Wednesday, February 15, 2017

Alzheimer's disease Repeating Failures

Chameleon Dementias
In 1976, a two-page editorial in the journal Archives of Neurology (now JAMA Neurology), penned by the neurologist Richard Katzman, transformed Alzheimer’s disease into an overnight sensation. The title of the paper emphasized the aim “The Prevalence and Malignancy of Alzheimer Disease: A Major Killer.” With the stroke of a pen, Alzheimer’s disease become the 4/5th killer in the world.

Katzman’s secret was simple. By eliminating the distinction between Alzheimer’s disease and senile (of old age) dementia Alzheimer’s disease become a major disease. Since “age” was the only reason that Alzheimer’s disease was defined as separate from senile (of old age) dementia—by Alois Alzheimer’s supervisor, Emil Kraepelin in 1912—this must have been difficult. But eliminating Alois Alzheimer’s definition proved surprisingly easy because there was no distinction in the first place. Katzman’s article by acknowledging this false distinction generated a lot of political capital in supporting the mission of the newly ordained National Institute on Aging. But if the reason for defining Alzheimer’s disease was wrong, what else is wrong with our interpretation of the disease?

And a hundred years later we still have no idea what causes dementia. Katzman threw us back into the past, and now, building upon this political tactic, researchers have again revisited the same issues that occupied them more than a hundred years ago.

From ancient Egyptians to the time of Alois Alzheimer in 1900s, dementia was known and rightfully, feared. Early Egyptians first document cases of what could be dementia more than two thousand BC. In a literary text from the beginning of the 2nd millennium BCE, a poem that damning description of aging is placed in the mouth of the embalmed city administrator and first historian Ptahhotep:

Senescence has come, elderliness descended.
Weakness has arrived, helplessness returns.
As one spends every night becoming more childish.
Eyesight has diminished, the ears become deaf.
Strength is perishing from my heart’s fatigue.
The mouth has fallen silent and cannot speak.
The heart is exhausted and fails to remember yesterday.
Bones ache because of length (of years).
Good has become evil.
All taste is gone.
What old age does to people,
Is evil in every respect
The nose is blocked and cannot breathe
from weakness in standing and sitting.

Throughout history, the diagnosis of dementia was confused with many other disorders. The cause was explained through the interpretative prism at the time. From the ancient Egyptians who conceived of dementia as a disease of the heart, to the middle ages where evil spirits invaded the body. Social norms and scientific fads at the time dictated how disease is explained, and dementia was no different. What was important in changing this was how we categorized diseases, especially dementia. And this formed in earnest in the late 1700s when French physicians took a more formal and objective approach to describing dementia.

Early French Scientists
We pick up the story in 1797 with the French psychiatrist, Philippe Pinel (1745-1826), who coined the term démence—deriving from the Latin de meaning "out of" and mens meaning "the mind." One of Pinel’s patients was a woman who over a period of just a few years, lost her memory, speech, and her ability to walk or use common household objects. After Pinel autopsied her brain. he described the woman’s brain as full of fluid and having dramatically shrunk to a third of normal size. In retrospect, Pinel’s patient is likely to have had normal pressure hydrocephalus (NPH). To this day NPH results in more than 9-14% of those admitted to nursing homes to be erroneously diagnosed with dementia. But despite this error, what was significant for the time was the identification of dementia as a biological disease.

After Pinel made this biological connection then it was up to another Frenchman, Jean Etienne Dominique Esquirol (1772-1840), to state more precisely the different types of dementias. Esquirol clearly distinguished dementia from mania—psychoses—and from mental deficiency. He also distinguished between acute, chronic and senile (of old age) dementia. His explanation is important as well since the different causes related to their distinguishing feature rather than their expression (i.e. they might be expressed in the same way). Acute dementia was short-lived, reversible, and followed a fever, haemorrhage or metastasis; chronic dementia was irreversible and caused by masturbation, melancholia, mania, hypochondria, epilepsy, paralysis and apoplexy; lastly, senile dementia resulted from old age, and consisted in a loss of the faculties of the understanding. Separating the observations of dementia into distinct categories based on what was assumed to be the cause, allowed for a more specific understanding of dementia. Although for senile dementia “age” was a good enough reason.

