Introduction

Dementia is a progressive global decline cognitive function, without impairment of consciousness. It is typically defined as a syndrome secondary to one or more of multiple causes, rather than a diagnosis in its own right.

Mild Cognitive Impairment (MCI) is defined a decline in cognitive function which does not affect day to day functioning. It is often seen as a pre-cursor to dementia – 50% of those with MCI go on to develop dementia.

Dementia is associated with increased mortality, and has a large economic impact.

The DSM-IV criteria for the diagnosis of dementia include:

• Clear evidence of decline in memory and learning (e.g. MMSE or MOCA), PLUS
• At least one of:
  • Reduce language ability – aphasia
  • Reduced motor ability – apraxia
  • Reduced recognition – agnosia
  • Reduced executive function – e.g. planning and organising
• Symptoms interfere significantly with social or work functioning
• Gradual onset and continual decline
• No known organic cause
• Not due to delirium
• Not due to mental health disorder – e.g. depression

• Normal reduced cognition of advanced age
• Delirium (see below)
• Depression – sometimes termed pseudodementia in this context. In this case, the decline in cognitive function will usually resolve when the mood disorder is treated. There is also often a previous history of depression or other mental illness
• Drug abuse / side effect
• Medical disorders
  • Anaemia
  • Hypothyroidism
  • Other endocrine disorders
  • Cerebral tumours / metastases
  • Syphilis (neurosyphilis)
  • Amyloidosis
  • Creutzfeldt-Jakob disease (CJD)
  • Poor nutrition (often also a feature of dementia)

Differentials for acute confusion (delirium):

Pathogenesis

Alzheimer’s disease

• Is associated with reduced life expectancy
• The mean survival is 7 years
• Death usually results from bronchopneumonia
• There is a general atrophy of brain tissue, and the weight of the brain is usually reduced. The frontal and temporal lobes are particularly affected.
• There is often compensatory dilatation of the ventricles, resulting in hydrocephalus.
• The cerebellum and spinal cord are normal

Pathological processes

It is believed that there are two important underlying pathological processes:

• Formation of beta-amyloid plaques (extracellular)
• Formation of intracellular “tangles”

Beta-amyloid plaques

• There may be the excess deposition of beta-amyloid in the brain – leading to the formation of beta-amyloid plaques
  • Amyloid precursor protein – APP is found in the cell membrane of neurones. It is thought to be involved in the cell repair process. Over time, due to normal cell repair, these APPs breakdown
  • α-secretase and β-secretase are enzymes involved in the breakdown of amyloid plaques
  • α-secretase breaks down the protein into soluble remnants that are easily taken away by the blood and lymphatics
  • β-secretin produces non-soluble remnants the end up being deposited as beta-amyloid plaques
  • These plaques often accumulate between synapses and affect nerve transmission
  • They also trigger an immune response, causing localised inflammation
  • They can also deposit around blood vessels in the brain – amyloid antipathy – which weakens blood vessel walls and can increase the risk of haemorrhage
  • However – it is not entirely clear if these plaques cause dementia, or are just a result of some other underlying process which may be the true cause of dementia

Tangles

• Within neurones are microtubules which are used to move nutrients around the cell
• The Tau protein is integral in the structure of these microtubules
• It is thought that beta-amyloid plaques outside the cell, leads to increased activation of kinase within the cell
• Kinase transports phosphate groups to the Tau protein – which causes structural changes in Tau proteins, causing them to dissociate from the microtubule, and TANGLE with other similarly affected tau proteins within the cell
• The lack of tau proteins in the microtubules also weakness the microtubules and they breakdown
• As a result of tangles and non-functioning microtubules, some neurones can’t function and undergo apoptosis

Other pathological effects

• There is also atrophy of cholinergic fibres that run from the hippocampus to the cerebral cortex. Initially there is a reduction on cholinergic transmission, and later a reduction in the synthesis of acetylcholine, particularly in the cerebral cortex itself.
• The damage is variable, and can occur at different rates in different parts of the brain. Most likely to be affected are the Amygdala, temporal cortex, and a few selected brainstem nuclei.
• There is no change in the number of muscarinic receptors, but the number of nicotinic receptors is reduced.
• In very late stage disease there can be variable depletion of other neurotransmitters

Vascular dementia

• Pseudobulbar palsy
• Shuffling gait with small steps – marche a petits pas – sometimes called atherosclerotic Parkinson’s disease.

Lewy body dementia

• Deposition of Lewy bodies in the brain
• Often associated with Parkinsonism and visual hallucinations
• Mental state often fluctuates quite widely

Differentiating types of dementia

• Treating risk factors for cerebrovascular disease in vascular dementia
• Consider specific medical treatments for Alzheimer’s disease

Management

• Even mild dementia increases the risk of accident whilst driving
• Asses the patient’s ability to drive, like you would with any other patient – based on their function
• Many patients will be very reluctant to give up their driving license
• Patients diagnosed with dementia must inform the DVLA (in the UK). In Australia – most states require the roads authority to be informed

I can recall several stories of patients known to me – whom, despite no longer having a driving license (and in some cases not even their own car), have been found to go driving. On one occasion, a patient of mine took his old, unregistered vehicle for a 20km joyride to the next town, was given several tickets by police (unregistered vehicle, driving without a license) – and then was subsequently allowed to drive home! I have no idea how he managed to find his way back again. – Dr Tom Leach

Non-medical management

• Take a patient-centred approach
• Advanced care planning
  • Adults should be assumed to have capacity unless proven otherwise – see below
• Promote independence as much as possible
• Refer to local support services – e.g. special interest groups, social worker
• Consider elder abusive from relative or others

Advanced Care Planning and making a will

• Understand and retain the information involved
• Believe the information is true
• Demonstrate they are able to weigh up the pro’s and con’s of an argument and come to a decision based on these – this doesn’t mean that the decision needs to match what others might deem acceptable. Eccentric or apparently unwise decisions are still just as valid if all of the above factors can still be demonstrated

Where is patient is deemed not competent to make a decision, then decision makers must be seen to act in the patient’s best interest – e.g. in medical care – when deciding on a treatment option (or deciding not to treat).

