Senile Dogs, Cats . . . and Cheetahs

Dementia and Alzheimer’s Disease

Whoever saves a life, saves the world entire.

—THE TALMUD

Marty, a fifteen-year-old neutered male Border collie, had been taken to his local veterinarian because he no longer seemed to recognize familiar people. He had less and less interaction with his owner, who noticed him staring off into space quite a bit, gazing at blank walls as though he might see something there.

There were other disturbing quirks. Marty had taken to pacing aimlessly from early evening into the wee hours. Although his sleeping at night was fitful, he slept most of the day. In addition, though fully house-trained for all his life, he was suddenly having accidents in the house.

Medically, there was nothing amiss. Marty checked out just fine in all areas. But the vet who referred Marty to me correctly diagnosed canine cognitive dysfunction (CCD), otherwise known as canine Alzheimer’s disease.

The acronym for the signs of this condition is DISHA:

• D for Disorientation

• I for altered social Interactions

• S for Sleep disturbance

• H for House soiling

• A for altered Activity level

Poor old Marty had the behavioral full house. Knowing a fair amount about CCD, the local veterinarian put Marty on a medication, selegiline, which can sometimes reverse the clinical signs, although it cannot cure the problem, any more than the medicines prescribed for humans with Alzheimer’s can cure the disease. But it can buy affected dogs more quality time.

Selegiline is an old-fashioned monoamine oxidase inhibitor (MAOI), an antidepressant that blocks the breakdown of dopamine in the central nervous system. Dopamine has effects on consciousness and mood. Alzheimer’s syndrome may involve a lack of dopamine. Increasing dopamine levels in the central nervous system should thus help reverse at least some signs of the disease. This is what can and does happen for some dogs.

With selegiline treatment, about a third of dogs with CCD have their condition almost completely reversed. Another third show noticeable improvement. The remaining third show no improvement at all, perhaps because the disease has progressed too far or their dementia has other sources. Unfortunately, because the disease is progressive, the improvement only lasts for a few months.

One amazing success story I heard during premarketing trials for selegiline was about an eleven-year-old Afghan hound. He was treated with a veterinary version of selegiline, trade name Anipryl. Selegiline is used to treat human Alzheimer’s under the medical trade name Eldepryl.

After treatment with the drug, the Afghan was behaving like a two-year-old, his owners reported.

“That’s great,” the researcher said.

“No, it’s not,” the owner replied, not entirely seriously. “We didn’t like him when he was two. Would you please reduce the dose to make him act like he is six?”

After six weeks on selegiline, Marty was much improved. His house soiling and aimless pacing decreased considerably. Two and a half months after beginning the selegiline treatment, there was some backsliding, so Marty’s owner brought him to see me to ask if anything more could be done.

In my consulting room, the old Border collie looked forlorn. His head was bowed. He had a vacant expression and appeared barely interested in his new surroundings. He did not investigate the premises, sniffing out novel smells the way a normal dog might do. Yet this afflicted creature slowly made his way across the room to approach me. I was touched and flattered when he wagged his tail slowly and offered his head to be petted.

Marty’s owner wanted to know if he was salvageable or whether the best thing for him would be to put him to sleep. I did not think it was time yet to go that route.

“Look at him,” I said, gesturing to the dog at my feet. “Marty still enjoys many aspects of life, doesn’t he? You say he’s eating well. He obviously enjoys petting and attention. Before we throw up our hands, I think there is more we can do to try to reverse symptoms of his condition.”

Hearing this, the owner almost wept for joy. I just hoped I hadn’t overstated my case.

I switched Marty’s diet to an antioxidant-rich dog food, Hill’s Prescription Diet b/d, a proprietary formula designed to address issues with brain health and aging. In research studies, aged rats were fed blueberries, rich in antioxidant flavonoids and vitamin C, and seemed to gain a new lease on life. Antioxidants can help turn things around with canine Alzheimer’s, too, or at least slow its progression.

I recommended two dietary supplements for Marty, acetyl L-carnitine and coenzyme Q10 (CoQ10). The first is an antioxidant that has other neuroprotective effects. CoQ10 is an antioxidant, too, and is known to boost cellular energy production. Finally, I prescribed the sleep hormone, melatonin, to be given to Marty at night to help him sleep more soundly. Melatonin also happens to have antioxidant properties and has been shown to increase life span in experimental animals.

