A Simplified Explanation
Section 03

The Liver-Brain-Theory was conceived De novo,
By a non-neurologist physician, using Nothing more
than Pure Deductive Reasoning.

ALS, Alzheimer’s, Primary Dementias, Parkinson’s, Multiple Sclerosis and Age Related Macular Degeneration are closely related diseases sharing a common cause, neurotoxins produced in each patient’s own liver, differing only in their clinical presentation.

  1. This is the most comprehensive theory ever presented, addressing neurodegenerative diseases, and the only one whose basic premise can be both challenged and tested quite easily.
  2. One routine surgical procedure, a liver transplant (replacement), in a patient with ALS will either confirm or refute the basic premise of the Liver-Brain-Theory.
  3. Should a liver transplant prove that it can permanently arrest, but not reverse; the previously lost muscle strength in a patient with ALS the basic heretical premise of this theory will have been validated. The specific hepatic generated neurotoxin(s), which the author postulates to exist, will be shown to be the direct proximate cause of ALS should be able to be isolated and identified with certainty shortly thereafter.
  4. This theory proposes that Hepatic Generated Neurotoxins leading to ALS, Alzheimer’s, Parkinson’s, specific forms of Macular Degeneration and Multiple Sclerosis will be demonstrated to have a similar structural configuration and chemical composition.
  5. It should be possible to develop specific protein blocking or neutralizing agents, precluding the development or progression of Alzheimer’s, ALS, Parkinson’s Multiple Sclerosis or age related macular degeneration once the specific neurotoxin causing these debilitating and frequently life shortening disease has been identified with certainty. The author sees the day when the genetic susceptibility to developing most forms of neurodegenerative diseases will be identified in infancy and treated accordingly.
  6. The multiyear prodromal period observed in Alzheimer’s will be confirmed to be due to the time required for the liver to produce a sufficient quantity of neurotoxins necessary to destroy glial-neuron cell complexes anatomically and physically adjacent to memory neurons leading to their death and the subsequent loss of each patients acquired memory.
  7. The much shorter prodromal period associated with ALS, contrasted with Alzheimer’s, will most likely be attributed to the much larger ratio of neurotoxins to motor neurons versus memory neurons. The fact that the time period of diagnosis to death in ALS appears to be in the range of 10% -15% of the equivalent time period for Alzheimer’s will likely be a reasonably accurate measurement of the ratio of memory neurons to motor neurons.
  8. In time most neurodegenerative diseases will be recognized to be a form of an inborn error of metabolism with a delayed recognition of onset. They will be demonstrated to differ from “storage diseases” in that the hepatic generated neurotoxins are not stored in glial cells or neurons, but rather precipitate the death of specific glial-neuronal cell complexes and their anatomically associated memory or motor neuron aggregates.
  9. An additional corollary of the Liver-Brain-Theory is that the Alzheimer’s present in Down’s syndrome will likely be shown to have the same direct proximate cause as that seen in the general population: “hepatic generated neurotoxins.” The fact that these clinical findings appear several decades or two earlier in Down’s patient’s may be directly attributable to the observation that Down’s patients have fewer cerebral neurons at birth. (13)
  10. The author’s primary impetus to engage in this multiyear undertaking was the direct consequence of his personal clinical health experience associated with advanced liver disease associated with progressive hepatic encephalopathy requiring a liver transplant and his attempt to explain why an increasing number of otherwise healthy seniors, develop Alzheimer’s, ALS, Primary Dementia, Parkinson’s and many other forms of degenerative brain diseases with ever increasing frequency as they age, without any known, obvious or otherwise conceivable explanation.

This theory provides a plausible explanation why the age distribution of ALS is slightly different from Alzheimer’s is directly attributable to the genetic directed development of more memory neurons than motor neurons.

The Liver Brain Theory does not attempt to explain why ALS is more common in white males in contrast to Alzheimer’s which is more common in females, other than to cite published data that suggest females tend to have fewer cerebral neurons than males. (3)

Currently there are an estimated 5.2-5.4 million Americans with Alzheimer’s; several million with Primary Dementia’s and approximately 12-15,000 with Lou Gehrig’s disease or “motor neuron diseases” as these diseases are named in most European countries. And additional million plus will develop Parkinson’s, another degenerative brain disease, the incidence of which is second only to Alzheimer’s. The variable and unpredictable clinical course if Multiple sclerosis remains an enigma.

In 2018, a newly diagnosed patient with Lou Gehrig’s disease (ALS) will have a greater probability of death (95 %+) within 5 years than with most malignancies. The same for Alzheimer’s: here the probability of death within 8 -10 years of diagnosis approaches 95% plus.

