?

Answer 2

Reduced cerebral perfusion (strokes), thromboembolism, small blood vessel disease in the brain, bleeding into the brain.

Question 3

How is VD diagnosed?

Answer 3

Confirmed lesions that are caused by vascular disease using MRI or CT scans

Question 4

How can VD be treated?

Answer 4

No approved treatments at present
Clinical trials; cholinergic stimulants, vasodilators, platelet aggregation inhibitors
Preventative measures to stop/prevent the initial blockage or interruption to cerebral blood flow

Question 5

What is Dementia with Lewy Bodies? (DLB)

Answer 5

Prominence of alpha-synuclein in dopaminergic neurons of substantia nigra (a-synuclein is the protein that is found in the Lewy body)

Question 6

How is DLB diagnosed?

Answer 6

Fluctuating cognition - varying attention/alertness
Visual hallucinations
Movement disorder
Dementia with Lewy Bodies is diagnosed at the same time as Parkinson’s disease or beforehand.

Question 7

What is Parkinson’s Disease Dementia? (PDD)

Answer 7

Diagnosed after Parkinson’s disease already present in patients with existing movement disorder

Question 8

What symptomatic treatment can be used to treat DLB and PDD?

Answer 8

Cognitive - cholinesterase inhibitors e.g. donepezil and rivastigmine OR NMDA receptor blockers such as memantine to block glutamate
Motor - levodopa
Psychiatric - antipsychotics are contraindicated
Non-pharmacological treatment
Memory prompts, education of caregivers, mobility aids etc

Question 9

What is Fronto-temporal Dementia? Refer to the role of two lobes affected.

Answer 9

Frontal lobe ; reasoning, personality, judgement
- loss of emotional warmth, apathy, selfishness
Temporal lobe ; speech, language and memory
- declines in language

Question 10

What is the cause of Fronto-temporal Dementia?

Answer 10

Mutation in tau protein

Disrupts normal cell processes leading to the death of nerves

Question 11

How is Fronto-temporal Dementia diagnosed?

Answer 11

Neuropsychological evaluation

Question 12

What is the pathophysiology of Alzheimer’s disease - beta amyloid plaques?

Answer 12

Normal function of alpha secretase alongside gamma secretase ensures that amyloid precursor protein is cleaved from the nerve cell membrane, to produce a harmless P3 protein fragment.
In an abnormal cell prone to Alzheimer’s, the alpha secretase is replaced by beta secretase (mutation?). When is cleaves the amyloid precursor protein it produces a beta-amyloid protein fragment. These fragments build up to form plaques that leads to neurodegeneration.

Question 13

What is the pathophysiology of Alzheimer’s disease - neurofibrillary tangles?

Answer 13

Related to the tau protein mutation. Normally the tau protein is responsible for the stability of microtubules that maintain a stable cell and also regulate nutrients in the brain. When tau is phosphorylated the microtubule tangles, impeding nutrients and causing neurodegeneration.

Question 14

What are cholinergic pathways involved in?

Answer 14

Cognition and memory

Question 15

What is glutamate involved in?

Answer 15

Learning

Question 16

What is serotonin (5-HT) involved in?

Answer 16

Psychoses and mood

Question 17

What is GABA involved in?

Answer 17

Anxiety and lethargy

Question 18

What is noradrenaline involved in?

Answer 18

Aggression

Question 19

Are there genetic factors affecting the aetiology of Alzheimer’s?

Answer 19

Genetic factors
(Icelandic Study) - variant in amyloid precursor protein gene that protected elderly against Alzheimer’s.
Autosomal mutations in chromosome 14, 1 and 21 in families displaying the disease.
Late onset Alzheimer’s disease is linked to the gene apolipoprotein E (APOE) (allele 4) associated with lower cognitive performance and mild cognitive impairment that leads to dementia.

Question 20

What environmental factors can lead to Alzheimer’s disease?

Answer 20

Head trauma survivors have been found to overexpress amyloid precursor protein which can increase the risk of amyloid plaque formation.

Question 21

Can diet and malnutrition affect development of Alzheimer’s?

Answer 21

High cholesterol in rabbits lead to formation of amyloid plaques
Greater vitamin B12 deficiency in families with Alzheimer’s

Question 22

Symptoms of Mild AD?

Answer 22

Short term memory impairment and aphasia (inability ot communicate in speech)
Reversal changes i.e. previously social person becomes disinterested.
Depression
Acute episodes of confusion, disorientation, agitation and hallucination

Question 23

Symptoms of Moderate AD?

Answer 23

Poor retention of recent memories that can be triggered by cues
Chronological sequences of events become muddled
Language and comprehension impaired
Executive / decisive function diminshes
Reduced capacity for self care
Evidence of neurobiological changes to the brain
Serotonin, dopamine and noradrenaline implicated in aggression
Reduced function in frontal lobes determined by imaging
Sleep disturbances as a result of changes in the brain stem

Question 24

Which neurotransmitters are responsible for display of aggression in patients with moderate Alzheimer’s disease?

Answer 24

Serotonin, noradrenaline and dopamine

Question 25

Symptoms of Late AD?

