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Dementia is an umbrella term for progressive disorders of learning and memory. Impairments in memory and other cognitive functions make it difficult for those afflicted to cope adequately with their everyday activities. “Neurocognitive disorder,” or “Dementia,” are nonspecific terms used interchangeably. In 2015, an estimated 47 million people worldwide suffer from dementia.
Common symptoms of Neurocognitive Disorder (i.e., Dementia) include
There are different forms of dementia; these include Alzheimer’s disease, vascular dementia, fronto-temporal dementia, dementia with Lewy Bodies, Parkinson’s disease dementia and Korsakoff’s syndrome. However, Alzheimer’s disease accounts for the majority of cases of dementia. In some of these instances, Alzheimer’s disease may occur together with one or more of the other forms of dementia. Below is a brief overview of the different types of dementia and a detailed account of Alzheimer’s disease, the drugs that are currently available for the treatment of this condition and the possible future pharmacological strategies presently under investigation.
Alzheimer’s disease (AD) is the most common type of dementia (60-80% of cases) and is considered a “cortical” dementia. That is, individuals with AD have problems in the outer “crust” of the brain called the cerebral cortex. The cerebral cortex has many functions depending upon the area. For example, the parietal cortex has a major role in attending to stimuli in the external and internal environments, the temporal cortex as an important role in the identification of stimuli, and the frontal cortex plays an important role in planning, making rational decisions, and preventing impulsive behaviors. In addition to degeneration of the cerebral cortex, other areas of the brain are also affected in AD. For example, memory loss is associated with atrophy of the hippocampus, a structure within the temporal lobes of the brain. Affective (mood) changes suggest problems within a group of structures that make up the “limbic system.”
Neurocognitive Disorder (NCD) due to Alzheimer’s disease is a clinical diagnosis and can be definitively diagnosed only by postmortem (after death) direct visualization of the brain. Neurocognitive disorder due to Alzheimer’s disease usually has a slow onset and symptoms usually progress gradually.
Patients and their caregivers may notice that tasks that were relatively easy have become more difficult, particularly more complex cognitive tasks. Anhedonia (loss of enjoyment of previously pleasurable activities) is also common. Anomia or anomic aphasia may be experienced, which is an ability to name familiar objects or people. Additionally, problems with misplacing items or getting lost in familiar places occur with increasing frequency.
As the disease progresses, these issues get worse, and other behavioral and cognitive changes occur. Changes in physiological processes, such as disrupted sleep, incontinence, and difficulty swallowing, are seen.
Psychiatric symptoms such as delusions, hallucinations, depressed mood, and agitation (including violent outbursts) may occur.
Tasks or activities of daily living (ADLs) eventually become difficult, including the ability to prepare food, to choose appropriate clothing, and, particularly, to drive. Additionally, the individual’s ability to recognize danger and to accurately and appropriately judge a situation is diminished. Reading and writing become more difficult, and strategies such as making lists may become less effective.
Verbal communication also suffers as the disease progresses, and language becomes confused, with incorrect word usage and mispronunciation of words. A sense of “self” is commonly lost in those with advancing AD. The loss of personal memories contributes to this. With loss of these functions comes withdrawal from social contact with family and friends. AD will eventually take away completely the ability to use language, interact with or even recognize family or friends, and live independently.
For additional information, visit the Alzheimer’s Association website at www.alz.org.
Amyloid Plaques and Neurofibrillary Tangles
FIGURE ABOVE: Pathological changes in the brain with advanced Alzheimer’s disease (AD) The brain of an individual with AD is compared with a healthy brain from an age-matched individual. The brain of the individual with AD shows significant atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. (Courtesy of Ann C. McKee, MD, Boston University School of Medicine/VA Boston Healthcare System.)
Amyloid plaques and neurofibrillary tangles are the classic pathological findings in the brain of patients with AD. These plaques and tangles cause degeneration of cells throughout the cortex, especially the frontotemporal association cortex. In addition, up to 45% of neuronal synapses are lost as the disease progresses and likely explains the significant cognitive impairment that develops over time in AD.
Amyloid plaques are the result of the accumulation of the beta amyloid protein (β-amyloid/A-beta [Aβ]) between neurons. Aβ is a protein fragment normally produced by the brain by enzymatic cleavage of amyloid precursor protein (APP). APP undergoes enzymatic cleavage by 𝜷-Secretase and 𝜸-Secretase Enzymes (see figure below) to eventually produce either the 40-amino- acid (Aβ40) or the 42-amino-acid (Aβ42) form of Aβ.