I asked Marty’s owner to keep his life interesting and engaging, giving him as many walks as he could handle, play dates with other dogs, and plenty of new toys. In research studies, novel environments have been shown to give aged rats new vigor. A rich social life has been shown to help stave off Alzheimer’s disease in people.

Within a few weeks under this new regimen, Marty was moving around more and showing more interest in his surroundings. When his owner went to give him a boost into the car, he surprised her by jumping in by himself. He slept through the night, and was almost “accident-free” in the house. Clearly his condition had improved.

When she first brought Marty to see me, she had said that, when she looked into Marty’s eyes, she saw an unfocused, anxious creature gazing back. “Now, he’s back, and it’s a beautiful thing,” she told me. “It was sort of like there was no one home before. Now the lights are on and Marty is in.”

Even though Marty’s condition would deteriorate in the future, we had bought him some more quality time. According to the folk wisdom formula, one more year in his life would equal about seven years in ours. The one-to-seven ratio has a lot of qualifications attached to it, but it’s a useful rule of thumb. So when you give your pet a three-minute massage, credit yourself with a full twenty minutes.

Older cats get a feline version of Alzheimer’s disease, called feline cognitive dysfunction (FCD). Typically, FCD develops in susceptible cats above eleven or twelve years of age. The onset is insidious and almost unnoticeable. The first sign of the condition might be a loss of interest in play and excessive daytime sleeping. Then comes the aimless walking and disorientation.

Kitty will go from bad to worse. The disease may progress to staring blankly at walls, decreased interest in food, and house soiling. As with canine cognitive dysfunction, nighttime hours seem the worst. Affected cats pace the floor as if they’re lovesick, caterwauling and moaning in a haunting and pitiful way.

I bore personal witness to a case of FCD in Monkey, my seventeen-year-old cat. With Monkey, the first sign was a changed personality. She became much less playful and interactive. She’s old, I would think. It’s only to be expected. Yet her mom, Cinder, did not undergo the same personality change, even though she was a couple of years older.

As time went by, Monkey started to have accidents outside the litter box—right next to the litter box instead of in it. I tried everything I knew to get her back to using the box: added other litter boxes in the house, tried different litters, scooped the box more frequently, all the tricks that usually work so well, to no avail. Luckily, I was feeding her a high-fiber ration so the stool she produced was compact and easy to clean up.

The next stage of Monkey’s decline involved constant nighttime perambulations. She accompanied these walks by moaning as if she were in pain. She had formerly yowled like that, but only when attempting to throw up a hairball. Now it was just ghostly crying in the middle of the night. By then, my wife and I knew our cat was in real trouble.

When Monkey reached nineteen years of age, on her last day on this planet, she wandered aimlessly across the living room floor, showed no interest in her food, and then disappeared. It took us ages to find her. We searched the house all day and finally had to pack it in for the night. As we were getting ready for bed, we heard a faint moan coming from the bathroom. Peering through an opening in the marble-tiled tub surrounds, we saw Monkey at the far end, hunkered down and almost out of sight.

We had to use a hammer and pry bar to break apart the tiles in order to reach her. Sadly, it was too late to do much. She was clearly in the last stages of life. Even before we could humanely dispatch her to prevent further suffering, Monkey passed away in our arms. Though we knew she was unwell, we were still devastated.

Human Alzheimer’s is hauntingly similarly to the dog and cat version, or perhaps it is more proper to say it is the other way around. Unfortunately, I have had firsthand experience of this condition, too, as my mother died of complications related to Alzheimer’s disease. As with the animals, the beginning of her decline was insidious. She would forget the odd word, like my daughter Victoria’s name, referring to her as “your little girl.”

Early on, my sister Angela informed me that our mom’s behavior indicated the initial stages of dementia, but I remained unconvinced. I suppose I wishfully ascribed my mother’s forgetfulness to senior moments. Then I greeted her at the airport after she returned from a transatlantic flight.

“I was tucked into bed by the nice nurses,” she told me. She wasn’t being fanciful. She really did believe the flight attendants were medical personnel. Only then did I realize how much she had deteriorated.

During that visit I had her stay in my guest room. I showed her the bathroom, right across from her room. That first night we woke to hear a tinkling noise in the bathroom off our own bedroom. I found Mom in there, confused and apologetic. I escorted her back to her own bedroom. I discovered a trail of urine from her room at the far end of the house all the way to our bedroom.

I felt so sorry for her being disoriented—which would be the D for disorientation in the DISHA acronym. That same trip she turned on the gas stove and forgot to light it. She also put the kettle on without turning on the gas, which was far less dangerous.

