KEY EVENTS

A timeline of events, from the discovery of neurodegenerative disease, to the groundbreaking treatments of the modern day.

The recorded history of neurodegenerative disease has its roots in the medical practices of ancient civilizations, when the term "Kampavata" was used by the Indians to describe what we now call Parkinson's. To treat the tremors, practitioners used Mucuna pruriens, a legume which was actually effective in improving the patients' conditions, as Mucuna pruriens naturally contained some amount of L-Dopa, a chemical still used to treat the symptoms of Parkison's today. [S3.8]

Start from the present.

KEY EVENTS

In A.D. 175, the Greek physician Galen described the disease as the"shaking palsy." However, it was

only with James Parkinson's publication of a piece of medical literature entitled An Essay on the Shaking Palsy in 1817, that one of the most commonly known neurodegenerative diseases was established as the medical condition then called

paralysis agitans. [S3.9, S4.1]

Mucuna pruriens, a natural source of levodopa (L-Dopa). [I1.2]

James Parkinson and An Essay on the Shaking Palsy. [I1.3, I1.4]

François-Amilcar Aran gives an account of a patient with chronic muscle weakness, giving the condition the name "progressive muscular atrophy" (PMA). Aran also describes one of the earliest recorded cases of ALS (amyotrophic lateral sclerosis), in a 33-year-old with muscle weakness and autonomic dysreflexia (hyperreflexia). Aran is believed to be the first physician to have reported hereditary motor neuron disease in a medical article titled "Recherches sur une maladie non encore décrite du système musculaire (atrophie musculaire progréssive)", in 1850. [S4.2, S4.3]

"Recherches sur une maladie non encore décrite du système musculaire (atrophie musculaire progréssive)" by Dr. François-Amilcar Aran, 1850. [I1.5]

The conclusion of a four year study conducted between 1865 and 1869 by Jean-Martin Charcot, a man now known as "the founder of modern neurology", described the symptoms associated with lesions of two areas of the spinal cord, the lateral column and anterior horn. Charcot noted that the area in which the lesions occurred greatly affected the health of the patient; lesions of the lateral column of the spinal cord would commonly result in paralysis and contractures, while lesions of the anterior horn caused paralysis and muscular atrophy. Based on his detailed research, Charcot was able to demonstrate how a physician might detect these lesions by analysis of clinical signs. The disease which Charcot studied is now known as ALS (amyotrophic lateral sclerosis), or, more famously, Lou Gehrig's disease. [S4.4, S4.5]

Jean-Martin Charcot and Contribution a Létude de L'atrophie Musculaire Progressive Type Duchenne-Aran. [I1.6, I1.7]

In 1906, German physician Alois Alzheimer first presented the case of the late Auguste Deter, the earliest recorded person to be diagnosed with what is now called Alzheimer's disease. Alzheimer described the patient as being plagued with a variety of symptoms, from reduced

comprehension and memory retention ability to paranoia, aphasia, disorientation, and abnormal psychosocial patterns. Upon examining her brain during autopsy, Alzheimer saw drastic reduction in the overall size of the brain, abnormalities of the neurofibrils, and deposits of a "peculiar material" in and around nerve cells, which were later named senile plaques by Dr. Teofil Simchowicz. [S4.6, S4.7]

In 1911, the uncontested treatment for Parkinson's disease, levodopa (L-3,4-dihydroxyphenylalanine), was synthesized by Casimir Funk, and isolated from seedlings of Vicia faba (legumes) two years later by biochemist Marcus Guggenheim. There was, however, still to be many years before

dopamine's role as a neurotransmitter in the brain was confirmed by Arvid Carlsson, and the treatment of organisms with dopamine deficiency using L-dopa is first tested. [S4.8, S4.9]

Frederick Henry Lewy, a German neurologist working with Alois Alzheimer, observed abnormal aggregates of proteins within the brain cells of people afflicted with Parkinson's disease in 1912. Seven years afterwards, Russian scientist Konstantin Trétiakoff encountered the same proteins clusters in his own research, and named them Lewy bodies, in honor of F.H. Lewy.

Trétiakoff, unlike Lewy, was able to correctly identify the area in which Lewy bodies commonly congregated to cause Parkinson's disease, the substantia nigra. [S5.1, S5.2]

[I5.5]

Many years after the discovery and studies of Lewy bodies in the brains of Parkinson's patients, a group of Japanese scientists discovered Lewy bodies in the brains of patients with other neurodegenerative disease, but no Parkinson's. This led to the understanding that Lewy bodies are present in multiple variants of different neurodegenerative disease, and are now categorized accordingly. (i.e. "Lewy body variant of Alzheimer’s disease.") [S5.2]

In 1957, Arvid Carlsson conducted an experiment that would change the path of research regarding

Parkinson's. Using reserpine, a drug known to deplete dopamine within the brain, Carlsson demonstrated that, while reserpine reduces the amount of dopamine in the brain, levodopa could replenish it. It was after the results of Carlsson's study were published that Oleh Hornykiewicz and

Walther Birkmayer actually began the injection of

L-dopa into patients with Parkinson's, with reported success (reversal of symptoms), save the side effects that accompanied the levodopa treatment. [S5.3]

George Cotzias also administered L-dopa to patients with Parkinson's and found that, with the high dosage used at the time, the adverse effects were severe. Cotzias decided to reconduct his study with a lower dose of L-dopa, and encountered the same reversal of symptoms, without many of the previously noted negative byproducts of the treatment. [S5.3]

In 1976, an aspiring chemist, Barry Kidston, abruptly developed Parkinson's disease and died following his injection of self-made MPPP

(Desmethylprodine). During the toxicology analysis, investigators found MPPP, but also discovered an impurity, MPTP, formed when Kidston's mixture overheated during the reaction process. Dr. J. William Langston connected the use of MPTP

with the development of Parkinson's, a hypothesis that was supported by an experiment

during which he administered MPTP to monkeys

that quickly developed Parkinsonian symptoms. It was discovered that MPTP is transformed into a neurotoxin known as MPP+ that can cause dopamine neurons within the substantia nigra to die. [S5.4]

One of the first attempts at transplanting fetal tissue into patients with Parkinson's was a surgical procedure conducted in 1986 by a Mexican group of scientists (Madrazo I, León V, Torres C, Aguilera MC, Varela G, Alvarez F, Fraga A, Drucker-Colín R, Ostrosky F, and Skurovich M), who reported a

dramatic improvement in the patients' symptoms after the surgery. A Chinese group (Jiang NJ, Tang Z, Zhang F, Li S, Jiang D) conducted a similar study with differing fetal tissue, and noted changes in the symptoms of the patients within the first few days, and satisfactory relief of symptoms within the first few months following the surgery. While the cases lacked long-term results, as well as psychological or behavioral assessments, they did provide a base for future scientists to develop techniques of using

stem cells to treat neurodegenerative disease. [S5.5, S5.6, S5.7]

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