Dementia

• Background

  Dementia typically refers to a gradual decline of mental functioning, characterised by memory problems and personality and behavioural changes.

  Pathophysiology

  Alzheimer's disease

  Brain amyloidosis and Tau pathology:

  • Mis-cleavage of the amyloid precursor protein by β and γ secretase, instead of the usual α-secretase, leads to the formation of β-amyloid (aka Aβ). Aβ deposits in the extracellular space and aggregates as senile plaques, occupying up to 20% of the brain, but potentially leading to lower levels in the CSF.
  • Also involves neurofibrillary tangles of Tau proteins in both the intra- and extra-cellular spaces.

  Vascular dementia

  • Cumulative effects of many small strokes.
  • Can co-occur with Alzheimer's, but rarely LBD.

  Lewy body dementia (LBD)

  • Aggregations of Lewy bodies in substantia nigra and other brain structures.
  • Lewy bodies consist of alpha synuclein, ubiquitin, and other proteins.

  Frontotemporal dementia (FTD)

  • Atrophy of frontal and temporal lobes.
  • 3 pathological subtypes based on the type of abnormal protein deposition, FTD: Fused in sarcoma (FUS) protein, phosphorylated Tau, or transactive response DNA-binding protein 43 (TDP-43).
  • May be part of motor neuron disease.
  • Usually younger onset (45-70). 20% have autosomal dominant inheritance.
  • Aka Pick's disease, frontal lobe dementia.

  Epidemiology

  • Prevalence by age: 1% at 65-70, 3% at 70-75, 5% at 75-80, 10% at 80-85, 15% at 85-90, 25% at ≥90.
  • Commoner in women.
  • Alzheimer's accounts for 80% of cases.

• Presentation

  Alzheimer's

  Pattern:

  • Insidious onset.
  • Progressive and global cognitive deterioration.

  4 A's:

  • Amnesia: recall is impaired first, with recognition initially intact. Short-term affected before long-term, with difficulty learning new things.
  • Aphasia: expressive first, with word-finding difficulties common.
  • Agnosia e.g. difficulty naming object in hand with eyes closed. Also anosognosia (poor insight).
  • Apraxia: impaired motor planning skills e.g. dressing apraxia.

  Also:

  • Visuospatial problems, so easily gets lots.
  • Affective and psychotic symptoms.
  • Reduced executive function, apathy.

  Vascular dementia

  • Stepwise, rapid decline in specific functions.
  • However, may fluctuate, with partial recovery.
  • Focal neurological signs.
  • Relatively preserved personality and insight.

  LBD

  • Fluctuating changes in cognition. Changes can be day to day, and cycles get progressively shorter (e.g. hours). Lucid periods may be very distressing, due to insight, leading to depression.
  • Visual hallucinations. Vivid and often frightening. May include children, animals, or Lilliputian hallucinations. No auditory hallucinations, so figures don't speak back.
  • Parkinsonism including falls.
  • REM sleep disorder.

  FTD

  Relative to Alzheimer's, more personality and speech problems early on, with episodic and topographical memory retained until quite late.

  3 main clinical syndromes:

  • Behavioural variant FTD: impaired interpersonal and executive skills, including apathy, disinhibition, obsessions, and stereotypies.
  • Primary progressive aphasia, which has 2 subtypes: progressive non-fluent aphasia, involving poor speech production, and semantic aphasia, involving difficulty understanding and remembering words and their meanings.

  Risks

  • Physical: falls, floods or fires in the house, self-neglect.
  • Behavioural: financial exploitation, wandering, aggression towards others.
  • Medication overdose – often accidental, but can be deliberate – or poor adherence.

• History

  Collateral history is often required.

  Function:

  • A significant change in functioning is a key criteria, so ask "is there anything you used to do which you are no longer able to do" and "why?".
  • Ask about ADLs: washing, dressing, cooking, cleaning, shopping, driving (any bumps or scrapes?).
  • When and how much of their medication are they taking.

  Specific symptoms:

  • Any trouble with memory or concentration?
  • Find yourself somewhere and you don't know why/how?
  • Hard to follow/focus on TV/books?
  • Difficulty using new things (e.g. remote control)?
  • LBD: any falls, hallucinations, or tremor?
  • Diurnal symptoms: are things worse in the evening (sundowning)?

  Ask about mood:

  • Depression is common, and a key differential and risk factor.
  • Often not disclosed in the elderly.

