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PubMed2002

Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have alpha-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and alpha-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, alpha-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The alpha-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and alpha-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and alpha-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and alpha-synuclein pathology occurs independent of beta-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.

Aged↗
PubMed2002

New apratoxins of marine cyanobacterial origin from Guam and Palau.

Two collections of the marine cyanobacterium Lyngbya sp. from Guam and Palau that both afforded the potent cytotoxin apratoxin A (1) each yielded different structural analogues with lower degrees of methylation. The new apratoxins, termed apratoxins B (2) and C (3), were evaluated for their in vitro cytotoxicity along with semisynthetic E-dehydroapratoxin A (4) to identify key structural elements responsible for the cytotoxicity and to initiate SAR studies on this novel family of depsipeptides. All analogues 2-4 displayed weaker cytotoxicity than 1, but to different extents. While compound 3 closely approached the cytotoxicity of 1, compounds 2 and 4 exhibited significantly reduced activity, possibly also related to a conformational change. The 16S rRNA genes of the different apratoxin producers have partially been sequenced and compared, and other genetic differences are currently being revealed.

Amino Acid Sequence↗
PubMed1987

Guam ALS/parkinsonism-dementia: a long-latency neurotoxic disorder caused by "slow toxin(s)" in food?

Parkinsonism (P) with progressive dementia (D) of the Alzheimer type is recognized as a clinical variant of a form of amyotrophic lateral sclerosis (ALS) that has occurred in high incidence among the Chamorro people of the islands of Guam and Rota in the Marianas chain of Micronesia. The declining annual incidence, upward shifting of the age of onset, narrowing of the sex ratio, and occurrence of the disease among non-Chamorros, point to a disappearing environmental causation peculiar to the traditional culture of these islands. Evidence is presented in support of the proposal that heavy use of certain toxic plants, notably cycads, a traditional source of food and medicine for the Chamorro people, plays an important etiological role. Clinical and epidemiological approaches are offered to test for a relationship between ALS/P-D and long-latency plant toxicity.

Alzheimer Disease↗
PubMed2003

Pregnant adolescents in Guam consume diets low in calcium and other micronutrients.

The purpose of this study was to assess diets of pregnant adolescents in Guam, including difference in age and trimester. The 434 subjects, aged 14 to 20 years, were primarily Chamorro and Filipino. Analysis of variance was used to determine differences in nutrient intake, and Tukey post hoc testing was used. Frequency distributions were calculated for intake at various dietary reference intake levels. Mean energy intake was 2,487+/-1,057 kcal. The nutrients that are inadequate in the diets of the adolescents are calcium, folate, vitamin E, magnesium, and iron. Calcium intake declined with increasing age (P<.0001). Notable differences (P<.01) among trimester existed only for iron, which was lower in the second than third trimester. Nutrient intake is similar to that in pregnant adolescents in the United States, with particularly low calcium levels. Culturally specific materials emphasizing nutrition during pregnancy and chronic disease prevention are warranted.

Adolescent↗
PubMed2002

Postencephalitic Parkinson's disease, amyotrophic lateral sclerosis on Guam and influenza revisited: focusing on neurofibrillary tangles and the trail of tau.

Circumstantial evidence links neuropathological changes in postencephalitic Parkinson's disease and amyotrophic lateral sclerosis on Guam to the 1918 influenza pandemic. Postencephalitic Parkinson's disease and amyotrophic lateral sclerosis have neuronal neurofibrillary tangles that anatomically correlate with clinical signs and symptoms. Occurrences of the disorders peaked in the early 1950s and are now disappearing. Neurovirulent influenza associated with the lethal 1918 pandemic is suggested as the etiology of both diseases. Permissive tissue antigens are considered an important contributing factor. Neurofibrillary tangles also correlate with signs and symptoms in Alzheimer's disease. Oxidative stress may be the pathological process that induces neurofibrillary tangles. Tangles contain abnormally phosphorylated tau. In Alzheimer's disease, tau is present in cerebrospinal fluid and is deposited in corpora amylacea, demonstrating the direction of cerebrospinal fluid flow.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Screening for non-protein amino acids in seeds of the Guam cycad, Cycas circinalis, by an improved GC-MS method.