In a single declarative sentence: the Liver-Brain-Theory proposes that the: “Primary inciting cause and subsequent clinical course of ALS, Alzheimer’s, Primary Dementias, Parkinson’s, age related macular degeneration in addition to many other neurodegenerative diseases result from the death of neuron-glial complexes directly attributable to the neurotoxins produced in the patient’s own liver.” (Hepatic Generated Neurotoxins)

The basic premise of the Liver-Brain-Theory is that Alzheimer’s, ALS, Primary Dementias, Parkinson’s, Multiple Sclerosis and Senile Macular Degeneration and other neurodegenerative diseases are more likely to be related to an aging liver, rather than to an aging brain!

If one accepts current thinking, that neurons are dependent on a glucose environment for their essential intracellular metabolism, the inescapable conclusion is that it is the death of glial cells per se, that precipitates the death of their anatomically adjacent, but nutrient dependent memory or motor neurons, resulting in neurodegenerative diseases. The death of adjacent neurons would appear to be the result of lack of vital nutrients and readily available substrates provided by functioning anatomically adjacent glial cells.

The proposed argument that glial cells are the primary target for neurotoxins is supported by present evidence that injury to specific glial cell, an oligodendrocyte, is responsible for the damage to the myelin sheath covering of axonal cells precipitating relapses in Multiple Sclerosis.

This theory further proposes that the proximate cause of glial-neuronal cell death is essentially similar in all neurodegenerative diseases including ALS, Alzheimer’s, Primary Dementias, Parkinson’s, age related macular degeneration as well as multiple sclerosis and many other forms of neurodegenerative diseases: namely, hepatic generated neurotoxins.

And to go one step further, the Liver-Brain-Theory makes another heretical, but reasoned argument. “A liver transplant (replacement) will likely prevent or arrest the inevitable progression of muscle weakness, the hallmark finding of ALS, giving afflicted patients a more normal life expectancy.

Some basic definitions:

“Prodromal Period” The time during which a disease process is in existence but is not yet clinically evident or diagnosable with currently available instrumentation or laboratory tests. Many diseases, including brain diseases, begin so insidiously that even the patient himself is totally unaware of their existence. Certain cancers, for example, those in the abdomen, can grow to a very large size before the patient has any symptoms. The exact length of the prodromal phase of Alzheimer’s is yet to be determined. The prodromal phase of ALS appears to be substantially shorter. The evidence in Lou Gehrig’s case is that ALS probably developed about a year prior to the start of the 1939 baseball season, his final season in which he played only 8 games.

“Dementia(s)” Non vascular types, “Primary Dementia”:
Symptoms characterized by memory loss, impaired thinking and loss of social skills, severe enough to interfere with many of the more common normal daily life’s functions. Clinical observation suggests there is an enormous variation in both the severity and rate of progression of Primary Dementia from one person to another.

Alzheimer’s is the most common type form of Dementia. A substantial number, but presently undetermined percent of patients with Primary Dementia progress to develop Alzheimer’s. There is no definitive test or clinical observation that can date the exact time of transition from Primary Dementia to Alzheimer’s.

Parkinson’s disease (Parkinson’s)
A progressive neurodegenerative disease characterized by rigidity, muscular tremors, slowness of motion and postural instability attributed to the death of vital neurons in a specific area of the brain: “Substantia Nigra: appears be the primary focus for the production of dopamine. The typical clinical onset of this debilitating disease is in the early sixties, slightly more common in males. Parkinson’s is the second most common form of neurodegenerative diseases, only Alzheimer’s occurs more frequently.

The similarity in age of onset, progressive nature of symptoms combined with a specific focus of origin in the brain (Substantia Nigra versus hippocampus) suggests to the author that Alzheimer’s, ALS, and Parkinson’s have a common etiology: hepatic generated neurotoxins.

Unfortunately, like Alzheimer’s, there are no easily measurable, quantifiable factors in Parkinson’s patients that lend themselves to further study at this time.

Dementia, vascular type
Cognitive deficits resulting from insufficient blood flow to various parts of the brain. Specific clinical findings will prove to correlate directly with the exact areas and quantity of ischemic or infarcted brain.

A secondary, but equally important observation, specifically applicable to the Liver-Brain-Theory is that the majority of body organs do not function as well as they age, as they did when they were younger.

Only brain function improves with age: due to its necessity of acquiring a requisite data base to facilitate deductive and analytical reasoning promoting a singular human attribute: conceptual thought and analysis, but only for a finite period, until the brain itself, falls victim to the ravages of time, as is the inevitable fate of all living cells and organs.

The best example supporting this concept and the one easiest to comprehend relates to the heart. The basic function of the heart is to pump blood throughout the body. It would be very difficult to find a random group of 70 year old individuals, whose hearts are as healthy and functional at age 70 as they were when they were forty to fifty years younger.

