Most of what we know about neurochemistry in these conditions is the result of correlational studies examining correlation.
For example, in most neurodegenerative disorders, activity of the enzyme monoamine oxidase B (MAO-B) is elevated and levels
of achetylcholine are either primarily or secondarily lowered. In the case of Alzheimer's disease and canine cognitive dysfunction,
the increased activity of MAO-B appears to correlate with depletion of dopamine and loss or decreased activity of dopaminergic
neurons. However, the primary MAO receptor in dogs appears to be of the subclass A, not B, a paradox that is unresolved.
One mechanistic hypothesis is a neuroregulatory one. Because of the increased activity of MAO-B, dopaminergic neurons are
unable to maintain production and so undergo some atresia. Normal dopaminergic function is essential for basal ganglia function.
Degeneration of dopaminergic neurons is invariably associated with motor and cognitive defects. In part, this decreased metabolism
may be responsible for further cellular deterioration and apoptosis/programmed cell death. Bombardment with highly reactive
free radicals can both induce and augment this effect. Free radicals increase with cellular degeneration, which may then cause
DNA fragmentation, which further worsens the functioning of cells. In fact, enzymes called capsases are increased in and around
amyloid containing plaques and tangles, and may be essential in encouraging DNA fragmentation and in promoting degeneration
of mitochondrial and endoplasmic reticulum products. All of these processes are capable of leading to cellular apoptosis.
Free radical production accentuates this process. Compounds that thwart free radical production or destroy them hinder programmed
cell death and may augment cognitive function. The newer foods and supplements for aging dogs are intended to redress the
pathology associated with free radical production and apoptosis.
Drugs that either are or could potentially be useful: There are numerous drugs - and the list is always growing for humans
- that may be affective in the treatment of cognitive decline. There is only one drug, selegiline (Anipryl® Pfizer), with
a label for canine cognitive dysfunction in the United States. It is important to remember that all other use is extra-label,
and that for some of the medications discussed canine and feline dosages have not been investigated. Once treatment with any
of these cognitive enhancers has begun, it is likely to be lifelong. Because most of these medications are metabolized through
renal and hepatic cycles, appropriate pre- and post-medication biochemical evaluation is warranted.
1. Selegiline (starting dose for dogs: 0.5-1 mg / kg po q. 24 h; starting dose for cats: 0.25-0.5 mg / kg po q. 24 h): This
is a selective inhibitor of MAO-B receptors (e.g., an MAO-I). MAO-Is that affect the B receptor enhance the degradation of
phenylethylamine, norepinephrine, dopamine and tyramine but have little effect on serotonin. Selegiline exerts its effect
both by blocking this degradation and inhibiting the re-uptake or recycling of neurotransmitters in the synaptic cleft, resulting
in an increased amount of neurotransmitter in the cleft and increased saturation of the post-synaptic receptors, primarily
on dopamine receptors. These actions are thought to be both neuroprotective and directly stimulatory for neuron function,
in part because dopamine is a precursor to norepinephrine.
2. Nicergoline: This compound is an ergoline derivative that has alpha-1 adrenergic blocking effects. Accordingly, one of its
main effects is to augment cranial and brain blood flow and distribution. Because of the feedback effects on neuronal metabolism,
nicergoline, like selegiline, may have a neuro-protective effect. Nicergoline's neuroprotective effects may be more direct:
it inhibits lipid peroxide formation, inhibits lipid peroxidation, and may act as a scavenger of free radicals.
3. Galantamine: Galantamine is a new acetylcholinesterase inhibitor that potentiates pre-synaptic nicotinic cholinergic neurotransmission.
4. Clomipramine (Clomicalm®: Novartis)(starting dose for dogs: 2 mg/kg po q. 12 h, or 1 mg / kg po q. 12 h x 2 weeks, then 2
mg / kg po q. 12 h x two weeks, then 3 mg / kg po q. 12 h as maintenance dosage; starting dose for cats: 0.5 mg / kg po q
24h): As a relatively specific tricyclic antidepressant (TCA) that has two functioning metabolites, one that acts as another
TCA that primarily affects norepinephrine and another that acts as a specific selective serotonin re-uptake inhibitor (SSRI),
clomipramine augments the functioning of both serotonin (particularly with respect to the pre- and post-synaptic 5-HT1A subtype
receptors) and norepinephrine. By blocking the re-uptake of these neurotransmitters clomipramine may alter neuronal metabolism,
and through these changes exert a cryo-protective effect. TCAs and SSRIs may also exert some of their beneficial effect in
conditions involving cognitive change by decreasing the anxiety attendant with the development of these conditions. Because
of the association of old-age onset separation anxiety and the potential advent of cognitive dysfunction, treatment with clomipramine
may be a rational first step when the diagnosis is unclear.
Behavioral interventions that may prove useful: By the time cognitive decline is fully advanced and the patient manifests
debility within each of the non-specific sign groups, intense, active behavior modification is unlikely to be helpful precisely
because its success depends on an intact cognitive system. The earlier behavioral, pharmacological and dietary intervention
are accomplished, the more likely that the dog or cat will experience improvement. That said, at present the course of this
condition can be slowed, not aborted.
Behavior modification designed to teach the dog or cat to sit or lie down and relax can act as a rule structure for affected
animals. If during regular times of the day the clients pay attention to their dog or cat in specific and routine ways, the
animals will have a rule structure that provides some degree of predictability and expectations about interactions. Such predictability
decreases anxiety. Additionally, regular interaction, particularly if it involves some cognitive stimulation (eg, requiring
the pet to sit for a treat) will help stimulate neuron function. Stimulation of neuronal function that involves second messenger
systems and new protein translation has been associated with increased mental flexibility and decreased cognitive decline
in humans. Routine interaction can be as simple as daily massage, including gentle extension and manipulation of all joints
or gentle grooming.