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.

The causes of dementia include:
  • Degenerative cerebral diseases:
    • Alzheimer’s disease (~50%)
    • Lewy Body dementia (10%)
    • Frontal lobe dementia (10%)
  • Diffuse vascular disease (aka multi-infarct dementia) ~25%
  • In practice it is often difficult to differentiate the type of dementia present. There may also be a mixture of causes

Poor memory is the main and often first symptom. Short-term memory is usually the worst affected and in mild to moderate disease, long-term memory is often remarkably well preserved. As the disease advances other cognitive ability is affected, including verbal skills, abstract thinking, judgement and the ability to perform complex tasks.

Depression is a common differential diagnosis for depression, and the two also often co-exist.

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.

Epidemiology

  • Very rare <55 years
  • 5-10% prevalence in >65’s
  • 20% in >80 years
  • 80% in >100 years
  • Female:Male ratio = 2:1
  • The incidence of dementia is declining slightly, however the total number of sufferers of the condition is increasing due to increasing life expectancy

Aetiology

Alzheimer’s disease
  • Genetic predisposition
    • About 15% of cases are familial. These fall into to two categories:
    • An early on-set autosomal dominant disease
    • A later onset type of disease, whose inheritance is variable
    • The most common gene mutation is apoE4 although mutation of this gene does not necessarily mean you will develop Alzheimer’s.
  • Insulin resistance may be a predisposing factor
  • The majority of cases are sporadic with no obviously identifiable cause
  • Risk factors

Symptoms

General symptoms of dementia
  • Memory loss – this is usually the first symptom to appear
    • The damage to brain tissue is not universal, and thus some areas of memory, notably autobiographical and political memory is stored in areas that are less often affected.
    • Short term memory is more readily affected, and confusion may often result. For example, patients may buy many identical items of food on separate occasions, and then wonder why their cupboards are full of these items.
  • Visuo-spatial problems – patients may be easily disorientated by unfamiliar surroundings
  • Emotional disturbance
  • Loss of normal social behaviour
  • Language problems  – Problems both understanding what is being said, and naming objects
  • Concentration issues
  • Short attention span – Also unable to plan, organise, or sequence activities
  • Behavioural changes – Delusions (persecutory), agitiation, aggression, wandering
  • Variable mood
  • Poor sleep
  • Restlessness
  • Hallucinations
  • Apathy
  • Depression / euphoria – Severe depression is rare, due to loss of insight
In later stages of the disease, there may also be:
  • Self-neglect, e.g.
    • Poor hygiene
    • Skin ulcers
    • Poor dentition
  • Change in personality – which generally involves loss of inhibition. This can include previously very uncharacteristic behaviour, such as:
    • Sexual promiscuity
    • Aggression
    • Anti-social behaviour
    • Violence
  • Motor and sensory abnormalities
  • Seizures
In very late stage disease there may be:
  • The patient may become mute
  • They may take little interest in anything
  • Parkinsonism
  • Wasting
  • Seizures
  • Incontinence
These later symptoms can be particularly distressing for relatives and carers.

Presentation

On first presentation, the signs and symptoms may be mild and variable. History is very important, and almost always should involve a collateral history from a relative, friend or carer. Dementia is slowly progressive, and the symptoms may have started years ago.

Common ways dementia can present are outlined below:

The Patient

  • Muddled complaints
  • Multiple presentations of confusion
  • Relapses of previously well-controlled physical disorders
  • Strange or uncharacteristic behaviour

Relatives or carers

  • Report change in personality
  • Unsafe driving
  • False accusations against family members or others
  • Emotional, irritable
  • Wanders off (e.g. in the street)
  • Losing items around the house
  • Confused waking in the night

On Observation

  • Vague, rambling conversations
  • Difficulty putting events in chronological order
  • Repeating phrases
  • Avoidance of memory testing

Diagnosis

The main symptom of dementia is usually reduced memory. Diagnosis is usually clinical, and made with the help of the MMSE (Mini-Mental State Exam) or similar – e.g. MOCA.
  • Patients with a higher IQ have been shown to score more highly on MMSE, despite early dementia
  • Sometimes, IQ tests (Wechsler Adult Intelligence Scale, may also be used).

However, as confusion is often apparent, you may have to perform many other tests to rule out other differentials. The later on in life the presentation, the less likely it is to be investigated.

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

  • Clear evidence of decline in memory and learning (e.g. MMSE or MOCA), PLUS
  • At least one of:
    • Reduce language ability – aphasia
    • Reduce 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

Differentials

  • 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

Differentials for acute confusion (delirium):

The diagnosis of dementia is usually clinical, but often at the time of diagnosis / on the first presentation investigations are performed to rule out other differentials. Always assume confusion is due to an acute illness until proven otherwise.
  • Frequently, patients with dementia will suffer from acute delirium, secondary to an overlying disorder (most commonly UTI or another infection).

