Guam is the largest of the Mariana Islands in the Western Pacific. In March 1521, the Portuguese sailor Magelhaes was the first Western explorer to land on Guam. Pigafetta, the writer aboard Magelhaes’ ship, made a short description of the island and its native people, the Chamorro. Guam was occupied by the Spanish in 1565. In 1668 a near-genocide was started and by 1710 most Chamorros had disappeared. In 1819, an extensive description of the island and its surviving inhabitants was made by Jacques Arago, an artist aboard the French expedition corvette Uranie. Leprosy and other illnesses were described, but he made no mention of a severe paralysis. At the end of the Spanish-American war in 1898, the island was handed over to the US government. After the Second World War, the island was retaken from the Japanese by American Forces. There has been a dramatic improvement of the Chamorro standard of living after World War II.

During the long period of foreign occupation, not one explorer, missionary or colonist mentioned a fatal paralysis among the Chamorro. This healthy state of affairs continued till the beginning of the 20^th century. Even in 1902, the American vice-governor William Safford reported that the Chamorro were "remarkably free from disease and physical defects, and lived to a great age". However, in1904, three death certificates mentioned some form of paralysis. The number of cases grew, until by 1940, neurological disease was the leading cause of death among adult Chamorro. After the second World War, Harry Zimmerman, a US Navy doctor, described that a special neurological disease was very common among adult Chamorro. In some patients the symptoms were similar to those of amyotrophic lateral sclerosis, and in others, the disease resembled Parkinson’s disease ± dementia. It became known as ALS/PDC (amyotrophic lateral sclerosis and Parkinson-dementia complex). The local names were lytico and bodig. Lytico referred to a progressive paralysis which resembled amyotrophic lateral sclerosis. Bodig resembled parkinsonism, sometimes with dementia. Between 1940 and 1965, lytico-bodig became the leading cause of death for adult Chamorro. In the remote village of Umatac, the incidence was the highest of all.

Lytico-bodig was though to be unique for Guam, but in 1962, Carleton Gajdusek (discoverer of the prion disease kuru) discovered a disease which resembled lytico-bodig, among the Jakai and Auyu people in the southern coastal plain in western Papua New Guinea. Kiyoshi Kimura and Yoshiro Yase discovered in Japan a third focus on the Kii peninsula (Honshu, Japan).

The disease has a wide spectrum of symptoms ranging from ALS-like muscle degeneration and weakening to Parkinson-like tremor and catatonia as well as dementia. Parkinson-dementia complex (PDC) refers to a disorder that combines the tremor of Parkinson's disease with the memory loss of Alzheimer's. The disease has a late onset and generally appears between the ages of 25-40 years old. In general, patients with bodig tend to be about 10 years older than lytico patients. They can have difficulties in taking initiatives, e.g. waiting for a question to be asked in order to answer, but not starting a sentence without being asked. Severe dementia, speaking and swallowing problems, spasticity of arms and legs, sometimes with contractures, characterise some patients. A loss of sense of smell is common. Many have memory problems. The akinesia which mimics catatonia with extreme lack of movement, with little tremor or stiffness, and with an immobility which can suddenly disappear, resembles encephalitis lethargica (Von Economo's disease). The parkinsonism is characterized by disturbed sleep, stupor, mental and physical slowing and immobility. Some have tremor and stiffness, others have increased salivation and sweating. About 50% of patients with lytico-bodig have strange, curly tracts on the retina (visible with indirect ophthalmoscopy). About 20% of the Chamorro older than 50 years have these lesions. Treatment is based on physiotherapy. L-dopa became available in 1967. Patterns on the ground or music can help in walking. Especially the acceptance and care provided by the family is of major importance.