Kidney, (Renal) Function
The primary function of the kidney is to remove liquid waste from the body and to contribute to fluid and electrolyte homeostasis. Tests of kidney function and urine volume can be measured with exquisite accuracy. Kidney function decreases with age and the rate of decrease is accelerated by two other commonly associated diseases: diabetes and hypertension in particular.

A specific example of how one body organ can do harm to another body organ is readily apparent: a secondary effect of an ischemic kidney can lead to high blood pressure. Hypertension can weaken the heart by forcing it to work harder pumping blood against an abnormally high pressure gradient. (14) In an extreme example, uncontrollable hypertension can causes the heart to fail precipitating untreatable congestive heart failure with subsequent death of the host, independent of age or sex.

“The heart will be the innocent victim of its own failing kidney.”

Although some might question the relevance of these heretical ideas to the Liver-Brain-Theory, they were intentionally inserted to support the premise that the brain is most likely the innocent victim of its own aging liver. The patient’s aging liver could very well be indirectly responsible for the development of Alzheimer’s, ALS, Primary Dementias, Parkinson’s and most other forms of neurodegenerative diseases by its inability to completely metabolize common foods in man’s diet as a consequence of the poorly understood aging process.

Age related macular degeneration results from the loss of central vision due to the death of specific macular neurons which have the ability to detect light while transmitting images to the brain. Simply by recognizing that the retina is as an extra cranial appendage of the brain suggests that this specific form of decreased vision could easily be classified as another, but distinct form, of neurodegenerative disease

The basic premise of this theory applies directly to the patient’s liver. The liver is the largest internal organ in the body, with an average weight of 1,500-1,600 grams; approximately 3 1/4 lbs. One of the liver’s many important functions is to provide primary appropriately metabolized nutrients to other body organs, including both the brain and heart.

Neurodegenerative Brain Diseases, Definition: “Neuro”, having to do with the brain, spinal cord or other nerves in the central nervous system.

Degenerate: a fundamental biologic process during which individual cells or a group of cells gradually lose function and eventually die, leaving just scar tissue behind as evidence documenting where these specific cells previously existed.

Glial cells: physically adjacent supporting cells for neurons, whether in the brain or elsewhere in the nervous system. There are several different specific types of glial cells, each with relatively distinct attributes and functions. One of the most important functions of glial cells appears to be to supply essential nutrients to their adjacent neurons.

No brain cell (neuron) is capable of completely supplying its own specific nutrients required to thrive and function normally. Neurons are dependent on a complex, but poorly understood, glial cell- neuronal relationship. Specific glial cells may well be the first cells damaged by hepatic generated neurotoxins, leading to the subsequent death of their nutritionally dependent adjacent neurons: (perhaps by simple starvation.)

These initial changes would be occurring long before they could be recognized or appreciated during routine clinical exams (Prodromal period,) thus accounting for the fact that Alzheimer’s is truly a disease of aging. Non genetic Alzheimer’s disease is rarely diagnosed before age 60-65, using presently available diagnostic methods.

Alzheimer’s has been a recognized as a distinct and unique disease since 1907. Alzheimer’s disease robs senior citizens of their memory and their ability to think clearly and care for themselves. An otherwise healthy patient, diagnosed with Alzheimer’s will die within 5-10 years of his initial diagnoses. Death is precipitated by increasingly severe memory loss even to the point of failure to recognize hunger, the necessity of adequate caloric intake and importance of basic personal hygiene.

“Alzheimer’s is the only Cause of Death in America
That Cannot be Prevented, Cured of Slowed.”*

*(Alzheimer’s Association)

ALS, (Lou Gehrig’s disease) is distinctly different in that it is characterized by the death of motor neurons: (the nerves that instruct the body muscles to move and/or breathe.) ALS is easily recognized by the rapid development of irreversible muscle wasting, associated with loss of muscle mass and strength secondary to the degeneration of motor neurons in specific areas of the brain.

ALS is extremely rare. The incidence of new cases of ALS is estimated to be 4-6,000 per year, affecting 12-15,000 patients in America in contrast to more than five million patients afflicted with Alzheimer’s. Reasonably accurate estimates of the incidence and number of patients with Primary Dementia are much less certain.

ALS may develop in a few patients younger than thirty. The majority of ALS patients are white males diagnosed between ages 40-70’s. Only a small minority of ALS patients lose significant memory.

ALS was essentially unknown to both physicians as well the general public until it was diagnosed in Lou Gehrig in 1939. Gehrig was then one of the world’s most prominent and best known baseball players in the world. He died at age 37, 25 months to the day; he took himself out of the starting Yankee lineup, “for the good of the team”.

