Neurodegenerative Disorders Overview

Neurodegenerative Disorders (NDs)

• Neurodegenerative disorders are conditions involving progressive cell loss in the brain and spinal cord.
• Symptoms vary depending on the affected region and rate of change.
• Causes are unknown for most.
• Common NDs include Parkinson's Disease, Alzheimer's Disease, and Huntington's Disease.
• NDs significantly impact quality of life.
• Neurological disorders, including those listed above, affect over 1.5 billion globally.
• Incidence increases exponentially after age 65.
• Current treatment strategies for NDs are limited, and CNS drug delivery presents a significant challenge.

Alzheimer's Disease (AD)

• AD involves brain shrinkage and neuron loss, primarily in the hippocampus and basal forebrain.
• Loss of cholinergic neurons is linked to cognitive deficits and short-term memory loss.
• Two key microscopic features:
  • Extracellular amyloid plaques: amorphous deposits of β-amyloid protein (aβ).
  • Intraneuronal neurofibrillary tangles: filaments of phosphorylated tau protein.
• Both are protein aggregates resulting from protein misfolding, also present in normal brains (though fewer).
• AD causes gradual but relentless cognitive decline.
• Short-term memory impairment is often the first sign.
• Long-term memory retrieval usually remains intact for a longer period.

Treatment of Alzheimer's Disease

• Treatment attempts to enhance brain cholinergic function.
• Cholinergic precursors (choline chloride, lecithin) have limited effects.
• Acetylcholinesterase inhibitors are effective.
• Currently approved drugs are cholinesterase inhibitors and memantine.

Cholinesterase Inhibitors

• Four approved inhibitors: Tacrine, Donepezil, Rivastigmine, and Galantamine.
• Tacrine is a potent central inhibitor, but side effects limit its use.
• Other inhibitors (Donepezil, Rivastigmine, Galantamine) produce mild cognitive improvements but don't alter disease progression.
• Memantine, an NMDA glutamate-receptor antagonist, reduces clinical deterioration in moderate-to-severe AD.

Huntington's Disease (HD)

• HD is an autosomal dominant, inherited neurodegenerative disorder.
• It causes progressive brain degeneration starting in adulthood.
• Leads to rapid decline and death.
• Characterized by gradual onset motor incoordination and cognitive decline in midlife.
• Symptoms include:
  • Chorea (brief, jerky movements)
  • Personality changes
  • Fine motor incoordination, rapid eye movement impairment, and/or bradykinesia/dystonia
  • Motor deterioration to include dysarthria, dysphagia, and balance impairment.
• Neuronal loss is prominent in the striatum (caudate/putamen).

Treatment of Huntington's Disease

• Treatment is symptomatic; no current treatment slows progression.
• Medication is used to manage various symptoms:
  • Antidepressants for depression
  • Antipsychotics for paranoia, delusions, and psychosis (especially clozapine, quetiapine or carbamazepine for predominantly rigid symptoms)
  • Dopamine-depleting agents (tetrabenazine, reserpine) for severe chorea
  • Sedatives or anxiolytics (benzodiazepines) for chorea worsened by anxiety
  • Anticonvulsants (clonazepam, valproic acid) for myoclonus and seizures.

Ischemic Brain Damage (Stroke)

• Stroke is a common cause of death and disability (after heart disease and cancer).
• Ischemic strokes (85%) are caused by thrombosis.
• Haemorrhagic strokes (15%) result from artery rupture.
• Recombinant tissue plasminogen activator (tPA) is the only approved stroke treatment.
• tPA dissolves thrombi when administered intravenously within ~3 hours of the event, should not be given for hemorrhagic strokes.
• Stroke management focuses on prevention (blood pressure control, aspirin, atherosclerosis prevention).

Stroke Supportive Care Medications

• Oxygenation: Maintain adequate tissue oxygenation to prevent hypoxia.
• Antihypertensives: Manage elevated blood pressure.
• Antipyretics: Manage fever.
• Insulin: Normalise high blood sugar.