She continued to decline when she returned home to England, her condition going from bad to worse, as it always does with Alzheimer’s disease. One by one she gradually ticked off all the elements of the DISHA acronym. I was there with her the day the diagnosis of Alzheimer’s disease was confirmed. Afterward, walking down the hospital corridor hand in hand, she told me that she had a wonderful son now living in the United States.

“It’s me, Mom,” I said.

“Oh, I am bad, aren’t I?” she replied.

Mom eventually faded further and further away. Her activity level fell to near zero (note the A in the DISHA acronym, for activity). She slept each day away, and was put to bed at six p.m. At this stage, I was not sure she even recognized me.

On my very last trip to see her, a few weeks before she died, I gave her a big hug as I was leaving the home. I made my way toward the door saying, “I have to leave now, Mom. Time to catch my plane.”

She straightened up from her hunkered-over posture, looked mistily at me, and gave me a weak wave. As I looked into her eyes, I saw a tear roll down her cheek. The light was on and someone was home after all. It broke my heart.

This was the woman who had first set me on my path in life. Gwen Dodman taught me the fundamental basis of One Medicine; that all life is related and that animals are more like us than we sometimes think.

Whether it occurs in people or in pets, Alzheimer’s is a cruel disease. Piece by piece, it robs the afflicted of their memories and leaves them an empty shell of what they used to be. Some say it’s worse for the family, who have to witness the inexorable deterioration that occurs with this merciless condition. There may be something to that. We don’t know how the afflicted feel, since they can’t tell us. Alzheimer’s seems to take people back to childhood, erasing memories in reverse. Living with Alzheimer’s is a Groundhog Day–like existence. Each day there is a mental whitewashing of what came before.

At some point, people who are affected with the disease do not even realize they have it. As my colleague Lou Shuster says, “If you think you may have Alzheimer’s, then you don’t.”

The steady, unstoppable course of Alzheimer’s over time is a feature of the disease in both animals and people. In dogs, various psychomotor tests have been used to examine and monitor the condition’s progression. Demographically, the number of dogs affected with CCD increases steadily from age ten onward. Similarly, human Alzheimer’s disease is more prevalent in older age groups.

Another parallel between human Alzheimer’s and animal Alzheimer’s is the pathological change that takes place within the brain. In both humans and animals, a protein called beta-amyloid accumulates between brain cells, developing into what are called senile plaques. Amyloid accumulation is associated with a decrease in brain volume. Such buildup of plaque correlates closely with the degree of cognitive impairment in both people with Alzheimer’s disease and pets with cognitive dysfunction.

So-called neurofibrillary tangles of a protein called tau also correlates with the cognitive impairment of Alzheimer’s. Though tau tangles do occur in aged dogs, the link between this change and clinical deterioration is not quite so clear as it is in humans.

Studies have ascertained the link in another species, a surprising one: cheetahs, Acinonyx jubatus, the fastest land animal in the world. Researchers at the School of Veterinary Medicine of Azabu University in Japan have demonstrated that in cheetah research subjects, spontaneous development of amyloid plaques and tau tangles do occur. Both are seen more frequently in aged animals. Similar to human patients with Alzheimer’s disease, in cheetahs the amyloid changes were mostly distributed in the parahippocampal cortex in the CA1 region. Two cheetahs in the study with the most severe cognitive impairment also had the most severe tau pathology.

Compelling pathological similarities have made canine cognitive dysfunction an interesting model for study of the human condition. For example, treatments suspected to be effective in people can be tested much more quickly and easily in dogs. A constellation of genes have been implicated as increasing risk for Alzheimer’s disease in people. To study genetic contributions to CCD in dogs might help further elucidate the role of individual suspect genes and their most relevant interactions.

One relatively new theory posits that Alzheimer’s disease may be a form of diabetes. Type 3 diabetes is what some physicians are calling it. Brain cells need glucose to function. Insulin packs glucose into cells. If brain cells are bombarded with too much insulin for too long for reasons of a bad diet, they become insulin-resistant. When this happens in the brain, watch out. Certainly the incidences of type 2 diabetes and Alzheimer’s disease have increased in lockstep of late. I believe the type 3 diabetes hypothesis could be studied more rapidly and easily in canines than in people.

