The Root of Thought (19 page)

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Many degenerative diseases of the brain, especially Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease) have a curious aspect. In all of them, the first thing to go is the sense of smell. Why smell? No one knows. Many reasons for this might exist—the disease somehow attacks the neurons transmitting the sense of smell into the brain. Maybe some primitive evolutionary imprint has left its mark on our nose and it just gives up when the brain begins to degenerate in any area. However, we are taught that in Alzheimer’s, the point of attack is the hippocampus, which is the area responsible for forming new memories—the area cut out of Brenda Milner’s famous patient HM. In Parkinson’s, the debilitated area is the basal ganglia, and particularly the substantia nigra, an area that helps control movement. In Amyotrophic Lateral Sclerosis, it is the cortical motor neurons, where neurons extend long axons out of the cortex to tell our body what to do. What does the sense of smell have to do with any of this?

It turns out that, in reality, regardless of what they teach you in biology class, many of these diseases are related. Labeling the diseases undercuts the fact that they are like the color spectrum—blue and red are different but can be combined to create purple. Alzheimer’s and Parkinson’s are different, but a type of degenerative disease exists that is a combination of both. A doctor who specializes in treating diseases of the brain will tell you that each person is different, and someone can be classified as having Alzheimer’s but can have symptoms of other diseases and so on. Again, the human desire to label and characterize to understand something can impede our understanding.

Before modern science, people with degenerative diseases were neglected, tossed aside, and allowed to die. People didn’t live long enough to get diseases. If they made it to 90 and they couldn’t remember
their own name, well, they had made it to 90. However, as people live longer, we feel the need to lump a group of people who can’t remember anymore into a category or a group of people who have trouble moving into another category. What might have been lost in all the categorization is that an afflicted person might be experiencing a disorder similar to what other people might have, but is still unique.

It started with James Parkinson (1755–1824) who observed six people in London and wrote an article in 1817 describing “the shaking palsy.” He observed in detail the tremors and the inability to start and stop movements.

In France, 60 years later, Jean-Martin Charcot (1825–1893), one of Sigmund Freud’s mentors who was also an advocate of hypnotism and the main culprit in disease labeling, capitalized on Parkinson’s observations. Charcot was the first proponent of describing aberrant behavior and then comparing that with the brain using the cell stains developed by Cajal and Golgi. He was prolific in naming diseases—among them, multiple sclerosis and Charcot-Marie-Tooth syndrome (the degeneration of nerves in the limbs). Charcot also coined the shaking palsy “Parkinson’s Disease” based on clients he saw who resembled Parkinson’s outline of symptoms in his well-known essay.

At the famous Salpétriére Hospital in Paris, Charcot didn’t stop at naming diseases and created the first “neurology” clinic in a European Hospital. Perhaps his most famous finding, though, was the description of Amyotrophic Lateral Sclerosis (ALS), which is called Maladie de Charcot in Europe. In the United States, it is called Lou Gehrig’s Disease after New York Yankees’ first baseman Lou Gehrig. Halfway through the summer of 1938, Gehrig, who finished second in the league in hitting the year before and third in homeruns and was generally regarded the best player alive, suddenly couldn’t hit at the age of 35. He finished the season with a .295 average, a good average for a normal player, but about 50 points lower than Gehrig was used to. At the beginning of 1939, he had no strength and, after previously playing 2,130 games in a row without an injury, took himself out of a game. When the Yankees were playing in Chicago, Gehrig went over to the Mayo clinic in Minnesota and was diagnosed with ALS by the famous Dr. Mayo. Eventually he had to retire, but fans were troubled by his sudden decline, from the best player in the game to an apparition of a figment of himself. He died two years later.

In degenerative disease of the brain, the complete loss of one’s health and mind is the sad result. Nothing can prepare anyone for the destructive nature of the disease, especially friends and relatives of the afflicted—and in the instance of Gehrig, millions of fans who felt a special relationship with him. ALS is a particularly horrific disease. The degeneration of cortical neurons extending into the brain stem and the spine was elucidated after Charcot described the disease. The degeneration of the brain stem and the spine causes horrible pain, inability to walk, and eventually the inability to breathe.

