S8) Dementia and Delirium

Question 1

What is dementia?

Answer 1

It is an umbrella term - best described as a set of symptoms

The result of the progressive destruction of neurons- a chronic, progressive syndrome of insidious onset

Symptoms will differ depending on where the damaged neurons are within the brain

Question 2

Identify cognitive symptoms of dementia.

Answer 2

– Impaired memory (temporal lobe involvement)

– Impaired orientation (temporal lobe involvement)

– Impaired learning capacity ((temporal lobe involvement)

– Impaired judgement (frontal lobe involvement)

Question 3

Identify non-cognitive symptoms of dementia.

Answer 3

– Behavioural symptoms

• Agitation
• Aggression (frontal lobe involvement)
• Wandering
• Sexual disinhibition (frontal lobe involvement)

– Depression and anxiety

– Psychotic features

• Visual and auditory hallucinations (hallucinations=false perceptions)
• Persecutory delusions (delusions=false beliefs)

– Sleep symptoms

• Insomnia
• Daytime drowsiness (decreased cortical activity)

Question 4

Identify the different types of dementia in order of prevalence

Answer 4

1. Alzheimer’s disease
2. Vascular dementia
3. Lewy body dementia
4. Frontotemporal dementia
5. Aids related dementia - uncommon

Question 5

In Alzheimer’s disease, there is plaques and tangles.

Which protein is involved in the plaque formation and what is its normal role?

Answer 5

There’s this protein called Amyloid precursor protein (APP)

This helps to repair neurons following damage

Question 6

In Alzheimer’s disease, there is plaques and tangles.

How are the plaques formed?

Answer 6

This is an extracellular process.

Protein called Amyloid precursor protein (APP) → this helps to repair neurons following damage
Being a protein, it is periodically replaced

Enzymes called alpha and gamma secretase normally chop it up for disposal (normally into soluble parts)

However, if Beta secretase gets involved, the resulting parts of APP are no longer soluble

These insoluble peptides accumulate outside the cell.: we get Beta amyloid plaques (not soluble .: can’t be disposed off - formation of plaque)
•It fills up the space between neurons + reduces signal transmission (leading to death)

Question 7

What is the effect of the beta amyloid plaques seen in AD?

Answer 7

Plaques can also induce an inflammatory response → Causing neuronal death

If plaques deposit around blood vessels:
– Amyloid angiopathy can occur

– Weakened blood vessels can bleed

Note: usually we get a definite diagnosis of AD post-mortem to find the plaques

Question 8

In Alzheimer’s disease, there is plaques and tangles.

Which protein is involved in the tangle formation and what is its normal role?

Answer 8

Tau proteins

play a role in stabilising microtubules within the neuronal cytoskeleton

• Microtubules help to mobilise nutrients around the neuron

Question 9

How do we get the formation of tangles in AD?

Answer 9

This is an intracellular event

→ Beta amyloid plaques (outside the neuron) induce pathological processes within the neuron

→ Results in hyperphosphorylation of Tau proteins

→ Causes a change in the shape of Tau proteins

→ No longer able to support cytoskeleton

→ Neuron death

→ Also aggregate together into tangles - neurofibrillary tangles

Question 10

What are the macroscopic changes seen in AD?

Answer 10

→ Global cortical atrophy
→ Sulcal widening
→ Enlarged ventricles (primarily lateral and third affected)

Question 11

What are the microscopic changes seen in AD?

Answer 11

→ Plaques
• Composed of amyloid beta

→ Tangles
• Hyperphosphorylated tau protein

It is believed that plaques and tangles kill neurons.

Since neurogenesis is limited in the CNS, any neurones that die are unlikely to be replaced

* Predominant neurons affected:
o Cholinergic (treatments target this)

o Noradrenergic o Serotonergic

o Those expressing somatostatin

Question 12

What is the correlation of acetylcholine and AD?

Answer 12

Acetylcholine (ACh), a neurotransmitter essential for processing memory and learning, is decreased in both concentration and function in patients with Alzheimer’s disease.

This deficit and other presynaptic cholinergic deficits, including loss of cholinergic neurons and decreased acetylcholinesterase activity, underscore the cholinergic hypothesis of Alzheimer’s disease.