Pinel and Esquirol’s view that dementia was caused by many factors, was in contrast with the explanation used by a contemporary French physician Antoine Laurent Jessé Bayle (1799–1858).  Bayle view was that dementia was caused by an organic disease that caused swelling in the brain. Unknown at the time, Bayle was referring to the effect of long term syphilis infection. Bayle also observed that dementia progresses and becomes increasingly more severe. This interpretation was so influential at the time that dementia was also called Bayle’s disease and dementia paralytica.

By the late 1800s, French physicians already started engaging in a discussion about different types of dementia and identifying senile dementia, the initial observation of a biological cause of dementia, and the progressive nature of the disease.

German Scientists
While this discourse was going on, there was a parallel push to study dementia in Germany. The German scientists had a slightly different approach, including attracting a different name. Senile dementia was named as Presybyophrenia—from the Greek Presby meaning “old” and phrenia meaning of the “mind”—dementia of older age. This term was coined by the German physician Karl Ludwig Kahlbaum (1828–1899). With his associate Ewald Hecker (1843–1909), Kahlbaum introduced a classification system that applies terms that described the disease as expressed depending on biological developments in the body. These German physicians concentrated on nosology—how diseases are categorized. Their observations and methods have contributed to how we categorize disease today.

They argued that by grouping mental disorders based on how they are expressed ignores how the diseases progresses and how it affects the person. Supporting Pinel-Esquirol-Bayle contention that the cause of the disease should be the defining feature of the disease.  For example, a fever that comes on in a day and dissipates in a few days is very different from a fever that comes on slowly and lasts longer. Differences in how a disease progresses and the eventual outcome as a method of classifying different diseases proved providential. Kahlbaum and Hecker’s evaluation of earlier classification of diseases was that physicians were often prejudiced. By making judgements on how diseases are similar to each other, prevented physicians from gaining useful insights into its causes and how to address treatment.

There was a convergence between the French and German physicians at the turn of the 20th century. At the time the final stages of the bacterial infection of syphilis that results in dementia—neurosyphilis—was contributing to between 10-24% of all hospitalized mental health patients at the time. This is what led Bayle to identify physical causes of dementia but did not know that it was syphilis. In fact, Alois Alzheimer’s specialization—and how he met his wife, the widow of one of his patients—was as an expert in treating syphilis. In 1910, Alzheimer already knew of the connection between syphilis and the plaques and tangles that came to characterize his disease. This biological cause encouraged further parallels between an infection and senile dementia.

But both Kahlbaum and Hecker were moving away from simplistic explanations of diseases. Together with Emil Kraepelin (1856-1926), who later coined Alzheimer’s disease, these three men also shared a deep skepticism for the localization of behavior in the brain. Such brain explorations were becoming very popular during the latter half of the 19th century. Paul Broca (1824-1880) together with Carl Wernicke (1848-1905) were leading pioneering work on the localization of brain functions, specifically in speech. But Kahlbaum-Hecker-Kraepelin had bigger worries than such collegial competition.

The 1900s saw an explosion of academic proliferation. Some of the most famous scientists at the time included: Max Planck (quantum physics), Albert Einstein (physics), Marie Curie (X-rays), Sigmund Freud (psychoanalysis), Niels Bohr (physics), Ivan Panlov (medicine/psychology), Santiago Ramón y Cajal (neuroscience), Franz Boas (anthropology), Wilhelm Wundt (experimental psychology), Richard J. Ussher and Robert Warren (zoology), Ferdinand von Zeppelin (aeronautics) among many other. Together with the new science fiction of H. G. Wells, the early 1900s saw a proliferation of academic disciplines and new hope for the scientific method.