Another treatment that is used for people with Alzheimer’s is Namenda, a drug with the generic name of memantine. Namenda is an NMDA blocker, prescribed off-label to alleviate obsessive-compulsive disorders in animals and people by negating the effect of the excitatory neurotransmitter, glutamate. Another theory about the causes of Alzheimer’s disease is an overactive glutamate system. It’s thought that beta-amyloid does its damage by wreaking havoc at the glutamate-sensitive synapses. High levels of glutamate cause calcium to flood into the cells, which triggers overproduction of toxic substances, including tangled tau proteins. This can lead to cell death. Namenda helps regulate this and may slow the progression of cognitive deterioration in dogs with CCD or cats with FCD, as it does in people.

Nitromemantine, a derivative of memantine, is also designed to block glutamate receptors and to reestablish damaged synapses. In a mouse model of Alzheimer’s, the treatment reversed synapse damage almost completely in a matter of months. Nitromemantine might be a more effective drug than memantine, as the latter is repelled from the so-called eNMDA site by a conflicting electrical charge. Unfortunately, this drug is not yet available for routine use.

Another promising drug, Aricept, works by allowing the buildup of a neurotransmitter called acetylcholine in the gaps between certain brain cells. Acetylcholine is a neurotransmitter that can be at a low ebb in patients with Alzheimer’s. I feel sure this medication would help animals suffering from dementia, but it has yet to be tried in nonhuman applications.

Along the same lines, the herbal derivative, huperzine, which I mentioned for treating complex partial seizures, is known by herbalists to be a treatment for cognitive impairment. One other potentially useful pharmacologic action of huperzine is that it binds, however weakly, to NMDA receptors, so it could conceivably act like Namenda and Aricept together as an NMDA blocker and acetylcholine enhancer, a double whammy of cognitive boosters. While huperzine’s value in treating CCD can be posited from first principles, there is not yet any direct clinical evidence of its efficacy in people or animals. With that said, I would expect it to be helpful in dogs and cats with cognitive dysfunction—and cheetahs, too, for that matter.

A number of new experimental treatments for Alzheimer’s have come along recently, many developed first with animal models. One of the more promising treatments is with a drug which currently only has a generic name, bexarotene, tested at Case Western Reserve University. It has been shown to clear more than half the amyloid plaques in a mouse within seventy-two hours of administration. Ultimately, the total reduction of amyloid was 75 percent. Researchers claim that bexarotene “programs the brain’s immune cells to eat the amyloid deposits.” This drug may eventually find its way into human clinical trials, although not all researchers are enthusiastic about it, because other studies have not been able to replicate the earlier promising results in mice. Science marches forward, but sometimes it takes a step back along the way.

Canine and human brains both show similar structural changes during the aging process. One effective way of studying this change is by using voxel-based morphometry, or VBM, a type of MRI technique that I mentioned before in the discussion of compulsive disorders. With VBM, researchers found frontal lobe atrophy and age-related changes in areas of the cerebral cortex. Also affected were the thalamus, one of the brain’s relay stations; the cerebellum, which affects motor control, some cognitive processes, attention and language; and the brain stem, responsible for controlling vital functions. There is also atrophy of the brain and enlargement of the normally fluid-filled spaces within the brain, seen in both the normal course of aging and more severely in Alzheimer’s in humans and dogs.

It is now possible in people, and therefore in dogs and cats, to scan the brain for beta-amyloid. We can detect an early increase in beta-amyloid level before clinical signs appear. This new advance lends itself to early diagnosis and preemptive treatment, although the effectiveness of preventive treatments in clinically normal patients is controversial. I would advocate that we study the efficacy of the new treatments in at-risk dogs instead of waiting for the full-blown condition to develop. While not all studies of treatment in a mouse have translated into efficacy in human trials, I feel sure that the canine condition has more to offer.

I often stop in the middle of such meditations to give a thought to my late mother. She would be delighted that research in pets might benefit humans. Gwen Dodman gets my nomination as a patron saint of One Medicine. Considering the cruel way she passed away, losing her faculties to the ravages of dementia, there is poetic justice in applying her belief in the unity of all life to the battle against the disease that killed her.

The number of people with Alzheimer’s increases each year. An effective treatment is tragically overdue. A similar increase in the prevalence of cognitive dysfunction is also being seen in the population of aging dogs and cats. As we care for them more effectively and provide them with healthier, better-balanced diets, our pets live longer. That’s a good thing. But some live long enough to develop cognitive impairment. Canine cognitive dysfunction, like Alzheimer’s disease, is a bad moon on the rise. We desperately need to find a way of treating it.