This is important to be aware of as certain Alzheimer’s medications target this problem e.g. acetylcholinesterase inhibitors - inhibits the breakdown of AcH .: enhances the levels of AcH at the synapse.

Question 13

What are the two types of AD?

Answer 13

1. Sporadic
2. Familial

Question 14

Identify features of sporadic type of AD.

Answer 14

– 90-95% of AD is this type
– Causes are poorly understood
• Genetic and environmental (in other words, we don’t know)
– Prevalence increases with age
• 50% of 85 year olds

Question 15

Identify features of familial type of AD.

Answer 15

– 5-10% of AD
– Early onset dementia
– PSEN 1/2 genes - mutated- implicated
– Mutation of gamma secretase - resulting in formation of beta amyloid plaques

– Trisomy 21 (Down’s syndrome) - more likely to produce beta amyloid plaques
– Disease may present as early as 40 years old

Question 16

Identify symptoms of AD.

Answer 16

Related to severity of disease

• Initially symptoms hard to detect
• Short term memory (hippocampus) often first to show
• Motor and language skills affected
• Long term memory loss
• Disorientation
• Immobilisation is often linked to cause of death
• Pneumonia

Question 17

How can we diagnose AD?

Answer 17

– CT scan – showing macroscopic changes (can also rule out other intracranial pathology)

– Brain biopsy (postmortem) is only definitive method

Diagnosis by exclusion:

• Exclude organic causes of cognitive decline
  o Hypothyroidism

o Hypercalcaemia

o B12 deficiency

o Normal pressure hydrocephalus
→ Abnormal gait
→ Incontinence
→ Confusion

• Exclude delirium
• Look for features of progressive cognitive decline, impairment of activities of daily living in a patient with a normal conscious level (cf. delirium where conscious level is diminished with acute cognitive decline)

Question 18

How can we assess mental health?

Answer 18

Mental State Examination (MMSE - 30 points) can be used to classify the severity of cognitive impairment in Alzheimer’s disease

– mild Alzheimer’s disease: MMSE 21 to 26

– moderate Alzheimer’s disease: MMSE 10 to 20

– moderately severe Alzheimer’s disease: MMSE 10 to 14

– severe Alzheimer’s disease: MMSE less than 10

Question 19

What treatment is available for AD?

Answer 19

– No cure
– Acetylcholinesterase inhibitors - due to deficient AcH Associated with AD - inhibits the enzyme that breaks down Act the synaptic cleft.
– Memantine (for advanced cases)
• Glutamate receptor antagonist. - glutamate is an excitatory neurotransmitter - v high levels of this is said to make AD worse .: we give an antagonist.

Question 20

Describe features of Lewy body dementia.

Answer 20

– Dementia like features early

– Parkinsonian features later

– Occurs 50-85 years old

– More rapid progression

Essentially the same disease as Parkinson’s. If movement disorder followed by dementia then we call this Parkinson’s disease. If dementia precedes movement disorder we call it dementia with Lewy bodies

– often misdiagnosed as it has similar presentation to AD and Parkinson’s disease.

Question 21

What is the protein involved in Lewy body dementia?

Answer 21

Alpha synuclein

Question 22

What is Lewy body dementia caused by? (pathology)

Answer 22

Caused by misfolding of a protein (in the neuron) called alpha-synuclein

These misfolded proteins aggregate into Lewy bodies. - forms spherical intracytoplasmic inclusions

Question 23

What are the main sites of deposition of the misfolded protein in Lewy body dementia?

Answer 23

Main sites of deposition are the:

– Cortex (dementia type symptoms) - similar to Alzheimer’s disease symptoms

– Substantia Nigra (parkinsonian features)
– Temporal lobe

– Frontal lobe

– Cingulate gyrus (found just above the corpus callosum)

Note: Can label alpha synuclein in the brain using advanced imaging techniques

Question 24

How does a person with Lewy body dementia present?

Answer 24

o Fluctuating cognition and alertness

o Vivid visual hallucinations

o Parkinsonian features
→ May cause repeated falls

o Do not give antipsychotics (dopamine antagonists) as can cause neuroleptic malignant syndrome, a psychiatric emergency
→ Fever
→ Encephalopathy (confusion)
→ Vital signs instability (tachycardia, tachypnoea (v.sensitive sign), fluctuating BP)
→ Elevated creatine phosphokinase
→ Rigidity (caused by dopamine antagonism)

Question 25

In a person with Lewy body dementia, why should we not give antipsychotics?

