Alzheimer's Disease Overview

Alzheimer's Disease

• Alzheimer's disease (AD) is a progressive dementia with no known cause or cure.
• It is a common age-related dementia distinct from vascular dementia caused by brain infarction, stroke, trauma or alcohol.
• AD is associated with brain shrinkage and localized loss of neurons, primarily in the hippocampus and basal forebrain.
• AD has a devastating impact on patients and families due to its effects on cognitive, emotional, and physical function.

Features of Alzheimer's Disease

• AD has three distinguishing features:
  • Accumulation of senile plaques (β-amyloid accumulations)
  • Formation of numerous neurofibrillary tangles
  • Loss of cortical neurons, particularly cholinergic neurons
• Patients with AD have a deficit in cholinergic neurotransmission due to the destruction of neurons producing acetylcholine.
• Pharmacologic interventions for AD are palliative and provide modest short-term benefit.

Treatment Goals

• Current therapies for AD aim to:
  • Improve cholinergic transmission within the CNS
  • Prevent excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors

Acetylcholinesterase Inhibitors

• Donepezil, Galantamine, Rivastigmine, and Tacrine are examples of acetylcholinesterase inhibitors.
• These drugs are used to improve cholinergic neurotransmission in the affected areas of the brain.
• While they may slow cognitive deterioration, they don't affect the underlying neurodegenerative process.

Tacrine (Cognex®)

• The first centrally acting cholinesterase inhibitor approved for AD treatment.
• Slows the progression of AD.
• Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps.

Memantine (Namenda®)

• An NMDA-glutamate receptor antagonist approved for AD treatment.
• It works by attenuating the excitotoxic effects of glutamate, implicated in neuronal loss in AD.
• It is excreted largely unchanged.
• Namzaric®, a combination of memantine extended-release and donepezil, is available.

Caprylidene (Axona®)

• A medical food metabolized into ketone bodies, which the brain can use for energy when glucose processing is impaired.
• MRI scans of the elderly and those with AD reveal decreased glucose uptake, the brain's preferred energy source.
• Caprylidene aims to replace depleted glucose levels for patients with age-associated memory impairment and AD.

Multiple Sclerosis (MS)

• An autoimmune inflammatory demyelinating disease of the CNS with variable course.
• Demyelination disrupts nerve transmission, leading to inflammation and plaque formation in the brain and spinal cord.

MS Symptoms & Treatment

• Symptoms include pain, spasticity, weakness, ataxia, fatigue, and problems with speech, vision, gait, and bladder function.
• Many patients experience relapses and remissions, but some have progressive disease.
• Acute exacerbations are treated with prednisone, which shortens exacerbations and ameliorates symptoms.
• Prednisone is administered orally in milder cases and parenterally in more severe cases.

Disease-Modifying Therapies

• Drugs approved for MS aim to reduce relapse rates and prevent disability accumulation.
• These medications modify the immune response by inhibiting white blood cell-mediated inflammatory processes that damage myelin sheaths.

Interferon β-1b & Interferon β-1a (Betaseron®)

• Interferon β-1b was the first drug to demonstrate the ability to halt and even reverse the progression of MS.
• It reduces inflammatory responses that lead to demyelination.
• Clinical studies showed it reduced relapse frequency and new lesions in patients with relapsing-remitting MS.

Interferon β-1b Mechanism of Action

• Increases natural killer cell cytotoxicity and macrophage phagocytic activity.
• Reduces interferon-γ secretion by activated lymphocytes, which may halt MS progression.

Interferon β-1a

• Approved for relapsing MS and is a synthesized recombinant protein.
• Peginterferon β-1a, a PEGylated derivative, provides longer action.
• Adverse effects may include depression, injection site reactions, hepatic enzyme elevations, and flu-like symptoms.

Glatiramer (Copaxone®)

• A synthetic polypeptide mimicking myelin basic protein, a component of myelin sheaths.
• May act as a decoy to T-cell attack.
• Clinical trials showed reduced relapse episodes compared to placebo.
• Post-injection reactions with flushing, chest pain, anxiety, and itching can occur.

Fingolimod (Gilenya®)

• An oral drug that alters lymphocyte migration, reducing their presence in the CNS.
• Used for relapsing MS patients.
• Exact mechanism unknown, but it is a sphingosine-1-phosphate receptor modulator.
• Prevents lymphocyte egress from lymph nodes, lowering peripheral blood levels and reducing CNS lymphocyte migration.
• May cause first-dose bradycardia and increased risk of infection and macular edema.
• Siponimod and Ozanimod are similar drugs on the market.

Teriflunomide (Aubagio®)

• A pyrimidine synthesis inhibitor used to treat relapsing MS.
• Reduces proliferation and concentration of active lymphocytes in the CNS.
• May elevate liver enzymes and cause hepatic toxicity.
• Avoid during pregnancy.

Dimethyl Fumarate (Tecfidera®)

• Oral drug for relapsing MS that reduces oxidative stress to diminish disease progression.

Amyotrophic Lateral Sclerosis (ALS)

• Characterized by muscle wasting, weakness, respiratory failure, and death within 2-5 years.
• Cause is unknown but involves a defect in superoxide dismutase, an enzyme that scavenges superoxide radicals.
• Treatment for ALS is largely symptomatic.
• Riluzole and Edaravone are indicated for ALS management.
• Baclofen and Gabapentin are used to control spasticity.

Riluzole (Rilutek®)

• The first drug approved for ALS treatment.
• Exact mechanism of action unclear, but it is an NMDA receptor antagonist and may inhibit glutamate release and sodium channels.
• May improve survival time in ALS patients.
• Prolongs time before tracheotomy and extends life by approximately 3 months.

Edaravone (Radicava®)

• A neuroprotective agent that reduces neuronal damage due to oxidative stress, potentially slowing ALS progression.
• FDA-approved for ALS treatment.

Anti-Spastic Agents for MS & ALS

• Used to treat skeletal muscle spasms that may occur from injury or neurological diseases.
• Physical therapy is used for spasticity, but anti-spastic drugs may be helpful in severe cases.

Baclofen (Lioresal®)

• A GABAB receptor agonist that reduces motor neuron excitability.
• Useful for reducing MS-related spasticity, particularly flexor spasms, pain, clonus, and muscle rigidity.