Dementia

Clinical syndrome caused by a number of brain disorders which cause memory loss, decline in some other aspect of cognition, and difficulties with activities of daily living

Aetiology

Some of the more common causes of dementia are:
  • Alzheimer’s disease - most common cause, 50-70% of cases of dementia
    • Usually occurs in old age - 1/5 of individuals over 80 years old are affected
  • Vascular dementia - accounts for ~25%
    • Brain damage due to cerebrovascular disease: either major stroke, multiple smaller unrecognised strokes (multi-infarct) or chronic changes in smaller vessels (subcortical dementia)
  • Dementia with Lewy bodies - about 15% of cases
    • Deposition of abnormal protein (⍺-synuclein) within neurons in the brain stem and neocortex
  • Frontotemporal dementia - < 5% of cases
    • Specific degeneration/atrophy of the frontal and temporal lobes of the brain
  • Potentially treatable dementias (<5%)
    • Metabolic e.g. uraemia
    • Toxic e.g. alcohol
    • Vitamin deficiency - B12 and thiamine
    • Traumatic - severe or repeated brain injury
    • Intracranial lesions e.g. subdural haematoma, tumours
    • Infections e.g. HIV
    • Endocrine e.g. hypothyroidism
    • Psychiatric - depression causing 'pseudodementia'

Rare causes

  • Huntington’s disease
    • Autosomal dominant trait
    • Onset usually between 30 and 50 years - age dependant penetrance
  • Parkinson's disease
  • CJD

Pathophysiology

Molecular pathology and aetiology of Alzheimer's disease

  • The pathological hallmarks of AD include:
    • Loss of cortical neurones
    • Neurofibrillary tangles
    • Senile plaques - extracellular protein deposits containing amyloid β protein
  • Initial symptoms generally forgetfulness
  • Degeneration of medial hippocampus + later parietal lobes: forgetfulness → apraxia/visuospatial difficulties
  • Genetics have been implicated in AD
    • A first-degree relative with AD confers a doubled lifetime risk of AD
    • There are rare autosomal dominant monogenic early-onset forms of familial AD with high penetrance, caused by mutations in specific genes
    • Genes which have been linked to the development of AD include: the E4 allele of the apolipoprotein E gene, point mutations in the APP gene, and mutations in presenilin (PS)-1 and 2
    • The presence of three copies of the APP gene on chromosome 21 in Down’s syndrome patients is responsible for the high incidence of AD in that condition - onset in 3rd or 4th decade
  • <65 years - early onset AD, genetic influences, may be atypical presentation
  • <65 years - sporadic AD, environmental > genetic influences, usually typical initial forgetfulness

Molecular pathology of Huntington's disease

  • The genetic mutation that causes Huntington's is a CAG repeat encoding poly-glutamine - has a toxic effect on cells, resulting in neuronal loss
    • Caudate atrophy - loss of cells from the basal ganglia causing flattening of the normal convex curve of the lateral ventricles
    • Cells are lost from other brain areas including the cerebral cortex
  • Huntington's demonstrates anticipation - number of repeats increases over generations, so symptoms will develop sooner in each successive generation

Clinical presentation

Alzheimer's disease

  • Gradual onset, decline of particularly short-term memory
  • Autobiographical and political memory often well preserved
  • Poor concentration, poor sleep, low mood
  • Personality change - disinhibited, aggression, lack of self-care
  • In end stages - hallucinations, poor dentition, skin ulcers, loss of verbal communication
  • Atypical presentations:
    • Posterior cortical atrophy - visuospatial disturbance
    • Progressive primary aphasia

Vascular dementia

  • Dysphasia, dyscalculia, frontal lobe symptoms and affective symptoms more common than in Alzheimers
  • May have focal neurological signs
  • May have vascular risk factors
  • May have step wise decline

Frontotemporal dementia

3 syndromes:
  • Behavioural variant - behavioural changes, executive dysfunction, disinhibition, impulsivity, loss of social skills, apathy, obsessions, change in diet
  • Primary progressive aphasia - effortful non-fluent speech, speech sound/articulatory errors, lack of grammar, lack of words
  • Semantic dementia - impaired understanding of meaning of words, fluent but empty speech, difficulty retrieving names

Dementia with Lewy Bodies

  • Dementia - common early involvement of reduced attention, executive function and visuospatial skills
  • Two of:
    • Visual hallucinations
    • Fluctuating cognition (delirium-like)
    • REM sleep behaviour disorder
    • Extrapyramidal features (Parkinsonism) seen in 75%
      • Not more than 1 year prior to onset of dementia
    • Positive DAT scan

Dementia in Parkinson's disease

  • 80% after 15-20 years of Parkinson's disease
  • Must have Parkinsonism for at least 1 year prior to onset of dementia
  • Clinical presentation is similar to DLB

Huntington's disease

  • Involuntary movements
  • Dementia
  • Decline in executive function
  • Short and long-term memory deficits
  • Anxiety, psychosis, compulsions, suicidality, aggression, blunted affect
  • Late clinical signs:
    • Rigidity
    • Bradykinesia
    • Severe chorea
    • Serious weight loss
    • Inability to walk
    • Inability to speak
    • Swallowing problems, danger of choking
    • Inability to care for oneself

Investigations

Diagnostic criteria

  • History consistent with global cognitive decline over months-years
  • Cognitive testing consistent with history (ACE-III, MoCA etc.)
  • Decline in level of function
  • No evidence of reversible cause

Imaging

  • CT is currently standard
    • May not always be necessary e.g. 80 yr old patient with typical history of Alzheimers
    • Otherwise helpful in exclusing tumour, bleed, large stroke or quantifying vascular changes
  • MRI if young, fast progression or other atypical features
  • SPECT most useful for frontotemporal, may also be used if trying to clarify Alzheimer's diagnosis
  • DAT for suspected DLB/DPD when the patient doesn't have enough supporting features to be sure of a diagnosis

Management

  • It is rare for a reversible cause for dementia to be found (e.g. normal pressure hydrocephalus or frontal meningioma)
  • Therefore, management is supportive

Alzheimer's disease

  • Address vascular risk factors
  • ACh boosting treatments
    • Cholinersterase inhibitors - donepezil, rivastigmine, galantamine
    • Mematine - NMDA receptor blocker used in moderate or severe AD or where cholinesterase inhibitors are not tolerated

Vascular demetia

  • Vascular risk factors +/- cholineresterase inhibitor

Frontotemporal demetia

  • Trial of trazadone/antipsychotics to help behavioural features
  • Safety management - controlled access to food/money/internet, structured activities
  • Power of attorney

Dementia with Lewy Bodies

  • Small dose levodopa
  • Trial cholinersterase inhibitors - rivastigmine

Huntington's disease

  • Mood stabilisers
  • Manage chorea