In 1919, an Uzbek-born Russian biologist Konstantin Tretiakoff (1892–1958) noticed that patients diagnosed with Parkinson’s Disease had a loss of pigmented neurons in a nucleus deep in the brain called the
substantia nigra
. Substantia nigra is Latin for “black substance,” ironic in the year the Black Sox threw the World Series. It is believed the substantia nigra works with other cell nuclei under the cortex in a feedback loop to calibrate our movements.

In a section cut out of the midbrain, the substantia nigra resembles dark thumbprints. The reason for the dark coloring is melanin in the neurons, the same substance that pigments our skin. The substantia nigra is like the freckled cheeks on the face of the brain.

A German scientist using the same strategy that Charcot popularized, Alois Alzheimer (1864–1915), was the first to describe the disease of forgetfulness. Auguste Deter, a 51-year-old housewife who had developed symptoms of memory loss was recommended to him as a patient. Fascinated, when she died five years later, Alzheimer exhaustively studied her symptoms and brain with a Golgi type silver stain; he found the cortex had shrunk and looked like a walnut, and neurons had been destroyed.

The only effective treatments exist for Parkinson’s. In the 1950s, Nobel Prize-winning Swedish scientist Arvid Carlsson discovered the transmitter dopamine. It was then learned that dopamine is the main transmitter in neurons signaling from the substantia nigra to other areas of the brain. By giving a dopamine depletion molecule to dogs, Carlsson showed they began to exhibit Parkinson’s Disease-like symptoms. Using an analog called L-Dopa, which crosses the blood brain barrier and is converted to dopamine, researchers can immediately reverse symptoms in some patients.

This cosmetic treatment does not cure the disease. Conversely, it is believed that excessive dopamine treatment can accelerate the disease. Although it has improved the life dramatically of patients with Parkinson’s in the few years after diagnosis, it does not reveal the cause of the disease.

Another current treatment in Parkinson’s Disease is Deep Brain Stimulation. An electrical stimulator is placed deep in the brain in the basal ganglia, the set of nuclei that encompasses the substantia nigra. The electrical stimulation can mimic the substantia nigra firing and restore movement. As one can imagine, this treatment is cosmetic and does not cure the disease, but it has increased the quality of life in many patients much longer than they would have had without it. The difficulty is that in Parkinson’s Disease, as well as other diseases of the brain, the methods of Charcot describing specific areas has proven simplistic. When, in fact, some areas might decline more rapidly at the beginning, but the entire brain of these patients, including the cortex, will eventually degenerate.

In the past 30 years, a lot of research and effort has been spent trying to connect the cause of diseases to proteins in the neurons. While studying Parkinson’s, in 1912, while working in Alzheimer’s laboratory, Frederick Lewy noticed that spherical protein deposits (now called Lewy Bodies) occur in neurons of people with dementia. The protein that comprises these structures has been pinpointed and is now called alpha-synuclein. It is an abundant protein highly expressed throughout the neuron and specifically in the axons and synapses. It is believed to be involved in transporting vesicles filled with transmitters for release at the synapse. As a neuron is dying, the protein begins to bind to itself. It almost works like Velcro; some minute difference in its shape causes it to clasp together. As it keeps binding to itself, like a billion magnets thrown in a room, it forms the ring-like Lewy Body.

In Alzheimer’s, the proteins discovered around dead neurons after autopsy are called amyloid beta and tau. When they accumulate after the cell dies, they form plaques and tangles. In the brain, they pile up beside neurons similar to rust on a pipe.

All these proteins have been shown to be expressed in high numbers in the neuronal machinery and are some of the most abundant proteins. When the neuron perishes in the disease, it is not a surprise that the proteins build up around the cells. Proteins implicated in Parkinson’s have been shown to build up in Alzheimer’s and vice versa.