The non-protein amino acid, beta-N-methyl-amino-L-alanine (L-BMAA) from Cycas circinalis seeds, has been implicated as a causative agent of amyotrophic lateral sclerosis-Parkinsonism dementia complex (ALS-PDC), a disease known from Guam and other areas in the western Pacific. We analyzed C. circinalis seeds for additional free non-protein amino acids by a recently developed GC-MS method. The samples were prepared by water extraction of seed flour. The amino acids present in the extract were derivatized by N(O,S)-isobutyloxycarbonylation of the amine functional groups and then tert-butyldimethylsilylation of the carboxyl functional groups. Peaks for a total of seventeen derivatives of non-protein amino acids were detected by GC-MS. In addition to L-BMAA, four other non-protein amino acids were identified as beta-alanine, gamma-amino-butyric acid, pyroglutamic acid, and alpha-aminoadipic acid.

Amino Acids↗
PubMed1984

Imaging of calcium and aluminum in neurofibrillary tangle-bearing neurons in parkinsonism-dementia of Guam.

We report the distribution and imaging of calcium and aluminum in neurofibrillary tangle (NFT)-bearing neurons within Sommer's sector of the hippocampus in Guamanian patients with parkinsonism-dementia, using a method of computer-controlled electron beam x-ray micro-analysis and wavelength dispersive spectrometry. Calcium and aluminum were distributed in cell bodies and axonal processes of NFT-bearing neurons. The elemental images show that both calcium and aluminum deposits occur within the same NFT-bearing hippocampal neuron in this dementing disease, suggesting that these elements are involved in NFT formation. No prominent concentrations of calcium and aluminum were imaged in non-NFT-containing regions within the pyramidal cell layer of the parkinsonism-dementia cases or in the control cases. These findings support the hypothesis that secondary hyperparathyroidism resulting from low environmental calcium and magnesium in the high-incidence focus of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam had led to abnormal deposition of calcium and aluminum in the central nervous system.

Aged↗
PubMed2000

Alpha-synuclein inclusions in amygdala in the brains of patients with the parkinsonism-dementia complex of Guam.

We investigated by immunohistochemistry the deposition of alpha-synuclein in the brains of deceased patients with the parkinsonism-dementia complex (PDC) of Guam. Five of 13 PDC brains showed numerous alpha-synuclein positive neuronal inclusions and abnormal neurites, chiefly in the amygdala. Similar alpha-synuclein positive lesions were observed, although to a lesser extent, in the entorhinal cortex and the dorsal vagal nucleus. No alpha-synuclein positive inclusions were observed in motor cortex or locus coeruleus, and only a small number of positive inclusions were found in the Sommer's sector, temporal cortex, or substantia nigra. Some of the alpha-synuclein positive inclusions were reminiscent of cortical Lewy bodies (LB), but many of those in the amygdala coexisted with tau-positive pretangles and/or neurofibrillary tangles (NFT) within the same neurons. In these neurons, tau-positive shells encapsulated alpha-synuclein positive central cores or irregularly shaped alpha-synuclein-positive deposition intermingled with pretangles/NFT. Thus, the present study suggests that a common mechanism may govern aggregation of alpha-synuclein and tau in the amygdala, and that aggregation of alpha-synuclein may play some role in the neurodegenerative process of a tauopathy (i.e. PDC) in which Abeta deposition is virtually absent.

Adult↗
PubMed2001

Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism-dementia complex.

We examined spinal cords of neurodegenerative disease patients and controls living on the Island of Guam and in the continental United States. These patients had pathologically confirmed parkinsonism dementia-complex (PDC) with or without amyotrophic lateral sclerosis (ALS), or Alzheimer disease (AD), respectively. Nearly all of the spinal cords examined from both groups of patients contained neurofibrillary tangles (NFT). The immunohistochemical profile of these NFTs indicates that they are composed of hyperphosphorylated tau protein like their counterparts in the brains of these patients. Western blot analysis confirmed this by revealing that sarcosyl insoluble tau in spinal cord extracts from patients with NFTs exhibited the presence of all 6 tau isoforms similar to that from AD and ALS/PDC cortical gray matter.

Aged↗
PubMed2001

Substantia nigra in progressive supranuclear palsy, corticobasal degeneration, and parkinsonism-dementia complex of Guam: specific pathological features.