Fragments of APP have important roles in kinase activation, facilitation of gene transcription, cholesterol transport regulation, and pro-inflammatory/antimicrobial activities. Normally, these fragments undergo degradation and removal. However, in the brains of those with AD, these protein fragments, particularly Aβ42, accumulate to form plaques. Several different subtypes of plaques exist. Three common types include:
Neurofibrillary tangles (NFTs) are fibrous inclusions that are abnormally located in the cytoplasm of neurons. The neurons particularly susceptible to NFTs are pyramidal neurons—those with a pyramid-shaped cell body. The primary component of these tangles is the protein tau, which is a protein associated with microtubules, which are long filaments that help maintain cellular structure and provide a “highway” for axonal transport. As a component of these tangles, the tau is abnormally phosphorylated. Other proteins, including ubiquitin, are also found in NFTs.
In early stages of the disease, NFTs are found in the entorhinal cortex, with progression to the hippocampus and neocortex as the disease process continues. Additionally, neurons in the basal forebrain cholinergic and monoaminergic systems are susceptible to damage by AD pathological processes.
Below is a PET scan comparing healthy brain and AD-affected brain. One of several new methods for visualizing amyloid plaques in living brains, Pittsburgh compound B (PiB) dye accumulates in the plaques and can be visualized using PET scanning. Presence of these plaques is more common in those individuals with Alzheimer’s or significant cognitive impairment. (From Wolk et al., 2009).
Genetic Risk Factors
Genetic contributors to AD consist of risk genes and deterministic genes. Deterministic genes are those that can directly cause disease. Three deterministic genes are known to directly cause autosomal dominant Alzheimer’s disease (ADAD):
In ADAD, symptom onset is likely to occur before age 60 (it can occur as early as the 30s). Although ADAD is of concern, only about 5% of AD cases are familial.
The risk gene with the greatest influence on disease development is the gene for apolipoprotein E (ApoE). ApoE is normally a component of very-low-density lipoproteins (VLDLs). These lipoproteins remove excess cholesterol from the blood and carry it to the liver for degradation. The presence of the gene for the E4 form of this (APOEe4) increases risk; inheritance of this form from both parents increases risk further and may lead to earlier onset of the disease.
Down Syndrome and Alzheimer’s Disease
AD is closely linked to trisomy 21 (Down Syndrome). By the age of 30 to 40, most patients with Down syndrome will develop the plaques and tangles that are associated with AD. These changes are nearly universal among patients with Down syndrome who reach this age, and although the severity of plaque and tangle accumulation mimics that found in AD, not all such individuals will develop AD. One of the possibilities for the connection is that patients have three copies of the APP gene, which is located on chromosome 21.
Non-medication interventions are essential, effective, and first-line recommendations in the management of AD.
While there are no medications to date that have reliably reversed or prevented AD, there are medications that may slow down progression of the disease.
Recall that Alzheimer’s disease is associated with loss of cholinergic (acetylcholine) neurons, which are important in memory formation. Acetylcholine neurotransmission can be enhanced in many ways. Pharmacologically, the most common method is to inhibit the enzyme that breaks down acetylcholine, acetylcholinesterase. It seems reasonable to assume that these medications would only prove beneficial in patients who still have adequate cholinergic activity (you can’t promote a neurotransmitter if no neurotransmitter is there to begin with).
NMDA Receptor Antagonists
As previously mentioned, glutamate is the most abundant neurotransmitter in the human brain and high concentrations can be toxic to neurons. When neurons die, they can release intracellular glutamate into the extracellular environment. The glutamate that is released can act on nearby glutamate receptors located on other neurons.
When NMDA receptors are over-activated by glutamate, calcium channels within the NMDA receptor open and allow a large influx of calcium into the neuron which then induces apoptosis and neuron cell death via biochemical mechanisms that are beyond this discussion.
Therefore, NMDA receptor antagonist medications like the noncompetitive NMDA receptor antagonist Memantine (Namenda) have been developed to “protect” neurons from NMDA receptor over activation and destruction. Unfortunately, Memantine has shown mixed results in clinical trials but remains an important medication often co-prescribed with acetylcholinesterase inhibitors.
Recall that accumulation of A𝛽 amyloid proteins make up the pathological amyloid plaques. Scientists are looking into developing monoclonal antibodies specific for A𝛽 amyloid to tag them and destroy them by our immune systems before they can aggregate.
