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Friday, November 18, 2016

What are the treatment options for Alzheimer’s disease?

Alzheimer’s disease: The most common cause of dementia
Alzheimer’s disease: The most common cause of dementia
Alzheimer’s disease is a progressive irreversible degenerative disease of brain. Most cases of Alzheimer’s disease are sporadic but 5% are familial (inherited as an autosomal dominant condition).

Unfortunately at present, there is no cure for Alzheimer’s disease. At present the main goal of treatment is to focus on managing the disease symptoms such as memory loss. Current medications may for some time reduce the progression of memory loss and also improve the person’s quality of life by inducing cognitive changes.

The treatment programs vary depending on the stage and symptoms of the Alzheimer’s disease, the supporting care facilities available, the presence of any concurrent illness, other drugs taken by the person which may interfere with the Alzheimer’s medications and the person’s tolerability to the prescribed medicine. Other than pharmaceutical treatment it is often recommended that the person be given counseling and other therapies. In a nutshell, at present we just treat the symptoms and there is currently no cure available for Alzheimer’s disease which treats the underlying pathology of the disease and prevents its progression. However, Scientists are constantly trying their best to come up with new medicine which attacks the disease at its root and not symptoms, but such drugs require further clinical research and trials before they can be approved for regular clinical use.

    Important Facts about Alzheimer's disease

    • The most common cause of dementia in the UK is Alzheimer's disease followed by vascular and Lewy body dementia. 
    • Alzheimer’s disease is the single most common cause of dementia. 
    • Approximately 10% of all persons over the age of 70 have significant memory loss, and in more than half the cause is Alzheimer’s disease.
    • In Alzheimer’s and Parkinson’s, olfactory loss may be the first clinical sign of the disease.

    Before we talk about the treatment of Alzheimer’s disease, it is important that we cover some basic background information such as the pathophysiology of Alzheimer’s disease so that we understand the science behind the treatment.

    An overview of Alzheimer's disease
    An overview of Alzheimer's disease

    What is Alzheimer’s disease?

    It is a neuro-degenerative disease of the brain characterized by progressive loss of short term memory which is followed by general deterioration of cognitive and other neurological functions. It is present in about 17% of people aged over 65 and 40-45% of people who are aged over 95. It is one of the most common and major medical problems of our time.
    Alzheimer's disease mainly affects people aged over 65
    Alzheimer's disease mainly affects people aged over 65

    What are the causes of Alzheimer’s disease? Basic pathophysiology of Alzheimer’s disease

    To understand the basic mechanism of how Alzheimer’s occur, we need to understand how brain transmits information from one nerve cell (called a neuron) to another. Exchange of information between two neurons occur the by exchange of chemical mediators (such as acetylcholine, noradrenaline, serotonin, dopamine and others) which are released at the junction where one neuron ends and another neuron begins. This junction is called a Synapse. In Alzheimer’s disease, this process of information transmission is interrupted and there is eventual damage and destruction of neurons which ultimately leads to memory loss, behavioral changes and other features of Alzheimer’s. The number of neurons lost and the location of the brain that is affected are factors which determine the specific type of disorder that develops. Damage to the noradrenergic, serotonergic, and dopaminergic pathways (these pathways release the neurotransmitters noradrenaline, serotonin and dopamine) lead to behavior and mood disorders while damage of the cholinergic neurons (which release acetylcholine - vital neurotransmitter for memory) lead to memory impairment.

    Comparison between Normal brain vs Alzheimer's brain
    Comparison between Normal brain vs Alzheimer's brain

    Why memory loss is the first symptom in Alzheimer’s disease? 

    In Alzheimer’s disease memory impairment is the prominent feature as the cholinergic neurons are affected first. These neurons release the neurotransmitter acetylcholine which is crucial for the maintenance of intact memory. As the disease progresses in severity other neuronal pathways are affected leading to other features of Alzheimer’s disease such as behavioral and global cognitive damage.

    Pathological progression of Alzheimer’s disease in the brain

    In Alzheimer’s disease, the pathology starts in the part of the brain called entorhinal cortex, from there is affects the hippocampus, then the posterior temporal and parietal neocortex and ultimately causes global degeneration of the entire cerebral cortex. The main function of entorhinal cortex is related to memory and navigation. Similarly hippocampus serves to move short term memory to long term memory and navigation. The temporal lobe is associated with the maintenance of visual memory, language comprehension, and emotional balance. The parietal neocortex is responsible for language processing and integration of other sensory information. Since, these areas of the brain are predominantly and primarily affected in Alzheimer’s disease, the usual presenting features of Alzheimer’s disease is memory loss, aphasia and disturbance of language. However, it is seen that around 20% of patients with Alzheimer’s disease initially present with non-memory symptoms such as word-finding, organizational, or navigational difficulty. So, in a nutshell, there is diffuse atrophy of the brain with enlargement of the ventricular system.