Disease-specific findings in the substantia nigra were examined in cases of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and parkinsonism-dementia complex of Guam (PDC); diseases in which the patients exhibit dementia and parkinsonism, with neurofibrillary tangles (NFTs) and glial tangles composed of hyperphosphorylated tau. Loss of pigmented neurons was extremely severe in these 3 diseases, and decrease of the nonpigmented neurons was severe in PSP and CBD. On the other hand, in PDC the decrease of the nonpigmented neurons was different in each patient. Topographically, in PSP the nonpigmented neurons were particularly depleted in the ventral part and relative preservation of the pigmented neurons was observed in the medial part at the level examined. Many NFTs were observed in PDC. Although the number of NFTs was small, many pretangles were seen in the neurons in CBD. Granular and hazy astrocytic inclusions were identified exclusively in PDC. Numerous argyrophilic neuropile threads were identified in CBD and PSP, but these were few in PDC. Many foamy spheroid bodies as well as coiled bodies were observed in PSP and CBD, but only a few were observed in PDC. In conclusion, PDC is a disease that is distinctly different from PSP and CBD. It is possible to differentiate between PSP and CBD by the occurrence of many pretangles in CBD, but some similarities between these 2 diseases indicate the existence of common pathological mechanisms.

Adult↗
PubMed1986

Amyotrophic lateral sclerosis and parkinsonism-dementia on Guam: a 25-year prospective case-control study.

Familial and genetic studies of high-incidence amyotrophic lateral sclerosis and parkinsonism-dementia among the Chamorro people of Guam were initiated in 1958 with the establishment of a prospective case-control registry. The major objective of this registry was to determine if first-degree relatives and spouses of patients with amyotrophic lateral sclerosis or parkinsonism-dementia had an increased risk of developing disease compared with relatives of nonaffected controls individually matched for age, sex, and village. At the time of its closing in 1963, the registry included 126 patients (77 with amyotrophic lateral sclerosis, 42 with parkinsonism-dementia, and seven with both amyotrophic lateral sclerosis and parkinsonism-dementia) and an equal number of controls; 994 living first-degree relatives (parents, siblings, and offspring) of patients and 1,218 of controls; and 88 living spouses of patients and 101 of controls. The present analysis of the 25-year follow-up study (1958-1983) demonstrated a significantly increased risk of developing amyotrophic lateral sclerosis or parkinsonism-dementia among parents, siblings, and spouses of patients, but not among relatives of controls. Offspring of both patients and controls showed no significantly increased risk of developing disease. The increased risk among spouses of patients and the lack of increase among their offspring, together with recent histochemical findings, support the contention that exogenous factors are strong contributors to the etiology of amyotrophic lateral sclerosis and parkinsonism-dementia. The present results also demonstrate a declining incidence of both diseases.

Aged↗
PubMed1979

Utilization of hospital services in the Individual Practice Association on Guam: a comparative analysis.

The HMO Act of 1973 gives impetus on a nationwide scale to the development of health care delivery systems capable of providing or arranging for comprehensive health services for our nation's consumers. However, while the organizational mode of the group-practice model HMO is well defined and tested, there has not been a similar "track record" established for the individual practice HMO. In this study, the author compares the utilization of hospital beds in two operating programs: an individual practice and a group-practice HMO, serving employees of the Government of Guam, U.S.A. Substantial differences in utilization between the two systems are observed over a 12-month period. With the focus on developing the IPA to meet the objectives for which it is intended, it is suggested that organizational structure, provider incentives, and how utilization controls were employed account for the discrepancy.

Cost Control↗
PubMed1993

An unusual retinal pigment epitheliopathy endemic to the island of Guam.

An unusual retinal pigment epitheliopathy resembling ophthalmomyiasis interna posterior (OMI) is endemic to Guam. Sixteen percent of a sample of the indigenous population were found to have the retinopathy. Fifty-two percent of a group of individuals suffering from amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC) were found to have the same retinopathy. Although the retinal appearance is similar to that caused by a subretinal parasite, a definite etiology has not been identified. Three case reports are presented as samples of the clinical presentation of the condition.

Adult↗
PubMedDate not supplied

Airplane crash in Guam, August 6, 1997: the aeromedical evacuation response.

