Dementia

Definition and Possible Aetiologies of Dementia

  • Dementia

    • An acquired decline in intellectual function resulting in a loss of social independence

    • Characterised by impairment of memory and at least one other area of cortical functions, such as:

      • Language

      • Calculating

      • Decision making

      • Judgement

      • Spatial orientation

      • Abstract reasoning

    • As opposed to confusional states, (i) symptoms progress over months to years, and (ii) alertness is preserved until the very late stages of disease

    • Although it affects 5-20% of persons over 65 years, it is not part of normal ageing

    • When dementia is diagnosed with no antecedent cause…

    • Alzheimer's disease (50% of all dementia cases)

  • Major causes of dementia

    • Cerebrovascular disease and multiple strokes

    • Prion disease

    • Parkinson's disease

    • Alcoholism

    • Neoplasms

    • Chronic meningitis

    • Huntington's disease

    • Vitamin deficiencies (e.g., B1 and B12)

    • Hypothyroidism

 

Alzheimer's disease: Introduction and Clinical Manifestations

  • At age of 65 years: 5% -> at the age of 95 years: >90%

  • Alzheimer's disease has slow onset, usually develops over 5-10 years, and first impacts learning and recent memory

  • Earliest signs and symptoms

    • Spatial orientation -> pts get lost

    • Aphasia

    • Anomia (i.e., inability to recall names)

    • Acalculia

    • Frontal lobe gait disorder with short, shuffling steps and a tendency to fall backwards

  • Later stages

    • Personality changes

    • Paranoia

    • Hallucinations and delusions 

  • End stage

    • Pts are bedridden, mute, and incontinent

  • Brain areas affected the most by Alzheimer's disease

    • Frontal lobe (prefrontal cortex)

      • Intelligence, judgement, and behaviour

      • Determine personality, character, intelligence, behaviour, and judgement

    • Temporal lobe

      • Memory

    • Parietal lobe

      • Language

    • Amygdala

      • Needed to perceive emotions and to control aggression

    • Hippocampus

      • Required for converting short-term memories to long-term memories

 

Alzheimer's disease: Pathogenesis

  • Amyloid beta-peptide accumulates as the consequence of improper degradation of a physiologically present protein (i.e., beta-amyloid precursor protein (APP))

    • APP is improperly cleaved, which results in the production of beta-amyloid protein (amyloid beta-peptide)

    • Amyloid beta-peptide is water-insoluble

    • Amyloid beta-peptide proteins accumulate in the extracellular space and aggregate

    • Amyloid plaques are formed

    • Amyloid beta-plaques interfere with synaptic transmission and cause neurodegeneration

  • Tau pathology

    • Healthy tau protein stabilises microtubules that are essential for axonal transport

      • In Alzheimer's disease, tau is dysfunctional and accumulates in the cytoplasm (even in the cell body where it is not supposed to be)

      • Neurofibrillary tangles

      • Neuronal destruction

    • Abnormal tau proteins accumulate intracellularly and appear ass neurofibrillary tangles

  • Alzheimer's disease is progressive and irreversible

    • Amyloid beta-plaque formation and depositions start about 30 years before the onset of mild cognitive impairment

 

Alzheimer's disease: Management

  • Prefrontal cortex, hippocampus, and amygdala

    • The loss of cholinergic neurons in the hippocampus and prefrontal cortex is thought to underlie the cognitive deficit and loss of short-term memory that occur in AD

    • In AD, there is a decrease of acetylcholine in relevant neuronal circuits

    • Acetylcholine gets degraded by an enzyme called acetylcholinesterase (AChE)

      • By inhibiting acetylcholinesterase, we can boost acetylcholine levels and prolong its effects in cholinergic synapses

  • Inhibition of acetylcholinesterase

    • Acetylcholinesterase inhibitors detectably improve cognitive impairment in clinical trials but have significant adverse effects and are of limited use clinically

    • They have not been shown to restart neurodegeneration

    • Some NSAIDS reduce the likelihood of developing AD

  • If you don't use it, you lose it… (synaptic pruning)

    • Keep your brain sharp (learn languages, engage with cross-words, and learn for the sake of learning, etc.) + healthy lifestyle