Answer 25

Memory function is severely impaired, language skills are lost and speech is impoverished. Assistance is required with self-care and the patient is incontinent. Challenge with swallowing Mobility diminishes to person being chair bound or bed bound. Aggression, agitation, sleep disturbances, psychoses, depression.

Question 26

Symptoms of Advanced AD?

Answer 26

Dependent, mute, swallow, incontinence, pneumonia, influenza, cardiac, stroke. Death

Question 27

What is MMSE?

Answer 27

Mini Mental State Examination (MMSE) - assesses mental impairment rather than diagnosing dementia - accuracy is influenced by education

Question 28

What are some sample questions of MMSE?

Answer 28

Orientation to time - 'What is the date' Registration - told three words to repeat again at end of conversation Naming - 'What is this' Reading - 'Please read this and do as it says' i.e. close your eyes Clock test drawing

Question 29

What medical diagnostic tests are carried out?

Answer 29

MRI and CT Blood tests to eliminate organic disease state Cell loss - enlarged ventricles or shrinking of the brain tissue on MRI or CT

Question 30

What is the aim of management?

Answer 30

Current drugs aim to improve symptoms rather than treating the underlying cause

Question 31

What are the challenges with treatment?

Answer 31

Hard to distinguish between different forms of dementias Main side effect of drug treatment is further confusion Delay in efficacy Many drugs cause significant side effects before positive effect is observed and so are discontinued.

Question 32

How are cognitive symptoms treated?

Answer 32

Cholinesterase inhibitors: Donepazil (Aricept) - most suitable Rivastigmine as a transdermal patch Galantamine as extended release formulation.

Question 33

What are the side effects to Donepazil, Rivastigmine and Galantamine? (Cholinesterase inhibitors)

Answer 33

``` GI disturbances (increased constipation) Cardiac problems (reduced heart rate) ```

Question 34

How is the duration of treatment with CI's determined in mild to moderate AD?

Answer 34

As long as benefits outweigh the side effects | Decline in function - consider a higher dose or swapping to an alternative

Question 35

What is Memantine and how does it act? | What are the side effects?

Answer 35

NMDA receptor blocker Treats moderate to severe Alzheimer's disease Protects the brain nerve cells against glutamate that is released by damaged cells in Alzheimer's disease. GI disturbances, Hypertension and Dizziness are among the side effects of Memantine.

Question 36

What are 'other' treatments for Alzheimer's?

Answer 36

Gingko biloba - chinese herbs improves circulation Vitamin E - slows down progression (modest evidence) Selegiline - treatment for Parkinson's disease with evidence that t effects mood, behaviour, memory

Question 37

What are the ethical challenges with treating behavioural symptoms?

Answer 37

Legal consent is required, psychotropic drugs have a sedating affect. Are they being used for therapy or sedation?

Question 38

What are antipsychotic drugs used for in Alzheimer's?

Answer 38

Treats aggressive behaviour, agitation and other behavioural symptoms

Question 39

What are the risks in elderly patients with using some psychotropic drugs?

Answer 39

Cerebrovascular stroke in the elderly increased risk when taking Risperidone and Olanzapine. Best avoided in dementia with Lewy bodies due to induction of severe parkinsonism even at low doses.

Question 40

When are psychotropic drugs indicated? What kind of AD?

Answer 40

Lewy bodies Dementia - induces Parkinsonism

Question 41

How can depression in AD be treated?

Answer 41

CBT is the best option There is generally little efficacy of antidepressants SSRIs are fist choice - Citalopram due to fewest interactions Venlafaxine may also be considered If effective, prescription should be 6 months

Question 42

What drugs can be used to stabilise mood in AD?

Answer 42

In AD there is little or no evidence to show that Carbamazepine or Sodium Valporate can treat aggressive behaviour Side effects ; sedation and liver dysfunction

Question 43

What role do hynotics and anxiolytics have in AD treatment?

Answer 43

Benzodiazepines - limited use due to oversedation | Sleep disturbances; short acting benzos Temazepam or Melatonin

Question 44

What non-pharmacological management can be used in AD that is mild?

Answer 44

``` Memory training (diaries, memo books etc) Cognitive stimulation therapy - NICE approved for mild Alzheimer's ```

Question 45

What non-pharmacological management can be used in AD that is moderate to severe?

Answer 45

Validation Therapy re hallucinations Reminiscence Therapy - good at combatting depression Multi-sensory stimulation Physical therapy Music therapy etc No specific approach is deemed superior over the other

Question 46

What are some of the diagnostic tests and treatments of the future?

Answer 46

Diagnostic blood tests with biomarker for beta amyloid protein though translating changes in blood to brain ]Diagnostic CSF ; translatable to brain function Beta amyloid protein decreased in patient's CSF because used up in plaques Tau protein increased in patient's CSF Structural neuroimagining

Question 47

What drugs are in clinical trials for the treatment of AD?

Answer 47

Secretase inhibitors - gamma or beta secretase enzymes involved in beta amyloid plaques Beta amyloid vaccinations aim to increase the removal of beta plaques Gene therapy of the future also