𝜷-Secretase and 𝜸-Secretase Enzyme Inhibitors
These enzymes are involved in the pathway that leads to amyloid plaques. Inhibiting their activity is being studied as a way to reduce the formation of plaques.
ACh Receptor Agonists
The loss of cholinergic activity in the cortex and hippocampus is a key finding in individuals with Alzheimer disease and explains why acetylcholinesterase inhibitors (AChEIs) make sense as a treatment option. An alternative strategy to the use of AChEIs is the use of ACh receptor agonists instead. The use of mACh receptor agonists, such as cevimeline and talsaclidine, while effective in animal models of AD, were not effective in clinical trials at the doses used. ACh also acts on nACh receptors in the hippocampus and cortex. The main subtype of nACh receptor in the brain is the 𝛼7-nicotinic ACh receptor and activation of presynaptic 𝛼7-nicotinic ACh receptors increases the release of ACh from central ACh neurons. A𝛽 is also thought to act as an antagonist at this receptor and this action is blocked by stimulation of 𝛼7-nicotinic ACh receptors. Therefore, 𝛼7-nicotinic ACh receptor agonist drugs may be useful in treating the cognitive deficits in AD.
Other treatments being studied include metal Ion Chelators, antioxidants, and anti-inflammatory agents
Vascular dementia accounts for 20–30% of dementias and often co-occurs with Alzheimer’s Dementia. Vascular dementia can be caused by strokes, heart attacks or any ischemic event that disrupts normal blood flow to (or within) the brain. Impaired blood flow leads to cellular death and damage to brain tissue due to lack of oxygen and nutrients. Symptoms depend on the areas of the brain most affected.
Most common symptoms include
Individuals with vascular dementia usually remain functionally stable for a period of time and then suddenly decline in a step-like manner (see graph below).
Fronto-Temporal Dementia (FTD) accounts for 5–10% of patients with dementia and, as the name implies, is characterized by progressive damage to the frontal and temporal lobes. Symptoms depend upon the frontal and temporal cortical areas that are affected, but most patients display the following symptoms:
FTD is genetically linked in about 30–50% of cases. The gene for tau protein (discussed above) is most commonly affected. The treatment of FTD is symptomatic and supportive. At present, there is no cure or means of slowing down its progression.
Dementia with Lewy Bodies (DLB) is also referred to as Lewy Body Dementia and accounts for about 3–5% of dementias. LBD and Parkinson’s Disease Dementia (PDD) are very similar, and both are associated with the presence of Lewy Bodies (LBs) in the brain. Lewy Bodies are abnormal proteins that have aggregated or “clumped” together. These protein aggregates contain the protein 𝛼-synuclein and also play a role in Parkinson’s Disease (PD) with and without dementia. However, patients with DLB do not necessarily have PD, although some patients may have both conditions.
The symptoms of DLB are similar to that of Alzheimer Disease but patients tend to develop attention problems, disordered movements, visuospatial deficits, and visual hallucinations earlier in the course of the illness. Parkinson’s Disease Dementia (PDD) is slightly different than Dementia with Lewy Bodies in that the movement disorder (i.e., slowed movements and pill-rolling tremor) usually presents before the cognitive deficits. Currently there is no cure for DLB or PDD, and the treatment is supportive. However, recent clinical trials have suggested that the drugs used in the treatment of Alzheimer’s disease (acetylcholinesterase inhibitors and glutamate receptor antagonists) may be beneficial in alleviating some of the memory and cognitive problems associated with DLB and PDD. For more information about Parkinson Disease, click here.
Korsakoff’s Syndrome (KS) is usually due to a deficiency in thiamine (vitamin B1) that occurs most commonly from malnutrition. Malnutrition due to excessive alcohol intake is the most common cause. Alcohol interferes with the conversion of thiamine into thiamine pyrophosphate, which is its active form. The symptoms of WKS include memory loss, denial that there are any difficulties with memory (lack of insight), problems in acquiring new information and skills, personality changes and inventing convincing stories to fill in gaps in memories (also called confabulation). The lack of thiamine (vitamin B1) causes damage to structures in the brain called mammillary bodies. Mammillary bodies are located in the posterior hypothalamus and are connected to the hippocampus in the medial temporal lobe. Damage to these areas compromise the consolidation of short-term memories into long term memories. Treatment includes withdrawal and abstinence from alcohol and administration of high doses of thiamine.
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