Psychiatry - Dementia-Alzheimer's

Question 1

Alzheimer’s disease

Intoduction

Answer 1

Defined as a clinicopathological entity where there are histological changes of neurofibrillary tangles and senile plaques in a patient with dementia:

• affects predominantly the elderly
• progression is characterised by deterioration in cognition (thinking, conceiving, reasoning) and functional ability (activities of daily living) and a disturbance in behaviour and mood
• evidence suggests that Alzheimer’s disease progression is dependent on age, and the time from diagnosis to death is about 5-20 years (median 5 years in people aged 75-80 years)
• people with Alzheimer’s disease lose the ability to carry out routine daily activities like dressing, toileting, travelling and handling money and, as a result, many of them require a high level of care
• non-cognitive symptoms in dementia include agitation, behavioural disturbances (for example, wandering or aggression), depression, delusions and hallucinations.

Question 2

Alzheimer’s Disease

Pathology?

Answer 2

Characterised by neurofibrillary tangles and senile plaques:

• Neurofibrillary tangles found adjacent to the nucleus, within a cell body.
• They are found particularly in pyramidal cells of the association neocortex, in the hippocampus, and in certain subcortical nuclei which send projections to the cerebral cortex such as the nucleus basalis of Meynert, from which there is an ascending cholinergic projection.
• The tangles appear to contain an abnormally phosphorylated microtubule associated protein tau, which fails to bind to microtubules leading to collapse of the neuronal cytoskeleton.
• It is thought that the presence of neurofibrillary tangles may predict subsequent neuronal death.

Senile plaques consist of dystrophic axons and dendrites clustered around an amyloid core:

• The amyloid is composed of beta-amyloid protein which is a proteolytic fragment of a larger membrane-spanning protein called beta-amyloid precursor protein.
• Alternative proteolytic processing of the precursor protein yields peptides which have a high or low tendency to aggregate.

Question 3

Alzheimer’s Disease

Aetiology?

Answer 3

Environmental factors which predispose to Alzheimer’s disease include:

• a history of head injury
• low educational attainment
• there is evidence that increased plasma homocysteine levels is a risk factor for Alzheimer’s disease

Three genes have been linked to the pathogenesis of Alzheimer’s disease:

• beta-amyloid precursor protein:
  
  • chromosome 21
  • specific mutations result in familial Alzheimer’s disease with onset in the sixth decade
  • proteolytic processing of the mutant protein favours the formation of the amyloidogenic A-beta fragment
• apolipoprotein E4:
  
  • chromosome 19
  • the E4 allele increases the risk of Alzheimer’s disease and reduces the mean age of onset
  • the E2 allele protects against Alzheimer’s disease
• presenilin 1:
• transmembrane protein which is mutated in some forms of familial Alzheimer’s disease
• increases the proportion of amyloidogenic peptides derived from beta-amyloid precursor protein
• may be involved in apoptosis
• gene on chromosome 14
• presenilin 2:
  
  • homologous in structure and function to presenilin 1
  • gene on chromosome 1

Question 4

Alzheimer’s Disease

Clinical Features?

Memory Loss

Answer 4

Memory loss:

• the loss being the most prominent defect and is often the presenting complaint
• autobiographical memory, and memory of everyday events is lost early in the disease, whilst short term memory is initially preserved

Question 5

Alzheimer’s Disease

Clinical Features?

language and visuospatial deficits

Answer 5

language deficits:

• appear initially in disease and may mask cognitive impairment
• speech is often empty of meaning and they may have some difficulty finding words
• occasionally patients may be aphasic

visuospatial deficits:

• impairment of topographical memory and patients may become disoriented and get lost easily
• they may have problems with dressing - dressing dyspraxia
• occasionally patients may have a more focal onset of disease involving a breakdown of visual processing resulting in agnosias or rarely, Balint’s syndrome

Question 6

Alzheimer’s Disease

Clinical Features?

Non-Cognitive changes?

Answer 6

Non-cognitive changes common:

• 40% of cases may suffer from depression.
• delusions, hallucinations and the patient may be aggressive.
• fail to appreciate their cognitive deficit - anosognosia.

changes in personality include:

• positive changes - catastrophic reactions
• negative changes

behavioural changes include:

• disinhibition
• deficit
• adaptation to impairment

Question 7

Alzheimer’s Disease

Clinical Features?

Comparison of Alzheimer’s disease & Dementia with Lewy bodies (DLB)

Answer 7

Differentiating Alzheimer’s disease (AD) from dementia with Lewy bodies (DLB):

memory loss:

• in AD this is usually the presenting feature
• in DLB memory may be relatively normal in the early stages

course:

• progressive in AD
• progressive with marked fluctuations in DLB

parkinsonism:

• in the late stages of AD
• in the early stages of DLB

hallucinations:

• not a major feature of AD
• a major feature of DLB

Question 8

Alzheimer’s Disease

Differential Diagnosis?