Genetic forms of Parkinson’s Disease have all been linked to a mutation on proteins that are highly expressed in the cell, including alpha-synuclein. Mutations that cause a problem in alpha-synuclein leading to Parkinson’s disease have led many researchers to believe that alpha-synuclein is the cause of the disease. However, this is like seeing a bombed-out city and blaming the ruins.

Of course, a genetic mutation in an abundant protein like alpha-synuclein is going to cause disease. In fact, this is expected. But because of its placing in the neuron, researchers have tried to see what alpha-synuclein interacts with in other attempts to understand the cause of the disease. This is scientific detective work; they see a dead body and look at what the victim associated with to find the killer. But who is the killer when everyone is dead? With mutations, people develop diseases that are more cut and dry and occur much earlier in their life than what happens to people who develop degenerative diseases of the brain as they age.

The focus on neurons in all these diseases is mainly the result of Cajal’s Neuron Doctrine and electrical studies coming to prominence at the same time. Astonishingly little has been researched on glia until the twenty-first century. Researchers have simply discounted them without evidence for their insignificance. But as Willy Wonka says, “You should never, never doubt what nobody is sure about.”

In 1993, researchers at Duke University Medical Center discovered a major breakthrough in Alzheimer’s Disease by linking sporadic disease to the apoE gene. With more of this gene, the chance of Alzheimer’s increased from 20 to 90 percent, and the average age of onset of the disease compared to people without the excess gene dropped from 80 to 68. With the gene, people were virtually guaranteed to get Alzheimer’s by age 80. Previous head injury is a risk factor for all degenerative diseases of the brain. If an excess gene for the apoE protein is present and the patient had a previous head injury, she will have a much better chance of developing disease later in life. This protein is highly expressed in astrocytes. It works to shuttle cholesterol and lipids outside the cell. Recently it has been implicated in Parkinson’s Disease as well.

Astrocytes and neurons work together; neurons bring information to astrocytes from the senses and execute the astrocytes on the motor level. Astrocytes maintain neurons like cities maintain roads, so that they can always perform their high-speed transmissions. Astrocyte maintenance of neurons requires them to take up glutamate—a transmitter that can be toxic if built up in the synapse. Astrocytes can also take up excess reactive
oxygen species, toxic byproducts of the energy-producing mitochondria. When unconsumed oxygen is roaming through the cell, it can become destructive and cause cell death, and this destruction is termed “oxidative stress.” The dopaminergic neurons in the substantia nigra in Parkinson’s Disease are more susceptible to oxidative stress than in a healthy person. There is no other explanation for this other than astrocytes not maintaining the neuron.

Astrocytes also take up excessive amyloid beta when it leaks out of the neuron. The plaques that form around neurons when they die are filled with amyloid beta. The build up of this protein might likely be because no astrocytes are available to clean them up.

Glutamate, the main transmitter released in the cortex and released by upper motor neurons, when not broken down, washes over the neurons and kills them in ALS. In 1992, at John’s Hopkins, Jeffrey Rothstein showed that problems with glutamate transporters might be the reason for the beginning of ALS. It is now known that these transports reside in the membranes of astrocytes. Astrocytes take in glutamate at the synapse.

It makes sense for astrocytes to want to break down and clean up destructive molecules and proteins because they require their high-speed neuronal connections to send information long distances to have the body execute what they thought. Astrocytes don’t clean up some of the excess of neuronal communication because they are subordinate—they do it because they are dominant. Just as we must maintain the roads near our cities, the astrocytes must maintain the neuron. Astrocytes have access to the blood vessels that not only provide nourishment, but can also work as a garbage dump for the waste materials that build up when the neuron fires its energy. Whether some problem with apoE functioning or the inability for astrocytes to scavenge proteins, transmitters, or by products of oxidative stress, the evidence points to astrocytes as the cause in degenerative diseases of the brain.