Neurology - Dementia, delirium and amnesic syndromes Flashcards
Definition of dementia
= Global impairment of cognition with normal levels of consciousness
What is the incidence of dementia?
5% > 65 years
20% > 85 years
Mental test scores that would prompt concern about dementia
Mental test covers:
- Orientation
- Long term memory
- Concentration
- Short term memory
>8 = normal 4-7 = mild - moderate dementia
What symptoms occur in dementia?
- Personality change
- Nocturnal wanderings
- Reversed day-night sleep cycle
- Intellectual decline
- Mood change
Specific profile of higher cognitive function deficits depends on the extent and distribution of pathology in the cerebral cortex
What testes should be performed to rule out reversible causes of dementia?
- CT/ MRI (rule out normal pressure hydrocephalus, subdural haematoma, intracranial tumours)
- Na+ (chronic hyponatraemia)
- Vit B12
- Thyroid function (rule out hypothyroidism)
- Syphilis serology
- LFTs
- Renal function
- ESR (Paraneoplastic syndromes or autoimmune encephalopathy associated with anti voltage gated potassium channel antibodies)
- FBC (raised WCC occurs in Whipple’s disease which can cause dementia)
What are common causes of dementia?
1) Alzheimer’s disease (65%)
2) Vascular dementia
3) Frontotemporal dementia
What patients may present with “pseudo dementia”?
- Severe depression
- Uncontrolled epilepsy
NB - it is useful to do an MSE in patients with dementia to exclude depressive pseudodementia but be aware that depression is an element common to all dementias
What is normal pressure hydrocephalus? How does it present?
May result from a diffuse abnormality of CSF uptake causing ventricular dilation
It has a slowly progressive course
It presents as a triad of:
1) Dementia
2) Incontinence
3) Gait disturbance
Causes of dementia in a young person
- New variant CJD
- HIV
- Vasculitis
- Inherited disease
Clinical features of dementia affecting frontal lobe function
- Executive dysfunction = difficulty in performing complex tasks and planning ahead
- Alterations in behaviour and personality = caused by degeneration of the prefrontal cortex
- Expressive dysphasia = problems with expressive or motor aspects of language (due to degeneration of Broca’s area)
What are the clinical features of dementia affecting parietal lobe function?
- Apraxia = Impairment of visuospatial and motor abilities
- Dyslexia = inability to read
- Dyscalculia = deterioration in simple arithmetic
Clinical features of dementia affecting temporal lobe function
- Receptive dysphasia = difficulty comprehending language (damage to Wernicke’s area)
- Prosopagnosia = inability to recognise familiar faces
- Agnosia = inability to recognise familiar objects
- Episodic memory loss = due to hippocampal atrophy
- Mood changes = amygdala damage
Alzheimer’s disease (AD)
Leading cause of dementia in ALL groups
Vast majority of cases are sporadic but approximately 5% are familial and inherited in an autosomal dominant manner
How is AD diagnosed?
Diagnosis of AD is predominantly clinical, post mortem studies find that it is correct in approx 80% of cases
2 variants of AD can cause diagnostic confusion:
1) Frontal variant - prominent changes in personality and behaviour with disturbed executive function and expressive language. Usually misdiagnosed as FTD
2) Posterior cortical atrophy - parietal lobes are particularly affected leading to visuospatial and perceptual problems. Expressive language and memory are usually preserved
Key features of AD
Both early features are due to severe medial temporal lobe degeneration
i) loss of episodic memory that eventually produces global cognitive decline - i.e. early on new memories cannot be laid down, although childhood memory remains accessible. Later on no memory can be recalled
ii) Spatial disorientation
Disease progresses over 5-15 years with gradual decline in all aspects of cognitive ability plus changes in mood, personality and behaviour
What does imaging show in AD?
May be normal in early disease
Functional brain imaging in early disease shows reduced blood flow and glucose metabolism in posterior temporal lobe and hippocampus before obvious structural changes appear on MRI
Over time there is: progressive cortical atrophy, ventricular dilatation and hippocampal atrophy
What is the prognosis in AD?
Disease progresses relentlessly causing death from pneumonia or inanition after 8-10 years
Key to management is to care for the sufferer on a “symptom by symptom basis” and provide good support and relief for the carer
What is the most important risk factor in developing AD other than advancing age?