The typical clinical course of a patient with ALS is characterized by death, 24-48 months after it is initially diagnosed, usually due to loss of muscle strength required to breathe and or swallow. ALS has no known cause, cure or effective treatment. The FDA approved drug: Riluzol may add 3 months of additional life in some patients.

Initial Conceptualization of the Liver-Brain Theory

This heretical theory was conceived from the author’s personal health experience. In 2004 he was diagnosed with terminal liver disease of unknown cause and informed he was too old for a transplant. “You should make all your final arrangements now while you are alert”. In the second half of 2005 the author was well aware he was losing his innate cognitive ability. A professional colleague had to help him fill his gas tank in early fall 2005.

In December 2005, he was unexpectedly advised to move to Pittsburgh for further evaluation of a liver transplant (replacement) at the Thomas E. Starzl Transplantation Institute in the event a liver became available on short notice. “You would be more likely to get a new liver if you were already on site than if you had to be summoned from another state.”

When the author attempted to pack his suitcase realized he was not sure what a suitcase was or what it was for. The coup de grace was that he needed help to close the zipper on his suitcase.

Within an hour of arriving in Pittsburgh he found himself in the Montefiore Hospital ICU with tubes everywhere and placed in restraints. Almost by serendipity a “left over liver” became available on a moment’s notice on January 3, 2006. The author, then a patient, was already on site, still in restraints and in the ICU only a few feet from an empty OR. When he finally awoke many days post operatively he was in great pain but could not remember the word for “pain”. His subsequent clinical course and his self-diagnosis of Alzheimer’s generated these heretical ideas.

As the liver ages, it almost certainly must become less efficient in completely metabolizing a variety of normal substrates, including complex proteins or breakdown of waste products generated elsewhere in the body. Even more likely is that the liver might actually lose its ability to completely metabolize common substrates, resulting in a few by products that are neurotoxic per se or have secondary neurotoxic effects.

Neurotoxic metabolites would have a propensity to harm all neurons in general but specifically those with receptors configured to interact with spatially compatible neurotoxins, produced in the patient’s own liver. When viewed in an abstract manner, neurodegenerative diseases might soon be classifiable as an inborn error of metabolism but with a delayed onset of presentation and recognition.

These simple concepts easily account for the following observations:

  1. The extended length of the prodromal period of Alzheimer’s is five to ten years plus.
  2. Clinical observation confirms that Alzheimer’s is a progressive disease and that its clinical severity and incidence increases with age. This later observation is easily explainable by simple arithmetic: The quantity of hepatic generated neurotoxins produced would remain relatively constant while the number of cortical neurons would decrease due to their continued death.
  3. The specific and relatively unique clinical characteristics of ALS, Alzheimer’s, Primary dementias, Parkinson’s and MS appear to result from the death of nearly identical glial-neuronal cell structures located in different, but specific areas of the brain.
  4. The delayed recognition and diagnosis of any other type of primary disease is most unusual. The overwhelming majority of late onset diseases are typically degenerative in nature: (E.G) osteoporosis, aneurysm formation, joint destruction, hearing or vision loss, atherosclerosis and coronary artery disease. Well established mechanisms of neuron cell death described in the excitotoxicity pathways might play a significant role in the development of some forms of neurodegenerative diseases. (3) Definitive evidence is lacking.

It has long been well recognized that the origin of Neurodegenerative brain diseases is independent of: Geography, Ethnicity, Sex, Religion, Diet, Skin Color, Ambient External Temperature, Occupation, Innate Intelligence and any and all other factors ascertainable.

This proposed theory represents the cumulative thought processes resulting from reanalysis of all possible causes and origins of neurodegenerative brain diseases. Using this type of observation and analysis repetitively led the author to the near inevitable conclusion that the inciting causes of Alzheimer’s, ALS, Primary Dementia, Parkinson’s, Multiple Sclerosis and degenerative retinal diseases most probably originates in the patient’s own liver via the production of neurotoxins.

Should this heretical concept that neurodegenerative disease might represent a delayed form of inborn errors of human metabolism, it will be essential that other degenerative diseases be reevaluated as to their proximate cause(s).

A theory or hypothesis is nothing but a possible roadmap, going nowhere in particular, but charting unmapped thought processes leading to the development of additional new ideas.

The development of “theories” is a critical step in the Scientific Method. This theory, like any other theory, must be subject to critical analysis, review, repudiation, rejection, or acceptance as warranted by specific conclusions of well-designed studies and experiments. Other newer ideas and theories must be welcomed, developed and evaluated as a fundamental part of the Scientific Method.

New ideas must be welcomed: Not summarily rejected!

Fundamental to the Scientific Method is the inescapable conclusion:

Everything (including diseases) must have a primary cause!

10/10/2016, 5/11/2017, 11/25/2017, 3/5/2018

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