Amyotrophic lateral sclerosis (ALS), which occurs in unusually high incidence among the Chamorro people on the island of Guam, has developed in 28 Chamorro migrants--24 of whom had onset in the United States, Japan, Germany, or Korea--after periods of absence from Guam of 1 to 34 years. Thus, the latency period for the disease, if caused by environmental factors on Guam, may be over three decades. Four further patients developed ALS within 1 to 14 years of their return to Guam after long-term residence in the continental United States. The minimum exposure time to environmental variables on Guam, based on age at migration, was 18 years, and all patients had spent their childhood and adolescence on Guam. Estimates of crude mortality rates for ALS from these data are considerably higher than for the United States population, and lower than the ALS mortality rates for nonmigrant Chamorros on Guam.

We evaluated 16 Guamanian Chamorros with amyotrophic lateral sclerosis and 33 patients with parkinsonism-dementia for disturbances of calcium and vitamin D metabolism. The serum immunoreactive parathyroid hormone level was mildly elevated in 6 patients with amyotrophic lateral sclerosis and in 5 patients with parkinsonism-dementia. There were significant positive correlations between serum immunoreactive parathyroid levels and duration of illness in male patients with motor neuron disease, but not in female patients or in patients with parkinsonism-dementia. Intestinal absorption of calcium, as assessed by serum and urinary activity of calcium 47 following oral administration, was decreased in 2 patients with amyotrophic lateral sclerosis and in 4 patients with parkinsonism-dementia, all of whom had low levels of serum 1,25-dihydroxyvitamin D. Reductions in cortical bone mass were striking in patients with motor neuron disease. A significant negative correlation was found between the percentage of cortical area of the second metacarpal bone and muscle atrophy and weakness, and significant positive correlations were found between degree of immobility and ratio of urinary hydroxyproline to creatinine in patients with amyotrophic lateral sclerosis and parkinsonism-dementia. In general, abnormalities in calcium metabolism were subtle. Thus, if the demonstrated deposition of metals, particularly calcium and aluminum, in central nervous system tissues of Guamanians with these two conditions is a cause of the diseases and of the early appearance of neurofibrillary tangles in neurons, the accumulation has apparently occurred long before onset of symptoms, and detectable abnormalities of calcium and vitamin D metabolism may already have been corrected.

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The neostriatum, nucleus accumbens and basal nucleus of Meynert (bnM) in the parkinsonism-dementia complex of Guam (Guam PDC) were examined immunohistologically, ultrastructurally, quantitatively and topographically, and the results were compared with those in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Compared to neurologically normal controls, the number of large neurons in Guam PDC was reduced by approximately 70% in the caudate nucleus and putamen and by more than 90% in the nucleus accumbens. The decreased number of large neurons in the neostriatum was significantly correlated to that in the bnM. The remaining large neurons and many of the medium-sized neurons in the neostriatum and nucleus accumbens were immunopositive for tau protein and contained varying amounts of 21- to 25-nm-wide paired helical filaments (PHFs) admixed with straight tubules. Curly fibers and circularly arranged reactive astrocytes were seen in the nucleus accumbens of many PDC patients. Collectively, these findings, which are similar in part to those of AD and differ from those of PSP, suggest that the large neurons in the neostriatum and nucleus accumbens in Guam PDC degenerate through PHF formation, and that extremely severe loss of large neurons in the nucleus accumbens may be linked to marked degeneration of the limbic and ventral tegmental areas and nucleus dorsal raphe.

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To elucidate the fundamental differences and similarities of the neuropathological features and etiopathogenesis of the amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam, we conducted a topographic, quantitative and histological investigation of tau-containing neurons, neurofibrillary tangles (NFTs), Bunina bodies and ubiquitinated inclusion bodies in 27 non-ALS non-PDC Guamanian subjects, as well as 10 Guam ALS patients, 28 PDC patients, and 5 patients with combined ALS and PDC (ALS-PDC). The topographic distribution of NFTs was basically the same in each disease and also in the non-ALS non-PDC group. There were relatively few, if any, NFTs in non-ALS non-PDC subjects and ALS patients, but there were many, especially in the frontal and temporal cortex, in Guam PDC and ALS-PDC patients. The histological and ultrastructural features of Bunina bodies in Guam ALS and ALS-PDC patients were similar to those reported in classic ALS. The ratio of occurrence of the inclusion in Guam ALS and ALS-PDC patients was similar to that reported so far in classic ALS. Ubiquitinated skein-like inclusion bodies were observed in the spinal anterior horn cells in Guam ALS and ALS-PDC patients. These findings indicate that classic ALS does exist on Guam, that NFTs in Guam ALS patients are merely a background feature widely dispersed in the population, that the mechanism of neuronal degeneration of Guam ALS is basically different from that of PDC, and that Guam ALS occurs initially are classic ALS.

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.

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