For the emerging study on dementia and the newly identified Alzheimer’s disease by Emil Kraepelin there were other considerations. Primarily there was the perceived (and real) threat that psychiatry was facing from psychoanalysis and from psychology. The case in point was the story of Anna O, now known as Bertha Pappenheim (1859–1936), whose psychoanalytic “cure” created fervor and excitement. An Austrian-Jewish feminist, Bertha Pappenheim suffered from hysteria—paralysis, convulsions, hallucinations and loss of speech—without apparent physical cause. Josef Breuer ostensibly succeeded in treating Anna by helping her to recall forgotten memories of traumatic events. Psychoanalysts proposed that physical symptoms are often the surface manifestations of deeply repressed conflicts. At the turn of the 1900s, after centuries of treating madness as a mystical curse, here was a clear answer and a clear solution. After distinguishing idiocy, epilepsy and cretinism, the remaining maladies had the possibility of being psychosomatic. In hindsight, we now know that these particular case studies—including Bertha Pappenheim—were not cured, and the likely cause of these expressions of hysteria were biological in nature.

In addition to the new vogue of psychoanalytic models, there was a complementary interpretation of disease championed by Kraepelin’s own mentor, Wilhelm Wundt. Kraepelin submitted his thesis on "The Influence of Acute Illness in the Causation of Mental Disorders" under Wundt, for which he received his medical degree in 1878.  A year later Wundt founded the first formal laboratory for psychological research at the University of Leipzig. Wundt and experimental psychologists promoted the idea that we learn how to behave, including when we are behaving abnormally, a theory very much in keeping with the psychoanalyst’s view of disease. At the turn of the century in Germany, psychological theories were becoming the new norm. Kraepelin and his staff did not approve of this interpretation of mental illness. Max Isserlin, an assistant to Kraepelin, made disparaging remarks about psychoanalyses being “complex mythology” which Freud identified as arguments coming “from the blackest clique in Munich,” referring to Kraepelin’s clinical staff. Such animosity ultimately lead to Isserlin being personally expelled by Jung in 1910, from the Congress of the Psychoanalytical Association in Nuremberg. Despite such obvious animosity, there was an intellectual challenge as well. While psychologists and psychoanalysts repeatedly believed that they were gaining ground in understanding mental diseases, what did psychiatry have to offer?

Kraepelin, a seasoned administrator, was aware of this constant yearning for answers. Yearnings for a panacea were real. Kraepelin needed to distinguish psychiatry from the “learning” of the psychologists and the “unconscious” of the psychoanalysts. In doing so he had to resort back to the biology of mental illness. Psychiatry could contribute the biological aspect of mental health.

The contribution of Biology
Kraepelin (with Eugen Bleuler) gained a different kind of success by differentiating schizophrenia from a variety of mental disorders.  The 1880 U.S. Census only distinguished seven categories of mental illness: mania, melancholia, monomania, paresis, dementia, dipsomania, and epilepsy. Psychosis was categorized as hysteria, melancholy, mania, and paranoia. Within this morass of disorders, Kraeplein differentiated between premature (praecox) dementia (schizophrenia) and ‘manic depression’ as two separate forms of psychosis. Although schizophrenia was already described as dementia praecox, first in 1852 by the French physician Bénédict Morel and later in 1886 by Heinrich Schule, it was Arnold Pick in 1891 who defined schizophrenia as a psychotic disorder (hebephrenia from the Greek hebe “young,” and phrenia “mind”). In 1911, Eugen Bleuler revised this idea, renaming ‘dementia praecox’ (premature dementia) as schizophrenia. 

Kraepelin reverted back to the earlier French scientists Pinel-Esquirol-Bayle in arguing for a biological cause to schizophrenia by anatomical or toxic processes (as yet unknown.) When, on his second attempt, Alzheimer managed to publish his observations on Auguste Deter, Kraepelin jumped at the chance to reinforce the biological emphasis of disease by elevating Alzheimer’s disease as different from senile dementia. As with schizophrenia Kraepelin was intimating that Alzheimer’s disease is caused by anatomical or toxic processes which are yet unknown.