  Determine rate of progression:

  • Important prognostic indicator.
  • "What was the first thing you noticed? When?".

  Consider using structured cognitive instrument such as the 6-item cognitive impairment test (6CIT).

• Risk factors

  Alzheimer's:

  • Family history.
  • Specific mutations: ApoE e4, CL1, CLU, PICALM.
  • Down's
  • Vascular risk factors.
  • Limited intellectual activity or stimulation.
  • Depression
  • Traumatic brain injury, especially if later in life.

  Vascular:

  • IHD and its risk factors.
  • Diabetes

• Differential diagnosis

  Reversible dementias:

  • Hypothyroidism
  • Electrolyte abnormalities.
  • ↓B12
  • Anaemia
  • Normal pressure hydrocephalus. Classic triad of dementia, urinary incontinence, and gait ataxia

  Non-reversible dementias:

  • CJD
  • Huntington's

  Delirium:

  • An acutely altered cognitive state which should resolve with treatment of the underlying cause.
  • May co-exist with dementia.

  Depression:

  • In the elderly, often features pseudodementia i.e. subjective memory loss.
  • Unlike in Alzheimer's, cognitive impairment will be patchy not global.
  • Worse in the morning, while Alzheimer's is worse in the evening.

  Mild cognitive impairment:

  • Mild memory loss but no functional impairment.
  • 50% progress to dementia in 5 years, while the remainder are stable, improve, or have a non-dementia pathology.

• Investigations

  Refer to specialist clinic for diagnosis. This involves:

  • Bloods and imaging.
  • Formal cognitive assessment e.g. with Addenbrooke's Cognitive Examination-Revised (ACE-R). Scores <85 suggest cognitive impairment.
  • Detailed history from the patient and a collateral history.

  Rule out other causes:

  • Bloods: FBC, U&E, LFTs, Ca2+, TFT, B12, folate, ferritin, ceruloplasmin.
  • Urine dip for UTI, especially in an acute context.

  Tissue diagnosis:

  • CSF tau and β-amyloid testing can support diagnosis of Alzheimer's if unclear clinically.
  • A definitive pathological diagnosis can only be made post-mortem, but is rarely necessary.

  Imaging

  CT head for all:

  • To look for vascular disease and rule out space-occupying lesions.
  • Small vascular changes are common, but need to be significant to support diagnosis of vascular dementia.
  • Alzheimer's may show mesial temporal lobe atrophy.

  Further modalities only if diagnosis unclear:

  • FDG-PET or perfusion SPECT if Alzheimer's or FTD suspected. FTD also suggested by thin, 'knife-blade' gyri in the temporal lobes on MRI.
  • MRI if vascular dementia suspected.
  • (123)I-FP-CIT SPECT (DaTSCAN) if LBD suspected. Can show dopaminergic neuron loss.

• Management

  General

  MDT approach:

  • Falls: physio, OT, falls clinic, pendant alarm.
  • Social services for care package to help with ADLs.
  • Care home may be needed if carers four-times daily is not enough, or there are significant behavioural problems.

  Medical

  Oral cholinesterase inhibitors are the first line treatment for mild to moderate Alzheimer's:

  • Drugs: donepezil, galantamine, or rivastigmine (also available as a patch).
  • Can also be used in LBD, but not in vascular dementia or FTD.

  Memantine is a glutamate receptor antagonist used in:

  • Severe Alzheimer's (MMSE <10).
  • Moderate Alzheimer's or LBD where cholinesterase inhibitors are not tolerated or are ineffective (having tried 2).

  Other options for behavioural and psychological symptoms:

  • First optimize non-pharmacological methods and rule out underlying causes of distress e.g. pain.
  • Antipsychotics, at lowest dose and duration possible, only if risk to self or others, or experiencing distressing hallucinations or delusions.
  • Antidepressants only in severe depression.

• Prognosis

  Patients with Alzheimer's and LBD usually die within 7 years of diagnosis. Sooner in vascular dementia.

• Cholinesterase inhibitors

  Drugs

  Donepezil, rivastigmine, galantamine.

  Side effects

  • Diarrhoea and vomiting.
  • Cramps
  • Urinary incontinence
  • Headache, dizziness, insomnia.
  • Exacerbate peptic ulcer disease.
  • Bradycardia, AV block.

  Management

  • ECG first, as 2nd degree heart block is a contraindication.
  • Check pulse after starting for bradycardia.
  • Take after eating due to GI side effects.
  • Can switch to rivastigmine patch if GI side effects especially bad.