Amyotrophic lateral sclerosis and parkinsonism-dementia among Filipino migrants to Guam

Amyotrophic lateral sclerosis (ALS) has occurred in 9 Filipino migrants to Guam 1 to 29 years after their arrival and parkinsonism-dementia (PD) in 2 migrants 13 and 26 years after arrival. Seven additional Filipino patients developed more classic Parkinson disease (P) 5 to 24 years after their migration to Guam. Furthermore, 10 part-Filipino patients who were born on Guam of Filipino and Chamorro parentage developed ALS, while 6 such part-Filipino patients developed PD. An estimate of the average annual crude mortality rate for ALS among Filipino migrants was approximately six times that of the continental United States, yet half that currently observed among Chamorros living on Guam. A majority of all migrant patients were born in northwestern Luzon in the Philippine Islands, indicating the desirability of an intensive field epidemiological investigation in that area.     

Clinical features and changing patterns of neurodegenerative disorders on Guam, 1997-2000.

BACKGROUND: In the 1950s, high-incidence ALS and Parkinson-dementia complex (PDC) were identified among Chamorros, the native inhabitants of Guam. Brains of patients with these syndromes showed widespread neurofibrillary tangles. Although ALS and PDC were reported to have dramatically declined in the 1980s, new cases are still encountered. Late-life dementia has received little study among Chamorros. METHODS: From 1997 to 2000, the authors evaluated newly referred and previously identified patients. They screened first-degree relatives of previous registries, and subjects aged 60 or older. Subjects who scored below a cognitive test cutoff or had symptoms or signs consistent with parkinsonism or ALS underwent psychometric testing, assessment by a neurologist, and laboratory studies as appropriate. Consensus diagnoses were made. RESULTS: The authors identified 194 Chamorros with ALS (n = 10), PD (n = 11), PDC (n = 90), or late-life dementia (n = 83). Mean ages at onset were 55 for ALS, 68 for PDC, 63 for PD, and 74 for dementia. Late-life dementia was more common in women, and met criteria for probable or possible AD. The APOE-epsilon 4 allele frequency was uniformly low regardless of neurologic diagnosis. CONCLUSIONS: The rapid decline of high-incidence ALS on Guam over the past 40 years suggests the contribution of a modifiable environmental factor. PDC remains relatively common, with an unchanged clinical picture apart from later age at onset. Dementia among elderly Chamorros (termed "Mariana dementia") resembles AD. Autopsy studies will clarify whether this dementia is related to AD pathology or represents a late-life neurofibrillary tangle syndrome more closely allied to PDC.     

Incidence of amyotrophic lateral sclerosis and of the parkinsonism-dementia complex of Guam, 1950-1989

Studies representing the accumulated information from the first 30 years of research effort on Guam (1950-1979) have demonstrated a varying degree of decline in the incidence of amyotrophic lateral sclerosis (ALS) and the parkinsonism-dementia complex (PDC) of Guam. Analysis with more complete information for the period 1980-1989 provides more valid estimates of the later patterns in the incidence of ALS and PDC and affords a more extensive assessment of trends over a 40-year period. The annual age-adjusted incidence of ALS was 7/100,000 and the annual age-adjusted incidence of PDC was 22/100,000 in 1989. The incidence was much higher for the period 1980-1989 than suggested in previous reports. These findings provide compelling evidence that this spectrum of neurodegenerative diseases continues to have a significant impact on the health of the Chamorro people of Guam.     

Disappearance of high-incidence amyotrophic lateral sclerosis and parkinsonism-dementia on Guam

The high incidence rates of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) occurring among the Chamorros of Guam have declined to rates only slightly higher than those observed in the continental United States. This decline has occurred principally among males, especially those born after 1920 and living in areas where calcium and magnesium levels are low in soil and water. The male-to-female ratio among affected patients now approaches unity, compared with ratios of 2 to 1 for ALS and 3 to 1 for PD three decades ago. These changes are consistent with the hypothesis that the previously high incidence resulted from defects in mineral metabolism and secondary hyperparathyroidism, provoked by nutritional deficiencies of calcium and magnesium, with resultant deposition of calcium and aluminum in neurons.     

Amyotrophic lateral sclerosis among chamorro migrants from guam

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.     

Lessons from Guam ALS/PDC study]

An extraordinarily high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) affecting the native population was discovered on the island of Guam a half century ago. Guam ALS is identical to classic ALS clinically and pathologically while PDC is marked by progressive parkinsonism and dementia. The unusual histological finding in these fetal neurodegenerative diseases is the presence of numerous neurofibrillary tangles in a selective topographic distribution unassociated with senile plaques. There have been remarkable advances in field of age-associated neurodegenerative disease after our initial study of Guam cases. Four noteworthy topics are presented in this communication. 1) Clinically, the coexistence of parkinsonism and dementia was frequently recognized in Parkinson disease and Alzheimer disease. Some other new disease entities characterized by coexistence of parkinsonism and dementia have been reported. These include progressive supranuclear palsy, frontotemporal dementia and parkinsonism linked to chromosome 17. 2) Neuropathologically, abundant neurofibrillary tangles unassociated with senile plaques were demonstrated in many diseases such as aftermath of boxing and tangle-only dementia. Furthermore, tau-positive structures were recognized not only in neurons but in glial cells in certain diseases. Tauopathy is one of the current hot research subjects. 3) Familial aggregation of Guam ALS patients provoked investigation of familial ALS elsewhere. Familial motor neuron disease with SOD1 mutation is the target of worldwide intense investigation at the present time. SOD1 gene mutation is, however, not found in Guam ALS. 4) The most striking findings of the Guam study is the gradual decline in the incidence of ALS on Guam during a quarter century and virtual disappearance of new patients. This may be linked to a remarkable change in environment and life style of the Chamorro population. The etiology of ALS is still unknown and no new treatment is available. Guam ALS/PDC is certainly one of the most mysterious riddles among age-associated neurodegenerative diseases during the last half a century.     