Fast forward to 2017, with increasingly powerful biological tools that are now available we are about to enter this portal that was created more than a century ago.

Alzheimer’s disease guidelines published in 2011 by the U.S. National Institute on Aging and Alzheimer Association, has attempted to define how biological measures can be usefully classifying mental diseases. As with the early pioneers Kahlbaum, Hecker, and Kraepelin, a new method is being devised to better answer the question of what dementia is.  Current psychiatric classification of diseases—Diagnostic and Statistical Manual (DSM-5) and International Classification of Disease (ICD-10)—are focused on being reliable but are short on validity. Repeating the conflict between the early German and French scientists more than a hundred years ago, there is now a shift from surface expression of the disease to search for the underlying causes, except now we can measure biological indicators better than in the past.

To enable this biological emphasis, and in contrast to the DSM-5 and ICD-10, a new classification criterion is being promoted. Research Domain Criteria (RDoC) is a new classification of diseases initiated by the U.S. National Institute of Mental Health director Thomas Insel. Insel now works for Google Life Sciences with a new name: Verily, a for-profit health company. RDoC argues that mental disorders are biological disorders involving brain circuits. And the first test of RDoC’s approach is with dementia. Mirroring Bayle’s 1882 contention that inflammation of membranes that surround the brain and the spinal cord resulted in mental disease, RDoC is following a long line of psychiatrists looking for biological markers to mental health.

Biological determinism of dementia.
There are many faults with RDoC’s focus on neural circuits which excludes research on psychological processes and mechanisms. This is nothing new and we only have to see the arguments in the late 1800s to understand these criticisms. For example, Bayle’s colleagues, especially Esquirol, argued that although there might be correlation there is no indication of causation. Even if causation can be identified it does not explain all dementias. And there are other concerns that were voiced earlier on in the history. Especially by Erich Hoche (1865-1943) on our inability to accurately identifying mental disease; Karl Birnbaum (1878-1950) on how disorders are expressed differently by individuals or cultures; Robert Gaupp (1870-1953) on psychosomatic factors that involve mental, emotional, or behavioral factors. And of course, we now know that that these criticisms remain valid to this day. RDoC simple brushes them away, not by ignoring these factors, but by discounting their influence and importance. It succeeds in doing this because it is concentrating on dementia.

We still do not know what dementia is. The basic issue is a catch 22—in order to be able to differentiate diseases we need to understand their causes and to understand the causes we need to be able to differentiate it. We must be aware of the history in order to stop this cycle of oscillating between the false dichotomy of biological vs everything else. Normality is not simply the absence of pathology. Many symptoms exist on a spectrum or continuum from mild expressions that might be viewed as variants of normality through to severe symptoms associated with impairment. One way to escape this conundrum is to ignore the expression of the disease and to accept the underlying “cause” as proof. But what RDoC ignores is that there are many biological markers and that the brain is the most complex entity in the universe. In such circumstance then you have to approach dementia as a public health issue, where many causes are present. An approach which RDoC continues to ignore. Could it be because  you cannot commercialize public health?

Engstrom, E. J. (2016). Tempering madness: Emil Kraepelin’s research on affective disorders. Osiris, 31(1), 163-180.
Garrett, M. D., & Valle, R. (2015). A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol, 2(1), 1-9.
Kendler, K. S., & Engstrom, E. J. (2016). Kahlbaum, Hecker, and Kraepelin and the transition from psychiatric symptom complexes to empirical disease forms. American Journal of Psychiatry, appi-ajp.
Kurt, C.S. et al., The Realities of Ageing, Boston, 1990.
Wundt, W. (1881). Wilhelm Wundt to Emil Kraepelin, 23 January 1881. Max Wundt Papers: University of Tübingen Archives, 228, 17.

© USA Copyrighted 2017 Mario D. Garrett