A critical review of the postulated role of the non-essential amino acid, ß-N-methylamino-L-alanine, in neurodegenerative disease in humans.

The compound BMAA (ß-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer's disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

Cycad Palm Toxicosis in 14 Dogs from Texas.

The goal of this study is to report clinical information, diagnostic findings, and treatment modalities; assess variables that may help distinguish survivors from nonsurvivors; and review the outcome of cycad palm toxicosis in dogs. Fourteen client-owned dogs with confirmed cycad palm ingestion were identified by reviewing the medical record database at Gulf Coast Veterinary Specialists. Information on signalment, time of ingestion to presentation, clinical signs, physical examination findings, initial and peak/nadir laboratory abnormalities, radiographic and ultrasonographic findings, treatment modalities, liver histopathology, and clinical outcome was retrieved. Of the 14 dogs, nine (64%) died as a direct result of cycad palm intoxication, and three survivors had persistently elevated liver enzymes, signifying residual liver damage. Despite decontamination, patients continued to display evidence of illness, indicating rapid absorption of toxins. When evaluating initial and peak/nadir laboratory values, nadir serum albumin levels and nadir platelet counts were significantly lower in nonsurvivors compared to survivors (1.25 g/dL [0.4-2.1 g/dL] versus 2.6 g/dL [1.7-3.4 g/dL] and 21 × 103 [0-64 × 103] versus 62 × 103 [6-144 × 103], respectively). In this cohort of dogs, the case fatality rate was higher than previously reported. Nadir serum albumin levels and nadir platelet counts may help distinguish potential survivors from nonsurvivors.

Animal models of brain maldevelopment induced by cycad plant genotoxins.

Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably ß-N-methylamino-l-alanine l-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction.

Sleep alterations in an environmental neurotoxin-induced model of parkinsonism.

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.

Environmental neurotoxin-induced progressive model of parkinsonism in rats.

OBJECTIVE: Exposure to a number of drugs, chemicals, or environmental factors can cause parkinsonism. Epidemiologic evidence supports a causal link between the consumption of flour made from the washed seeds of the plant Cycas micronesica by the Chamorro population of Guam and the development of amyotrophic lateral sclerosis/parkinsonism dementia complex. METHODS: We now report that consumption of washed cycad flour pellets by Sprague-Dawley male rats induces progressive parkinsonism. RESULTS: Cycad-fed rats displayed motor abnormalities after 2 to 3 months of feeding such as spontaneous unilateral rotation, shuffling gait, and stereotypy. Histological and biochemical examination of brains from cycad-fed rats revealed an initial decrease in the levels of dopamine and its metabolites in the striatum (STR), followed by neurodegeneration of dopaminergic (DAergic) cell bodies in the substantia nigra (SN) pars compacta (SNc). alpha-Synuclein (alpha-syn; proteinase K-resistant) and ubiquitin aggregates were found in the DAergic neurons of the SNc and neurites in the STR. In addition, we identified alpha-syn aggregates in neurons of the locus coeruleus and cingulate cortex. No loss of motor neurons in the spinal cord was found after chronic consumption of cycad flour. In an organotypic slice culture of the rat SN and the striatum, an organic extract of cycad causes a selective loss of dopamine neurons and alpha-syn aggregates in the SN. INTERPRETATION: Cycad-fed rats exhibit progressive behavioral, biochemical, and histological hallmarks of parkinsonism, coupled with a lack of fatality.

The ALS/PDC syndrome of Guam and the cycad hypothesis.

There is a high incidence on Guam of a severe tauopathy known as the Parkinson- dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.

Analysis of neurological disease in four dimensions: insight from ALS-PDC epidemiology and animal models.

The causal factor(s) responsible for sporadic neurological diseases are unknown and the stages of disease progression remain undefined and poorly understood. We have developed an animal model of amyotrophic lateral sclerosis-parkinsonism dementia complex which mimics all the essential features of the disease with the initial neurological insult arising from neurotoxins contained in washed cycad seeds. Animals fed washed cycad develop deficits in motor, cognitive, and sensory behaviors that correlate with the loss of neurons in specific regions of the central nervous system. The ability to recreate the disease by exposure to cycad allows us to extend the model in multiple dimensions by analyzing behavioral, cellular, and biochemical changes over time. In addition, the ability to induce toxin-based neurodegeneration allows us to probe the interactions between genetic and epigenetic factors. Our results show that the impact of both genetic causal and susceptibility factors with the cycad neurotoxins are complex. The article describes the features of the model and suggests ways that our understanding of cycad-induced neurodegeneration can be used to decipher and identify the early events in various human neurological diseases.