The disease itself is dramatically clear, but the cause was a mystery. In Guam, ALS/PDC wasn't found among non-natives. Among the Chamorro, it runs in families, especially in those with a traditional lifestyle. The three main hypotheses which were put forward were toxins (organic or mineral), viruses (postencephalitis, slow virus or prions) and genetic mutations. Ciguatera neurotoxins which are common in Guam, were a suspect, as was Japanese encephalitis. Other forms of Parkinson’s disease are caused by manganese intoxication (in Chili), the drug MTTP, postinfectious, genetic or unknown. The lack of superoxide dismutase (SOD1) gene defects in Guam contrasts with the findings in ALS in the Western World, where defects of this enzyme are associated with familial forms of the disease. Lytico-bodig resembles to a certain extent neurolathyrism. Could both diseases have a similar cause? In 1963, the anthropologist Marjorie Whiting made an in depth investigation into the local cuisine, and she concluded that consumption and medicinal use of cycads were linked to the disease. Cycads contain a large amount of starch in roots, stem, seeds as well as many bioactive compounds. Fadang or federico is the name Chamorro give to the cycad flour. The people of Guam depended heavily on flour made from the starch extracted from cycad seeds, particularly when there were food shortages during and after World War II. Flour made from cycad nuts contains the neurotoxic beta-methylamino-L-alanine (BMAA). However, processing the flour reduced the concentration of the toxin to very low levels. The toxin was discovered in the brain of people who died of ALS/PDC with concentrations of around 7 microgram/gram. If this scenario would be true, then why did the disease not exist in earlier times? In the Kii peninsula, cycads were used in phytotherapy, where fresh seeds were used on open wounds. In Irian Jaya, a different species of cycad is used by the people.

One of the pathological features of the Guamian ALS-PD include neurofibrillary tangles, which are found in damaged nerve cells and are a hallmark of many neurodegenerative diseases, such as Alzheimer's disease and progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). The histological and cytological characteristics of progressive supranuclear palsy, Von Economo’s disease and lytico-bodig were very similar. Alzheimer plaques are not present in lytico-bodig. Mid 1970’s, the pathologists Frank Andersen and Leung Chen discovered that brains from traffic accident victims born before 1940 showed clear pathological abnormalities. People born between 1940 and 1950 had few neurofibrillary tangles and people born after 1950 never had any tangles. Prominent cerebral atrophy, especially of the temporal lobes, was observed. The substantia nigra and locus ceruleus were atrophied and depigmented. In general, Lewy bodies and senile plaques were absent.

The Kingdom of plants is divided in bryophytes (mosses, liverworts and hornworts) and vascular plants. Among the vascular plants there are seedless vascular plants (e.g. horsetails, ferns, lycophytes) and seed plants [(1) gymnosperms ["naked seeds"], such as cycads, ginkgo, gnetophytes and conifers; and (2) angiosperms, such as dicotyledons and monocotyledons]. Cycads are also known as sago palms. Do not confuse cycads with true palm trees. True palms are monocot angiosperms and cycads are gymnosperms. Cycads are among the most primitive living seed-plants found today. Cycads do not have flowers. The plants always have separate sexes, so that male and female cones are present on different plants. Male cones are warm, because of heat produced via the break down of lipids and starch. They produce massive amounts of pollen. These pollen were once suspected of causing the disease. The pollen produce gigantic sperm cells with many flagelles (higher plants do not have motile sperm). The female cones contain very large egg cells. Female seeds are as large as plums. The seeds are enclosed by a brightly colored soft layer (sarcotesta).

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There are almost two hundred cycad species, divided into 11 families. The Guam tree was initially known as Cycas circinalis, which was later changed into Cycas micronesica. Some botanic experts state that C. circinalis s.s. only occurs in Sri Lanka and India. C. celebica is another name which was proposed for the Guam tree. The etymology of Cycas circinalis refers to the Latin circinus, a spiral, in reference to the inrolled leaflets in developing leaves.

Cycads form symbioses with nitrogen-fixing cyanobacteria (formerly known as the blue-green algae). These cyanobacteria are endosymbionts, living within the roots. They provide fixed carbon and a stable environment for the cyanobacteria in exchange for nitrogen. In addition to normal roots, cycads develop specialized organs at a young age called precoralloid roots. These roots grow upward toward the surface of the soil, instead of downward. Upon successful colonization by cyanobacteria, precoralloids begin an irreversible transformation into coralloid roots, so named for their resemblance to coral. Within the coralloid root is a cyanobacterial zone, which is the region inhabited by cyanobacteria.