Answer 8

• dementia with Lewy bodies
• Pick’s disease
• dementia secondary to an acute event, e.g. head injury, acute encephalopathy, severe anoxia.
• chronic alcoholism
• syphilis
• brain tumour
• hydrocephalus and normal pressure hydrocephalus
• Creutzfeldt-Jacob disease
• atherosclerotic - multi-infarct dementia
• Huntigton’s chorea
• B12 deficiency
• ‘dialysis dementia’ secondary to aluminium intoxification
• myxoedema
• pseudodemtia in depression

Question 9

Alzheimer’s Disease

Diagnostic Criteria?

DSM IV Criteria A

Answer 9

The DSM IV criteria require criteria A to F to be met:

Criterion A:

1) memory impairment
2) one or more of the following:

• aphasia - (language disibility)
• apraxia - (difficulty with the motor planning)
• agnosia - (non-recognition of faces)

executive dysfunction:

• planning
• organizing
• abstracting

Question 10

Alzheimer’s Disease

Diagnostic Criteria?

DSM IV Criteria B/C

Answer 10

Criterion B:

The deficits in part A interfere with everyday living and represent a decline from previous functioning.

Criterion C:

The course is characterised by gradual onset and progressive decline.

Question 11

Alzheimer’s Disease

Diagnostic Criteria?

DSM IV Criteria D

Answer 11

The deficits in part A should not be due to:

other diseases of the central nervous system such as:

• Parkinson’s disease
• cerebrovascular disease
• Huntingdon’s disease
• subdural haematoma
• brain tumour
• normal pressure hydrocephalus

systemic causes of dementia:

• hypothyroidism
• B12 or folate deficiency
• niacin deficiency (pellagra)
• hypercalcaemia
• neurosyphilis
• HIV infection

substance abuse

Question 12

Alzheimer’s Disease

Diagnostic Criteria?

DSM IV Criteria E/F

Answer 12

Criterion E:

Deficits should not occur exclusively during periods of delerium.

Criterion F:

The condition should not be better explained by other psychiatric disorder such as depression.

Question 13

Alzheimer’s Disease

Diagnostic Criteria?

Classification of severity

Answer 13

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 14

Alzheimer’s Disease

Investigations (1)?

Answer 14

Apart from histology there are no specific tests for the diagnosis of Alzheimer’s disease. Rule out the differential diagnoses, and to diagnose by exclusion.

• FBC - anaemia and infection
• Urea and electrolytes; creatinine; glucose - to rule out diabetes; hyponatraemia - in case of renal failure
• clotting, LFTs - for liver function
• B12, folate - for vitamin deficiency
• TSH, T4 - for myxoedema
• ESR - for vasculitis
• ECG - for arrhythmias
• CXR - for malignancy and infection
• urinanalysis - for sepsis

Question 15

Alzheimer’s Disease

Investigations (2)?

Answer 15

Routine electroencephalography (to diagnose CJD) and syphilis serology (VRDL) are probably not indicated unless there are unusual features of presentation:

Other possible investigations include:

• CT/MRI scan - check for tumour, hydrocephalus
• Lumbar puncture in cases of chronic meningitis and TB

In selected cases further investigations may be indicated:

• angiogram
• jejunal biopsy - to exclude Whipple’s disease
• cerebral biopsy
• HIV test
• white cell enzymes
• heavy metal and drug screen

Question 16

Alzheimer’s Disease

Management?

Answer 16

Drug treatment:

• some patients will have a good response to the cholinesterase inhibitors, such as donepezil, rivastigmine and galantamine (in the UK) and tacrine (in the US).
• These drugs are available for the treatment of mild to a moderate AD. There may be a slowing or even arrest of cognitive decline for about 8-9 months; however the underlying disease process is not halted
• memantine is another possible drug treatment for AD
• first N-methyl-D-aspartate receptor antagonist to be licensed for the treatment of patients with moderately severe to severe Alzheimer’s disease
• avoid alcohol & drugs if possible, and treat any other disease which may exacerbate confusion
• social and community support - multidisciplinary approach
• exercise - there is evidence that regular exercise may lead to a slower decline in activities of daily living (3)
• there is study evidence that a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period

Question 17

Alzheimer’s Disease

Prognosis?

Answer 17

• Alzheimer’s disease is one of the nastiest afflictions that lies in wait to ambush in late middle age. It robs us of our memory, our wits, our dignity and ultimately of life itself.” - Professor J. Grimley Evans.
• Alzheimer’s disease is progressively debilitating, lasting for between one-and-a-half to fifteen years; median duration is 7-10 years. Death is most commonly due to bronchopneumonia.
• It is important to recognise the impact that Alzheimer’s disease can have on the family of a patient. The terminal stages of home care have been described as the carer suffering a living bereavement. The person they love is all but lost, whilst what remains serves as a constant reminder of this loss and source of grief.

Question 18

Alzheimer’s Disease

Senile dementia of the Alzheimer type?

Answer 18

• Senile dementia is a term used to describe an Alzheimer type of dementia that occurs in the elderly. Usually the condition begins after the age of 70.
• Pathologically the changes are the same as seen in pre-senile Alzheimer’s disease.
• On gross examination, the brain is shrunken with widened sulci and enlarged ventricles.
• Histological examination reveals cell loss, especially in the outer cortical cell layers.
• On silver staining, there is shown to be plaques throughout the cortical and subcortical grey matter.
• With electron microscope examination, the senile plaques are seen to have a central core of amyloid surrounded by abnormal neurites.