Relatives and carers should be involved in management decisions wherever possible.

Alzheimer ’s disease

Drug therapy is controversial

• Drugs are expensive
• Offer a modest effect at best – some trials have shown no benefit of the drugs over placebos
  • Greatest effect is with larger doses, but generally these are less well tolerated
  • No benefit has been shown in severe dementia
• In many cases it is thought that they at least allow a few more months in a home care environment
• Drug therapy is usually only initiated by a specialist after discussion with family and carers

• Mechanism – these drugs work by inhibiting cholesterases, and thus increasing cholinergic transmission within the brain.
• Unwanted effects – anorexia, nausea, vomiting, diarrhoea, abdo pain, insomnia, confusion, agitation, headache
  • Note that some of these effects are similar to the clinical symptoms of Alzheimer’s!
• Clinical use – thought to delay the decline of cognitive impairment in 40% of patients – probably only by about 3-6 months. Probably more effective in those without the gene apoE4.
  • Usually initiated at a low dose and titrated upwards whilst monitoring for side effects
  • Important to assess efficacy, and to stop treatment in those who do not respond.
  • Rapid decline is seen when the drug is stopped in previously responsive individuals
  • Have functional benefits that may improve QOL
  • Not recommended in mild cognitive impairment or severe dementia
  • The MMSE score is not designed to differentiate the severity of dementia – it is a useful tool as part of this process, but absolute scores are not indicative of whether or not treatment should be considered
  • NOT useful for non-Alzheimer’s dementia

• Mechanism – an inhibitor of glutamate NMDA receptors. It binds selectively, depending on the voltage, and thus prevents excitotoxicity, without altering gluatamtes role in normal memory and learning.
• It can be given in combination WITH anticholinesterases
• Unwanted effects:
  • Diarrhoea, insomnia, dizziness, headache, hallucinations
  • Again, note that some of these are similar to symptoms of dementia!
• Clinical use
  • Usually more well tolerated than anticholinesterases, but probably not as effective
  • May provide some benefit in cognitive function, and may slow cognitive decline
• Not widely used

• Advanced disease beyond this stage is unlikely to benefit from medical management

This is mild to moderate dementia
NICE guidelines state:

• Treatment to be reviewed every 6 months
• Don’t treat if MMSE <12, as side effects of drug likely to outweigh benefits
• Treatment only to be administered and monitored by specialist centres
• Don’t rely on MMSE as your only tool for aiding prescribing, e.g. get collateral histories, assess function and behaviour

• May be required – particularly at night
• Many types are used
• Rivastigmine – an anticholinesterase drug (as above) often used for this purpose
• Olanzapine (are commonly) or quetiapine (less commonly) may also be used – these are atypical antipsychotics
• Oxazepam or other benzodiazepines may be used to control anxiety at night. They should be used with caution, and only for short duration (e.g. less than two weeks) as they can exacerbate the cognitive impairment of dementia

Vascular Dementia

• Aspirin or warfarin therapy – aspirin often quoted anecdotally, but there is little evidence that low dose (e.g. 100mg daily) therapy provides any benefit against vascular dementia. Some high risk patients may be put on warfarin therapy.
• Controlling BP
• Anticholinesterases and memantine – may have some benefit in vascular dementia.

• Some recent evidence suggests that engaging in cognitively taxing activities late on in life can protect against dementia!
• Vitamin E – has shown in some instances to protect against dementia

• Are commonly found in association
• Medication can be difficult to manage – refer to a specialist for advice
• A common combination is levodopa with quetiapine at night

Prevention

There is evidence that lifestyle factors reduce the risk of dementia. Correcting these factors can also slow the progression of dementia in patients who have already been diagnosed. Factors include:

• Controlling BP – the most important factor
• Regular exercise – 150 minutes of moderate intensity exercise weekly (e.g. brisk walk or similar intensity)
• Controlling hyperlipidaemia
• Healthy weight
• Alcohol consumption – drinking within safe drinking limits reduces the risk
• Diet – e.g. mediterranean diet – maximising intake of plant-based whole foods
• Preventing diabetes and controlling blood sugar
• Mentally stimulating activities

Other Types of Dementia

• Symptoms fluctuate
• Permanent memory dysfunction is not apparent in the early stages
• Associated with Parkinsonianism
• Associated with depression and sleep disturbance
• Causes visual hallucinations – often frightening and persecutory
• There may be transient LOC

• Whipple’s disease
• Parkinson’s disease
• Alcohol/drug abuse
• Huntington’s disease
• CJD
• HIV

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Dementia – patient.info
• Dementia – an update on management – afp

Read more about our sources

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