Answer 25

These are **dopamine antagonists** - as can cause **neuroleptic malignant syndrome, a psychiatric emergency** → Fever → Encephalopathy (confusion) → Vital signs instability (tachycardia, tachypnoea (v.sensitive sign), fluctuating BP) → Elevated creatine phosphokinase → Rigidity (caused by dopamine antagonism)

Question 26

What are the symptoms seen in Lewy body dementia?

Answer 26

**Cognitive symptoms (early)** * Very **distressing hallucinations** (often small people and furry animals) * Depression * REM sleep disorders • Sleep walking/talking **Parkinson's symptoms (later)** * Bradykinesia * Resting tremor * Stiffness

Question 27

What is the treatment for Lewy body dementia?

Answer 27

– **symptom based** – **levodopa** (dopamine analogue) - precursor to dopamine - helps with the Parkinsonian symptoms

Question 28

What is frontotemporal dementia?

Answer 28

Over the past decade or two, it has become apparent that **FTLD** is an **umbrella term** for a **heterogeneous group of diseases** that can be characterized based on the type of glial and neuronal proteinaceous inclusions or underlying genetic mutation **2nd most common cause** of **early onset dementia** Affects the **frontal and temporal lobe atrophy** **Broadly similar disease process to Alzheimer disease** **Often younger patients**

Question 29

What causes frontotemporal dementia?

Answer 29

**Aggregated proteins (inclusion bodies)** • **Tau protein hyperphosphorylation (Pick’s disease) -** they are called Pick's bodies (not tangles) in this dementia

Question 30

What symptoms do you see in frontotemporal lobe dementia?

Answer 30

Symptoms are related to loss of function of these areas * *Frontal lobe** - Behavioral and emotional changes - Disinhibition (hostility) - Inappropriate social behaviour - Loss of motivation without depression (caused by damage to anterior cingulate cortex) - Repetitive/ritualistic behaviours - Non fluent (Broca type) aphasia * *Temporal lobe** - Language impairment (progressive aphasia)

Question 31

What investigation can you do to diagnose frontotemporal dementia? What will you find?

Answer 31

**MRI scan** * Unilateral (or bilateral) frontal/temporal atrophy * Ventricle enlargement

Question 32

What is vascular dementia?

Answer 32

– 2nd most common cause of dementia – it is a **heterogenous dementia** – can **affect multiple sites in brain** – Presentation related to area of brain affected – Risk factors are usual suspects

Question 33

Describe the presentation of vascular dementia.

Answer 33

**Stepwise**, maybe with **focal neurological features**

Question 34

What are the risk factors for vascular dementia?

Answer 34

o Previous stroke / MI etc o Hypertension o Hypercholesterolaemia o Diabetes o Smoking

Question 35

What causes vascular dementia?

Answer 35

**Cognitive impairment caused by cerebrovascular disease** Caused by **multiple infarcts and ischaemia** • Atherosclerosis/emboli/hypertension and vasculitis | (**multiple small strokes**)

Question 36

What is the treatment for vascular dementia?

Answer 36

Treatments target risk factors e.g. reducing blood pressure, thinning blood - anticoagulants? antiplatelets?

Question 37

Describe features of HIV and AIDs dementia.

Answer 37

Not particularly common as HIV and AIDs is not common – Individuals are living much longer - As patients with HIV infection live longer thanks to modern treatments, their chance of developing AIDs associated dementia is increasing – **Occurs when CD4+ count falls below threshold** – **Damage caused by virus itself** (not opportunistic infections) – **Viral proteins cause injury/inflammation** → Result is **neuron damage** – AIDS dementia complex can **affect behaviour, memory, thinking, and movement**

Question 38

What is the pathology of AIDs dementia?

Answer 38

– **Cause poorly understood**: : **entry of HIV infection** **macrophages** into the **brain** is thought to lead to **indirect damage of the neurons.**

Question 39

What is the presentation of AIDs dementia?