    Molecular pathology of degenerative dementia in Alzheimer’s disease

    Microscopically, there are neuritic plaques containing Aβ amyloid, silver-staining neurofibrillary tangles (NFTs) in neuronal cytoplasm, and accumulation of Aβ42 amyloid in arterial walls of cerebral blood vessels. These are all abnormal protein complexes which damage the synapses and ultimately cause neuronal death.

    Molecular pathology of Alzheimer’s disease
    Molecular pathology of Alzheimer’s disease

    What are the risk factors of Alzheimer’s disease?

    • The main risk factor for Alzheimer’s disease is Age. The incidence of Alzheimer’s increases exponentially with Age.
    • Family History: A first-degree relative with Alzheimer’s disease results in a doubled lifetime risk of developing Alzheimer’s disease. Family history usually denotes a genetic cause.
    • Presence of other genetic disease: Most Down’s syndrome patients will develop Early onset Alzheimer’s disease.
    • Vascular Risk Factors.
    • Female gender: This risk factor may be independent of the fact that females have a longer life span. 
    • Diabetes increases the risk of Alzheimer’s disease threefold.
    • Alzheimer’s disease is more common in people with very low educational attainment but then again it can affect people of all intellectual levels.
    • Environmental factors like aluminum, merury and viruses are suspected to have a role in developing Alzheimer’s disease, but there is not enough behind it.
    • Head injury: Boxers and Footballers are three times more likely to develop neurodegenerative diseases than normal people. 
    Risk factors of Alzheimer's disease
    Risk factors of Alzheimer's disease

    What are the clinical features and stages of Alzheimer’s disease?

    Initially, the symptoms of memory loss may be ignored by the patient and family member as just simple forgetfulness or clumsiness. Eventually as the disease progresses, normal day to day activities such as driving, shopping, managing finances are affected. Patient may become lost during driving or even walking. As the disease progresses further, the patient becomes unable to do any work, gets easily confused and starts requiring supervision. Patients may demonstrate difficulty doing tasks that require eye-motor coordination such as dressing, eating, solving simple puzzles and copying geometric features. In the late stages, even though some patients remain the ability to walk around, they do not know where they are going. There is marked impairment of judgment, reasoning and other cognitive abilities. Delusions become a prominent feature. About 10% of the Alzheimer’s patients at this stage develop Capgras’ syndrome where they believe that their caregiver is replaced by an imposter. Signs of agitation and aggression alternate with inactivity and passivity. Patient’s sleep pattern is affected and nighttime wandering becomes common. Patient becomes dependent on caregiver or family members for simplest tasks such as eating, dressing and others.

    Clinical features of Alzheimer's disease
    Clinical features of Alzheimer's disease

    What are the treatment options for Alzheimer’s disease?

    Now that we have covered the basics of Alzheimer’s disease, let’s focus on the management of the disease. The main goal of treatment in Alzheimer’s disease is the long term control (delaying the progression and improving the quality of life) of neurological and behavioral problems.

    Non-Pharmacological approach to treat Alzheimer’s disease

    The main treatment has to start within the patient’s family or caregiver because without their constant support, patience and tolerance it is impossible for a patient of Alzheimer’s to survive. Family members should focus their energy on activities that are pleasant and not pay much attention to activities that are unpleasant. It is important to make the patient feel safe by communication and repeated assurance. As the disease progresses, the patient will start exhibiting symptoms such as aggression, confusion, anger and other described above which need to dealt with calmly. It is important that family members research on Alzheimer’s disease so that they become aware of the disease progression and expect the natural course of the disease. It is extremely important that caregivers be given breaks as caregiver burnout is very common. It may be required to place the patient in a nursing home specialized to care for patients with neurodegenerative diseases. We have written an article on how to care for loved ones such as a parent with Alzheimer's disease that you might be interested in reading.

    Pharmacological treatment options for Alzheimer’s disease

    Medications for treatment of memory symptoms

    There are currently five drugs approved by the FDA for the treatment of Alzheimer’s disease. They are: Donepezil, rivastigmine, galantamine, memantine, and tacrine. Tacrine is no longer used due to its severe toxic effects on the liver.

