AD treatment with cholinesterase inhibitors
Increased synaptic action improves cognition
Alzheimer disease (AD) is historically associated with memory impairment in the geriatric population. Latter stages of the symptoms are also linked to cognitive dysfunctions like aphasia, agnosia, and problems with language and perception.
It is important to note that there is multiplicity of involvement, according to Dr. Paulino Tenchavez. "And this cognitive problem should produce a functional decline, otherwise you cannot call it a dementing disorder. It is not only a memory problem but it also has other cognitive problems," he said in a symposium during the annual convention of the Philippine Psychiatric Association in January. He also discussed the use of cholinesterase inhibitors in the treatment of AD.
Cholinergic neurotransmitters
Complex mental processes like use of language, the ability to recognize (perception), and coordination of skillful movements (praxis) are recognized as high-order functions. As such they are processed in the association areas of the brain, with inputs from the limbic and paralimbic areas, which further process the information in terms of their motivational significance to the individual.
"In ageing, when there is Alzheimer disease, all these functions can be affected because the primary site of pathology is in the cerebral cortex, affecting the neocortex, limbic system, and paralimbic systems," noted Tenchavez.
The processing of cognition in the brain is modulated by the subcortical modulatory system, located mainly in the basal forebrain. The multitude of signals is carried primarily through the nuclei of cholinergic neurotransmitters, which are heavily involved in memory and learning. This system is primarily affected in the neuropathology of AD.
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The cholinergic system in the basal forebrain innervates the entirety of the cerebrum, all the way from the cortex to the limbic and paralimbic areas. The septal nucleus projects to the hippocampus where memory is processed for storage, which in turn distributes neurons to the orbitofrontal part of the brain. These interconnections are made possible by passing through the cholinergic synapse, where the release of the primary neurotransmitter acetylcholine will activate both pre- and postsynaptic receptors and produce the necessary physiologic actions on both muscarinic and nicotinic receptors. Once the synaptic requirements for physiologic responses have been achieved, excess acetylcholine in the junction is hydrolyzed and eliminated by the enzyme acetylcholinesterase, found in its presynaptic AG-4 (basal forebrain) and postsynaptic AG-1 (cerebral cortex) isoforms.
Neuronal losses
In AD, there is preferential atrophy of the brain's association areas, primarily affecting the cerebral cortex, basal forebrain, and brainstem. The first two are profoundly affected, with the cholinergic nuclei in the basal forebrain earliest and most severely depleted. High-order cognitive processes are impaired in the frontal-parietal and temporal association areas, as well as in the hippocampus the limbic-paralimbic cortex. The causes of the deterioration of function are neuronal and synaptic losses.
On the molecular level, there is a 70- to 80-percent loss of cholinergic neurons presynaptically in the basal forebrain, while the cerebral cortex loses 35 to 45 percent on the postsynaptic side. There are also associated losses of acetyl transferase, the synthesizing enzyme for acetylcholine, but with abnormal increases in cholinesterase concentration.
Role of cholinesterase inhibitors
The use of cholinesterase inhibitors--donepezil, rivastigmine, and galantamine--has been shown to have a modest effect based on the median score of improvement, according to Tenchavez. Blinded clinical trials using the ADAS-COG (Alzheimer Disease Assessment Scale-Cognitive) scoring system have shown that over 24 weeks, cholinesterase inhibitors improved cognitive function over baseline versus a continuous downtrend for placebo. Subsequent positron emission tomography (PET) of the brain of an AD patient showed that cholinesterase inhibitors convert the hypometabolic state into a hypermetabolic state.
In the case of galantamine, Tenchavez said it binds preferentially to the presynaptic acetylcholinesterase, resulting in additional action via allosteric stimulation of the nicotinic presynaptic receptor. This mechanism attempts to enhance the concentration of acetylcholine in the synapse area.
Tenchavez warned of factors that can worsen side effects, like rapid and large dose escalation, level of cholinergic deficit, gender, low weight, and concomitant use of CYP40 inhibitors. "All of these can cause overstimulation of cholinergic transmission. As a rule, start with a small dose, [especially] if the patient is female, at an early stage of AD with no prior cholinesterase treatment, is using [dopamine blockers], or has low body weight," he advised.
Roger Badillo II, MD
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