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A Batty Hypothesis on the Origins of Neurodegenerative Disease Resurfaces

A study suggests bacteria-eating fish in the Baltic Sea might expose humans to dangerous levels of a neurotoxin, but scientists argue over the significance of the finding



ISTOCKPHOTO/peters99

Sprawling blooms of cyanobacteria have swathed the surfaces of lakes and oceans around the world for billions of years. But the serene, blue-green algae may be leaching a neurotoxin into the aquatic food chain, according to a study published May 3 in Proceedings of the National Academy of Sciences ( PNAS ). The report revived a nearly 50-year-old debate over the role, if any, of the toxin in the process of neurodegeneration.

In the wake of World War II a deadly neurological disease plagued the small island of Guam. The natives called it lytico-bodig (from the Spanish paralytico, meaning weakness) and it had features of Lou Gehrig's (ALS), Parkinson's and Alzheimer's diseases. Endemic to the native population (called Chamorros), the syndrome was 100 times more prevalent on Guam than anywhere else. After ruling out a genetic cause, scientists began the hunt for an environmental trigger that made Chamorros, but not immigrants, susceptible. A staple of the local cuisine raised suspicion. 

Chamorros made tortillas using flour ground from the seeds of cycads—plants often confused for ferns or palms and distantly related to both. The seeds were meticulously washed to remove toxins, such as beta-methylamino-L-alanine (BMAA), produced by cyanobacteria that inhabit cycad roots. Scientists wondered if BMAA could be causing neurodegeneration, but the concentrations ingested by the Chamorros were not sufficient to harm neurons in animal models. Huge concentrations, however, were.

In 2002 ethnobotanist Paul Cox from the Institute for Ethnobotany at the National Tropical Botanical Garden in Kalaheo, Hawaii, and neurologist Oliver Sacks from the Albert Einstein College of Medicine in New York City introduced a shocking theory about how Chamorros might be ingesting enough BMAA to damage neurons in the brain and spinal cord. The toxin, they proposed, was "biomagnified" in cycad-eating flying foxes—fruit bats. The bats ate up to 2.5 times their body weight (which can be as much as a pound for the species on Guam) in food such as cycads seeds every night and, on special occasions, Chamorros ate the bats. Cox and Sacks suggested that BMAA might accumulate in the bats' fat stores over time. But the main thrust of their hypothesis, published in Neurology, was the coincident decline in the flying fox populations on Guam and the incidence of lytico-bodig

Critically endangered by commercial hunting in the 1960s, the bats were virtually extinct on Guam a decade later. Carcasses imported from Western Samoa for consumption fetched up to $35 a piece. But Cox and Sacks argued the lack of indigenous cycads in Samoa meant the imports didn't contain cycad toxins, and that Chamorros were no longer being exposed to biomagnified BMAA. After a peak incidence in the mid-1960s, lytico-bodig dwindled into relative obscurity, now rarely affecting anyone born after 1960.

The theory led to a flurry of investigations into the possible role of biomagnified BMAA toxicity in neurodegenerative disease. Some researchers wondered if this tiny island in the South Pacific had revealed an elusive environmental trigger for neurodegenerative disease elsewhere in the world—the "Rosetta stone" of neurodegeneration. Since then many have spent years trying to confirm or refute the hypothesis. Believers, like Cox, think the potential for biomagnified BMAA to kill neurons should be studied in the interest of public health. They've cited elevated levels of BMAA both in Chamorro brains and in those of Alzheimer's disease patients in Canada to support their stance. Skeptics, such as neurologist John Steele of Guam Memorial Hospital, think BMAA research constitutes a "scientific misadventure," leaving the real cause of lytico-bodig unknown. They've looked for BMAA in similar brain samples, and haven't seen it.

"I think they should be skeptical," says Cox of Steele and others who think the hypothesis is wrong. "It's just a hypothesis, and it could be wrong. A lot more research needs to be done to validate the hypothesis."

But pouring valuable resources into what might be a red herring, Steele worries, detracts from more important research into the Guam disease's cause.

The unsolved mystery resurfaced in the PNAS cyanobacteria bloom study, which provides the first evidence for BMAA biomagnification in an aquatic food chain. After measuring BMAA levels in cyanobacteria blooms in the Baltic Sea and in the plankton, fish and mussels that feed on them, researchers from Stockholm University in Sweden concluded that, BMAA levels were six times higher in plankton and up to 200 times higher in some fish than in the blooms. 

But unlike Guam, the coastal regions surrounding the Baltic Sea are "not a hot spot for ALS or any neurodegenerative disease," says study lead author Sara Jonasson. And it's unknown whether the brains of fish analyzed, which reportedly contained BMAA levels up to 82 times higher than the fishes' muscles, showed evidence of neuronal damage. Jonasson says the elevated levels of BMAA found in fish from the Baltic Sea were still very low, and people should not be worried about eating seafood.

Neurologist Elijah Stommel of Dartmouth–Hitchcock Medical Center has been investigating the link between cyanobacteria-produced BMAA and neurodegenerative disease from an epidemiological angle. "We've seen a number of ALS patients that seem to be living near water bodies that have known present or historical cyanobacteria blooms," he says. In a preliminary analysis published November 2009 in the journal Amyotrophic Lateral Sclerosis, living near a bloom or the site of a former bloom more than doubled the risk of ALS.

Steele worries such studies will set off a great deal of needless public concern. "We need to reevaluate the whole hypothesis starting right back at the fruit bats of Guam," he says. He's calling for a consortium—a team of experts, including chemists skilled at detecting and quantifying BMAA, drawn from both camps—to settle the debate for good. "Guam is terribly important. If we can solve the puzzle on Guam, we might be able to better understand the cause and cure of neurodegenerative disease elsewhere."

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