Answer 39

– **Insidious onset** but **rapid progression once established** – Clinical features (related to global damage but also some manifestations of cerebellar involvement) o Cognitive impairment o Psychomotor retardation (slow thoughts and movements, also seen in depression) o Tremor o Ataxia o Dysarthria o Incontinence

Question 40

How can we generally manage dementia?

Answer 40

Using the **biopsychosocial model** **Use of drugs:** o Acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine, galantamine) -Modest efficacy for mild to moderate Alzheimer’s disease o NMDA antagonists (e.g. memantine) -Useful for treating agitation -NMDA antagonist **Psychological:** Few psychological treatments are available for dementia due to its progressive nature **Social:** – Mainstay of management – Key themes: o Explain the diagnosis sensitively o Talk about problems that will arise and how they will be managed o Give results of any special investigations (e.g. scans) o Driving – often a difficult topic to deal with as patients frequently desperate to retain their independence o Finances – Will – Power of attorney o Day care and respite care (mainly to allow carers to rest and provide supportive environment for patients) o Residential/nursing home placement

Question 41

What is delirium?

Answer 41

Delirium (sometimes called ‘**Acute confusional state**') is an **acute, fluctuating syndrome of disturbed consciousness, attention, cognition and perception.** **Often reversible, due to organic cause** * *Associated with a variety of insults to the brain which may cause** * *neuronal damage and inflammation**

Question 42

What is the relationship between dementia and delirium?

Answer 42

**Dementia can predispose to episodes of delirium** but is not the only reason behind delirium.

Question 43

How does delirium present?

Answer 43

– Presents **suddenly** **–** Rapid onset of confusion – Clouded consciousness (may be drowsy) – Fluctuating course – Maybe transient visual hallucinations – Often exaggerated emotional responses (e.g. aggression) Categorised as: • **Hyperactive** – Agitated/aggressive – Delusions – Restless • **Hypoactive** – Withdrawn – Drowsy – Quiet – Consequently more likely to be missed / confused with something else or can be a mixture of both … → Mood may rapidly fluctuate → Persecutory delusions (narrative of elusion often not coherent) → Symptoms worse at start and end of day • Maybe related to changes in endogenous cortisol levels

Question 44

What are some causes of delirium?

Answer 44

**D**rugs e.g. opioid - co-codamol, e.g. steroids → psychosis **E**pilepsy/ Electrolyte imbalance **L**iver failure/ low oxygen (MI, PE) **I**nfection e.g. UTI **R**etention (urinary/ faecal - constipation) **I**ntracranial **U**raemia **M**etabolism Multifarious (use a surgical sieve approach) o Nutritional  Vitamin deficiencies o Intracranial  Strokes, TIAs, epilepsy, infection etc. o Extracranial infections  UTI, pneumonia o Iatrogenic  Infections  Drugs o Alcohol  Intoxication  Withdrawal (including delirium tremens, caused by changes in GABA and NMDA receptors induced by long term alcohol consumption) o Endocrine  Thyroid  Pancreas o Metabolic  Hypoxia  Renal (e.g. electrolyte disturbances)  Hepatic

Question 45

What would the history be like for a person with suspected delirium?

Answer 45

– Not explained by previous neurological condition – Conversely, can be attributed to a known risk factor

Question 46

How can you treat delirium?

Answer 46

– **Find and treat the underlying cause** – Minimise/treat precipitating factors (e.g. correct electrolyte imbalance) – Encourage normal day/night cycle – Allow wandering if safe (don't want to upset/ aggravate them) – Involve family/loved ones – For challenging behaviours – distraction techniques – Medications last resort • Haloperidol/newer antipsychotics

Question 47

What is the prognosis of delirium?

Answer 47

– Increases risk of dementia – Associated with mortality – These patients often have lengthy hospital stays and have a high risk of readmission

Question 48

Fill in this table: delirium vs dementia

Answer 48

Question 49

What is the natural history of dementia? Why do people with dementia die?

Answer 49

It is a chronic progressive disorder - slow progression until death involves neurodegeneration - damage and death of neuron Dementia deaths can arise rom: – immobility - huge factor – lose ability to speak and swallow .: can die from aspiration pneumonia – UTI – general malaise (unable to swallow and therefore malnourished)