Possession of one or more copes of the APOE4 allele, which is present in more than 50% of patients with AD
Other risk factors:
- IHD
- History of head injury
- Low SES
- Susceptibility genes may be responsible for familial forms - mutations in Presenilin 1 and 2 genes and amyloid precursor protein (APP)
Are any factors protective in AD?
AD is more common in females and HRT may be beneficial in post menopausal women
Positive effect of anti-inflammatory drugs is unproven
Moderate alcohol consumption
What are the pathological features of AD?
Gross macroscopic features include:
- brain atrophy
- ventricular enlargement
- cortical thinning
Microscopic examination shows plaques and tangles in the cortex
What are the plaques seen in AD composed of?
Diffuse and neuritic plaques are composed of insoluble aggregates of amyloid beta (AB) peptide (like all forms of amyloid, the deposits take up the stain congo red and show apple-green birefringence under polarised light)
AB is deposited extracellularly in the compartment between neurones
Diffuse plaques = composed of AB but in a non-amyloid form, may be numerous in older people without dementia
Neuritic plaques = plaques associated with cognitive decline
What are neurofibrillary tangles seen in AD composed of?
Neurofibrillary tangles occupy the neuronal cytoplasm and are composed of insoluble filamentous aggregates of hyperphosphorylated tau protein (microtubule transport protein) arranged in paired helical filaments
Why is cholinergic transmission reduced in AD?
The cortex shows widespread loss of neurones, synapses and dendritic spines in AD
Cholinergic transmission is reduced due to degeneration of Meynert’s nucleus (a large cholinergic nucleus in the base of each cerebral hemisphere contributing to diffuse cholinergic system)
What is cerebral amyloid angiopathy?
AB is deposited in the cortical blood vessels in 90% of patients with AD which is called cerebral amyloid angiopathy
Amyloid deposition leads to degeneration of vascular smooth muscle , weakening of vessel wall and predisposition to micro-infarcts and intracerebral haemorrhage
CAA can occur in the absence of dementia and accounts for about 25% of intracerebral haemorrhages in the elderly - the haemorrhage is “cortical” rather than deep like those seen in hypertension
What is the “amyloid cascade hypothesis”?
Deposition of AB protein in the cerebral cortex is believed to be a key initiating event in development of AD leading to tau hyperphosphorylation and tangle formation within neurones
How is AB formed?
AB is produced by proteolytic cleavage of the precursor molecule APP. There are 2 pathways for processing:
- Processing via the primary pathway (alpha secretase) is dominant and does not lead to pathologic AB release
- Processing via the alternative (beta secretase) pathway releases soluble AB peptide with either 40 or 42 amino acids
The ratio of AB40: AB42 is determined by the gamma secretase complex
AB42 forms cortical plaques
AB40 gets deposited in blood vessels leading to cerebral amyloid angiopathy
What causes familial forms of AD?
Mutations in the presenillin or APP genes are responsible for most inherited (autosomal dominant) early onset forms of AD.
There is an imbalance in the AB40:AB42 ratio causing excessive AB42 deposition
How is AB deposition related to tau?
Deposition of AB in the cerebral cortex (particularly AB42) appears to trigger a cascade of events within neurones leading to accumulation of hyperphosphorylated tau
Tau hyperphosphorylation is caused by an imbalance between tau kinases and phosphorylases with excessive kinase activity (e.g. CDK5)
What is the progression of tau pathology in AD?
Tangles first appear in the medial temporal lobe (hippocampus, entorhinal cortex) and spread progressively throughout the limbic lobe and neocortex in six Braak stages
How does AB clearance play a role in AD?
In normal individuals a small amount of AB is continually produced and eliminated
Mechanisms for removal include enzymatic degradation and active transport into blood stream (which decline with age) and perivascular drainage (which also declines with age and is less effective in people with cerebrovascular disease)
Failure of AB clearance rather than build up appears to be important in sporadic cases
How does beta amyloid damage neurones?
Exact mechanism unclear
AB oligomers are known to be associated with neuronal membranes and form pore like structures (similar to those of the membrane attack complex) which allow sodium, water and calcium into cells
Cognitive reserve capacity
Alzheimer type changes are present to a variable extent in many cognitively normal older people, which is thought to reflect greater cognitive reserve capacity
Frontotemporal dementia
Frontotemporal dementia is a clinical term for a rare group of conditions (accounting for 5% of dementias) in which there is selective degenerations of the frontal and temporal lobes