Cycads are often highly toxic, containing both neurotoxins and carcinogenic compounds. George Rumphius was a botanist working as an officer for the Dutch East Indian Company, working mainly in Southeast Asia and India. He described the first cycad in Malabar. He wrote that the juice obtained from cycad seeds was used to kill young children in Celebes. In Honduras, Zamia roots were used to kill enemies or criminals. Members of Cook’s expedition became sick after eating cycad seeds in Australia and members of the La Pérousse expedition became ill after eating Macrozamia communis seeds in Botany Bay, Australia. Cycad poisoning in sheep is well known. Either gastrointestinal disturbances with liver damage is seen, or else paralysis of the hind limbs and death due to starvation. In Australia, this paralysis is known as 'zamia staggers' and results from cattle grazing on cycad leaves. In the affected animals nerve cell death is seen in the spinal cord.

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Cycasin is a glycoside and was isolated form cycads in 1950. Large amounts provoke liver failure; small amounts are carcinogenic. Methazoxymethanol is derived from cycasin and is neurotoxic. Another toxin is BMAA, an aminoacid which resembles BOAA, beta-N-oxalylamino-L-alanine (see lathyrism). Pete Spencer, a neurotoxicologist, discovered that large doses of BMAA provoked a neurological syndrome in cynomolgus monkeys after 8 weeks of administration. Very high doses provoked an ALS-like syndrome, and somewhat lower doses provoked a Parkinson’s disease-like syndrome similar to lytico. The symptoms were acute, non-progressive and dose-related (as opposed to the human disease). But neurotoxins usually act fast, in a matter of days or weeks, not years.

In 2002, neurologist Oliver Sacks and etnobotanist Paul Cox (director of the National Tropical Botanical Garden in Kalaheo, Hawaii), suggested that BMAA could still be the cause of lytico-bodig. Besides eating tortillas made from cycad flour, people also ate the local flying foxes. Cycad seeds were part of the animals’ diet. If BMAA would accumulate in the tissues of the bats, people could be exposed to damaging doses. Since flying foxes feed on the seed sarcotesta it is important to understand the distribution of BMAA in the various tissues of the cycad. BMAA is concentrated in cycad reproductive organs, with the highest concentrations being found in the outmost layer of the sarcotesta. This finding is consistent with the putative evolutionary role of BMAA as an antiherbivory compound, as well as the accumulation of the compound in flying foxes that ingest the seed sarcotesta.  Since the bats feed on cycads and eat twice their body weight every night, their tissues accumulate levels of toxin much higher than those in cycad flour.

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The disease appeared early in the 20^th century, reached a peak around 1940 and then began to decline. No one born since 1961 has developed the disease. This rise and fall mirrors the consumption of flying foxes. Fruit bats, boiled in coconut milk and then consumed from head to toe, were a meal usually reserved for special occasions. The traditional way of catching the bats was to net them in the bread fruit trees where they roost. This is however easier said than done. Flying foxes tend to notice hunters and fly away. However, after the American take over, the Chamorro began to acquire guns, making it much easier to kill flying foxes. At the same time, the island acquired a cash economy, allowing hunters to sell their bats. Consumption of flying foxes soared, and so did the number of cases of ALS/PDC. Demand eventually outstripped supply. By the mid-1970s, steady hunting and consumption had nearly extinguished the bats, and Guam began importing bats from Samoa, where there are no indigenous cycad trees. One of two native species of flying fox became extinct. The second, Pteropus mariannus, survived, but today, only a small colony (less than 100 animals) survives on the US strategic air command base.

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In cycads, the toxin is concentrated in the seeds and its protective coat, which on average contains 9 microgram per gram of tissue. The concentration in live bats could not be tested, but in 2003, researchers managed to test 50-year-old museum specimens. They contained almost 400 times as much as the cycad’s seed coat. It is now thought that a constant low level of toxins in the brain is enough to kill neurons.

In 2002, Cox, Banack and the Canadian biochemist Susan Murch discovered that BMAA is actually produced by a cyanobacterium that lives inside the cycad’s corraloid roots, which grow up through the soil and form clumps at the surface. The micro-organisms fix nitrogen, providing the cycad with an important nutrient. The cycad divert the BMAA to its seeds, possibly as a protection from herbivores. The cyanobacterial origin of the toxin might explain the existence of ALS/PDC in other places where there are cycads or bats are not a staple food, such as in the people of the Kii peninsula of Japan and the Auyu and Jakai people of Irian Jaya. It is possible that the toxin could find its way into the diet via other routes.