Investigations might include:

  • Vitamin deficiencies – ↓folate, ↓B12, (↓thiamine and ↓vit D  –not routinely tested but may be supplemented), –these could be primary deficiencies, or may be alcohol related.
  • TFT’s – thyroid problems
  • FBC – anaemia
  • Calcium
  • U+E’s – renal failure / dehydration
  • LFT’s – carcinoma, cirrhosis, encephalopathy
  • Glucose / HbA1c – diabetes
  • CRP/ESR – acute infection
  • Imaging of the brain – CT/MRI – this may be used to exclude treatable space occupying lesions, such as:
    • Hydrocephalus
    • Tumour
    • Subdural haematoma
    • HOWEVER – the most common abnormality seen on brain scan is general atrophy.
  • Other investigations to consider if specifically indicated:
    • CXR
    • Fasting lipid profile
    • ECG
    • MSU / urine MC+s
    • Syphilis and HIV serology

Differentiating depression and dementia

  • Dementia often has an insidious and poorly defined onset, whilst for depression this is often more clear cut
  • Patients with depression often have a past history of depression or another mental health disorder
  • Patients with depression often have insight, those with dementia do not
  • Patients with depression often complain about their inability to do their normal activities, and how difficult these activities seem, whilst patients with dementia often don’t realise that they are not capable of looking after themselves appropriately
  • In memory testing
    • Patients with depression often report they “don’t know” the answers
    • Patients with dementia will usually attempt an answer, even if it is marginally (or widely – and sometimes comically) incorrect
  • Remember that depression and dementia frequently co-exist – especially in the early stages of dementia

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
  • There may be the excess deposition of beta-amyloid in the brain – leading to the formation of beta-amyloid plaques.
  • 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

This is the result of many small infarcts. Cerebrovascular disease is usually well advanced for vascular dementia to become apparent, as large parts of the cortex have to be affected for patients to be symptomatic.
The disease will have a step-wise progression, so for instance, there will be no apparent change in the condition, perhaps for many months, and then there is a sudden drop in function. Infarcts are particularly likely to affect function if they damage the white matter.
As well as dementia, eventually there may be:
  • Pseudobulbar palsy
  • Shuffling gait with small steps – marche a petits pas – sometimes called atherosclerotic Parkinson’s disease.
There is often also a history if TIA’s

Differentiating types of dementia

The type of dementia can be differentiated by a combination of; history, CT/MRI and neuropsychological testing. This may be clinically relevant, as treatment is different, e.g.:
  • Treating risk factors for cerebrovascular disease in vascular dementia
  • Consider specific medical treatments for Alzheimer’s disease

Management

In all types of the disease, the management is only able to reduce the rate of progression of the disease. There is no cure.
Management includes social support, management of risk factors for further progression, and consideration of medical therapy.
It is also important to discuss the patient’s ability to drive.
  • 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

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

It is frequently possible for the patient to still make a valid will and/or an advanced directive before the patient becomes to ill for one of these to be accepted by law, so long as the patient is deemed to be competent (i.e. has capacity) to make such decisions. Adults should be assumed to have capacity unless proven otherwise, and should be offered all available support to help them make appropriate decisions. For a patient to be deemed to have capacity, the patient must be able to:
  • 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
Anticholinesterase drugs – e.g. donepezil, galantamine, rivastigmine
  • 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
NMDA receptor antagonists – memantine
  • 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
Drug treatment should only be initiated in those with a MMSE of >12!
  • 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
Antipsychotic medications
  • 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

Prevention
Reduction of vascular risk factors:
  • 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.
The burden of care
The course of the disease is often distressing for both families and patient. Supportive care is necessary to ensure the patient stays in a familiar home environment as long as possible. Often the burden of care falls to relatives.
  • 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
Dementia and Parkinson’s Disease
  • A common associated
  • 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

Vascular dementia
In Alzheimer’s disease the progression of the symptoms is always gradual, but in vascular dementia, the symptoms often being acutely followed by a ‘step-wise progression’’. This is due to the pathology -vascular dementia is the result of multiple acute ischaemic events causing damage to specific brain areas.
In cases of vascular dementia you may also find other vascular sings, for example:
  • Raised BP
  • Past strokes
  • Sudden onset / stepwise increase of symptoms
Lewy-body dementia (~15-25% of all cases of dementia)
This is characterised by the presence of Lewy bodies in the brainstem and neocortex. Also sometimes referred to as Pick’s Diseasealthough technically Pick’s disease is a sub-type of Lewy Body dementia. It can be differentiated from other types of dementia by:
  • 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
The drug rivastigmine may help to improve symptoms.

Diagnostic criteria include two of:

  • Visual hallucinations
  • Parkinsonism
  • Fluctuating mental state

Differentiating Lewy Body Dementia is important because in these patients antipsychotics needs to be avoided because they can advance the progression of the disease and are associated with increased mortality.

Fronto-temporal dementia (aka Frontal lobe dementia)

In this condition there is atrophy of the fronto-temporal region, without the histology seen in Alzheimer’s.

  • Is often more difficult to diagnose as it is typically more subtle
  • Causes personality change, and impaired social function

In some cases it may be difficult to differentiate from Alzheimer’s, but behavioural/personality change are more likely to occur early on, and things like memory and spatial awareness may be preserved for longer. There is often massive disinhibition.

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

References

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