A civilian airplane crash on the island of Guam in 1997 produced 16 burned survivors. The U.S. Army Burn Flight Team and U.S. Air Force Critical Care Air Transport Teams conducted a joint aeromedical mission in response to this disaster. This experience was reviewed from the Burn Flight Team perspective. A record of events was made during the mission, and an after-action review was conducted after the mission. Twelve patients were transported to Korea, and four critically ill patients were transported to the U.S. Army Burn Center in San Antonio, TX. The latter mission required 21 hours of in-flight critical care and was completed 4 days and 3 hours after the crash. After-action review resulted in changes in communications procedures, administrative oversight, supplies and equipment, composition of the Burn Flight Team, and readiness and training. These peacetime lessons contributed to the military's ability to transport wartime burn casualties in ensuing years and indicate the close interdependence of the disaster response and combat missions.

Accidents, Aviation↗
PubMed2005

Tau-positive fine granules in the cerebral white matter: a novel finding among the tauopathies exclusive to parkinsonism-dementia complex of Guam.

We examined the autopsied brains of cases of 6 types of tauopathy: parkinsonism-dementia complex of Guam (PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Pick disease, Alzheimer disease (AD), and myotonic dystrophy together with Guamanian controls. Light microscopy sections of these brains were examined using anti-tau antibodies. Tau-positive fine granules (TFGs) were globe-shaped, and 3 to 6 mum in diameter, were observed predominantly in the frontal white matter in 30 of the 35 patients with PDC. However, no TFGs were found in association with PSP, myotonic dystrophy, Pick disease, AD, or CBD. Western blot analysis of frozen brain tissue taken from the PDC cases revealed that the frontal cortex was hyperphosphorylated and contained 6 tau isoforms (3R+4R tau). However, in the present study, it was revealed that the novel TFGs in the white matter of patients with PDC was composed of 4R tau. Western blot analysis of sarkosyl-insoluble tau from the white matter of the PDC cases showed 2 major bands of 60 and 64 kDa and one minor band of 67 kDa. After dephosphorylation, these bands resolved into one major band of 4-repeat (4R) tau isoform and 3 minor bands of 3-repeat (3R) and 4R tau isoforms. Moreover, the TFGs observed in cases in which the number of neurofibrillary tangles (NFTs) was higher than the threshold level were not correlated with the presence of cortical NFTs. In conclusion, these novel TFGs were found almost exclusively in PDC brains and could therefore be considered as a characteristic neuropathologic marker of this particular tauopathy. The TFGs were hyperphosphorylated tau-positive structures that may be formed by a different mechanism from that used to produce cortical NFTs.

Aged↗
PubMed1991

Demonstration of beta amyloid protein-containing neurofibrillary tangles in parkinsonism-dementia complex on Guam.

This report concerns the immunohistochemical demonstration of beta amyloid protein-containing neurofibrillary tangles (beta-NFTs) from patients with parkinsonism-dementia complex on Guam (PDC). Formalin-fixed paraffin-embedded tissue sections from the temporal lobe of nine PDC cases and the spinal cord of three were examined. An affinity-purified antibody to the N-terminal peptide sequence of beta amyloid protein was used. beta-NFTs were demonstrated in the temporal lobes of the three oldest individuals. Some senile plaques, probably a manifestation of ageing, were also seen. The beta-NFTs were most frequent in the entorhinal cortex. Senile plaques were invariably present in the vicinity of the beta-NFTs. Conversely, in the regions without senile plaques, even though numerous neurofibrillary tangles were identifiable with the modified Bielschowsky method, no beta-NFTs were seen. The density of beta-NFTs appeared to be proportional to that of senile plaques, none was seen in cases lacking senile plaques. No beta-NFTs were detected in the spinal cords. Our data suggest that beta-NFTs result from secondary beta amyloid deposition on certain neurofibrillary tangles.

Amyloid beta-Peptides↗
PubMed2005

Return of the cycad hypothesis - does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?

Recently published work provides evidence in support of the cycad hypothesis for Lytico--Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of beta-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a 'tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of 'AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for 'ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for alpha-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of 'incidental'alpha-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico-Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies.

Amyotrophic Lateral Sclerosis↗