    Drugs used in Alzheimer's disease
    Drugs used in Alzheimer's disease

    How do Anti-cholinesterase drugs work?

    Donepezil, Galantamine and Rivastigmine are CNS cholinesterase inhibitors which means they inhibit the action of the enzyme cholinesterase whose function is to break down the neurotransmitter acetylcholine. Since cholinesterase is blocked, less acetylcholine is broken down resulting in an increased level of acetylcholine in the brain which keeps communication between neurons intact. As discussed earlier, in Alzheimer’s disease, there is a deficient status of acetylcholine in the brain which leads to impaired memory and so basically anti-cholinesterase drugs delays the breakdown of acetylcholine and thus increases its level in the brain leading to memory improvement. These drugs are also used to improve language, thinking, decision making and other though processes. Donepezil is the only anti-cholinesterase drug that is approved to be used in all the stages of Alzheimer’s disease. It can also be used in combination with memantine. The other two anti-cholinesterase drugs rivastigmine and galantamine are used in mild to moderate Alzheimer’s disease. It is usually seen that anti-cholinesterase drugs delays the progression of Alzheimer’s symptoms by 6 to 12 months.

    What are the side-effects of Anti-cholinesterase drugs used in Alzheimer's disease?

    Donepezil: Decreased appetite, nausea, vomiting, diarrhea, difficulty sleeping, muscle cramps. Side effects generally improve with time.

    Rivastigmine: Rivastigmine can be given orally or via skin patch. Side effects include as nausea, vomiting, decreased appetite and weight loss. Nausea and vomiting are less with skin patches. Skin rashes occur due to severe toxicity and can happen with both oral preparation and skin patch. For skin patches, the patient and caregivers should be aware of the potential warning signs such as severe itching, reddening, swelling or blister format on at the site of the patch. If any signs of toxicity occur the patch (if used) should be immediately taken off, the site should be washed with water properly and the patient should be taken to the hospital immediately for evaluation by a doctor.

    Galantamine: Side effects include most commonly nausea, vomiting and diarrhea. However, just like donepezil, side effects usually decrease with time. Some less common but serious side effects that were noted in some studies include decreased heart rate (bradycardia), atrioventricular block and syncope.

    How do mementine / NMDA receotor antagonists work?

    N-methyl-D-aspartate (NMDA)-receptor (Glutamatergic) antagonist: One of the hypotheses behind the pathology of Alzheimer’s disease is Neuronal Exitotoxicity. Neuronal Exitotoxicity is a pathological process where nerve cells are damaged or even destroyed by excitatory neurotransmitters. Memantine works by blocking the overexcited N-methyl-D-aspartate (NMDA)-receptor. It is used in moderate to severe disease where cholinesterase drugs are contraindicated or not tolerated by the patient. It can improve memory, logic, critical thinking, language and attention. It is seen that combination of memantine and cholinesterase inhibitors is better than either used alone. Since Donepezil is approved for the treatment of all stages, it is often combined with memantine.

    What are the side effects of mementine?

    Confusion, dizziness, drowsiness, headache, difficulty sleeping, agitation, hallucinations. Less common side effects include vomiting, anxiety, bladder inflammation and increased libido.

    Treatment for behavioral changes

    Why do behavioral changes occur in Alzheimer’s patients?
    Behavioral changes in Alzheimer’s patients occur mostly due to damaged nerve cells. However, side effects of medications, environmental factors and presence of simultaneous medical conditions also contribute to the behavioral changes.

    What are the behavioral changes in Alzheimer’s disease?

    In the initial stages behavioral changes can be expressed by anxiety, depression and irritability. As the disease progresses further, symptoms may include anger, aggression, agitation, confusion, hallucination, delusions (such as Capgras’ syndrome), sleep disturbances.

    How to treat the behavioral changes in Alzheimer’s disease?

    The main way to tackle behavioral changes is to identify the trigger that causes a certain type of behavior. The main non-pharmacological approach to tackle such situations is to produce an environment where the patient feels calm and safe. As the disease progress, depression becomes a common problem and it is often difficult to distinguish between true depression and Alzheimer’s related dementia. Some authorities suggest that anti-depressants should be tried out on a trial basis if depression is suspected.

    Anti-psychotics should only be prescribed (for symptoms like hallucination, delusion, aggression, agitation and others) as a last option because it is seen that there is an increased risk of stroke in Alzheimer’s patients who take anti-psychotic drugs. If prescribed, then the patient should be carefully monitored.

    That's all for today!
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