Prevalence, incidence, and mortality of PD: a door-to-door survey in Ilan county, Taiwan.

BACKGROUND: The reported prevalence and incidence rates of PD were significantly lower in China than those in Western countries. People in China and Taiwan have a similar ethnic background. OBJECTIVE: To investigate the prevalence, incidence, and mortality rate of PD in Taiwan. METHOD: The authors conducted a population-based survey using a two-stage door-to-door approach for patients aged 40 years or older in Ilan, Taiwan. Patients were diagnosed with PD by having at least two of the four cardinal signs of parkinsonism and exclusion of seconddary parkinsonism. To identify new cases of PD after the survey, patients with negative results of parkinsonism in the first stage were matched to the information on clinical diagnosis of PD from the Bureau of National Health Insurance toward the end of December 31, 1997. All cases of PD were linked to the Taiwan mortality registration to ascertain causes of deaths until December 31, 1999. RESULTS: The participation rate was 88.1% among the 11,411 contacted individuals. Thirty-seven cases of PD were identified. The age-adjusted prevalence rate of PD for all age groups was 130.1 per 100,000 population after being adjusted to the 1970 US census, assuming no cases of PD would be found among those younger than 40 years of age. Of 9972 non-PD subjects in the first screen, 15 new cases of PD were ascertained. The age-adjusted incidence rate was 10.4 per 100,000 population for all age groups. The case fatality rate of PD after a 7-year follow-up was 40.4% (21 deaths in 52 patients with PD). The relative risk of death for PD cases versus non-PD cases was 3.38 (95% CI: 2.05-4.34). The 5-year cumulative survival rate in PD cases (78.85%) was statistically lower than that in non-PD cases (92.84%). CONCLUSION: The prevalence and incidence rates of PD in Taiwan were much higher than those reported in China, but closer to those in Western countries. These results suggest that environmental factors may be more important than racial factors in the pathogenesis of PD.     

Motor neuron disease on Guam: geographic and familial Occurrence, 1956–85

We investigated the geographic and familial occurrence of motor neuron disease (MND) on Guam, and then considered etiologic hypotheses related to cycad use and metal intoxication. The research was based on 303 Chamorros from Guam and 3 Chamorros from other Mariana Islands, all with MND onset on Guam during 1956–85. Inarajan and Umatac, two southern districts, each had, for both sexes combined, an average incidence rate significantly higher than the corresponding overall rate for Guam. Also, for each sex, geographic patterns of incidence were significantly related to 1)socioeconomic level (men only), 2)cycasin concentrations in cycad flour samples (men and women), 3)iron concentrations in water samples (men and women), 4)silicon concentrations in water samples (men only), and 5)cobalt and nickel concentrations in soil samples (men and women). The MND risk in susceptible sibships was about 7–28 times greater than that in the general population. The cycad hypothesis conforms somewhat better than the metal intoxication hypothesis with the data presented.     

Similarities of guamanian ALS/PD to post-encephalitic parkinsonism/ALS: possible viral cause

Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilN1 strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD.     

Clinical characteristics of Parkinson's disease among Inuit in Greenland and inhabitants of the Faroe Islands and Als (Denmark).

In earlier studies, we found high age-adjusted prevalences of Parkinson's disease (PD) in the Faroe Islands (209 per 100,000 inhabitants) and in Greenland (187.5 per 100,000 inhabitants) compared to the age-adjusted prevalence on the island of Als in the southern part of Denmark (98.3 per 100,000 inhabitants). We thoroughly examined patients with suspected parkinsonism using internationally accepted diagnostic criteria. In the present study, we found no significant clinical differences between patients with PD in the three areas, despite this high difference in prevalence. However, comparing the age at examination and age at treatment, the patients were younger in Greenland, a higher proportion of patients had cognitive decline, and they had a higher mean Hoehn and Yahr rating score, although they received a lower levodopa dose. A higher proportion of the patients in Greenland were newly diagnosed than in the other two areas.     

Motor neuron disease on Guam: temporal xcurrence, 1941–85

Using a case registry, we investigated the temporal occurrence of motor neuron disease (MND) on Guam. MND with onset during 1941–85 was documented in 434 Chamorros and 9 non-Chamorro migrants who had lived on Guam before onset. Increased median age at onset and decreased age-adjusted incidence rates (since the early 1960s) were observed for Chamorros of both sexes. Our evidence about MND on Guam is consistent with: 1) The latent period duration has varied from years to decades; 2) With time, the exposure period or latent period, or both, have lengthened; 3) The high risk of acquiring the condition has been reduced since, at least, the early 1950s, and the most recent years of meaningful risk were the early to middle 1960s; 4) The critical age for acquiring the condition is in adolescence and adulthood; 5) Change of environment from Guam to overseas during childhood resulted in decreased risk of acquiring the condition.     

Studies on Amyotrophic Lateral Sclerosis by Neutron Activation Analysis-2. Comparative Study of Analytical Results on Guam PD, Japanese ALS and Alzheimer Disease Cases

Abstract: Metal analysis of calcium, manganese, aluminum and copper in CNS tissue samples of degenerative CNS disease cases (six Japanese ALS, three Japanese Alzheimer disease, four Guam PD, one Guam ALS) using neutron activation analysis, was conducted with following results: Five of six Japanese ALS cases, two of three Japanese Alzheimer disease cases and all of four Guam PD cases showed a high content of calcium and aluminum in CNS tissue with a significant positive correlation between calcium and aluminum and/or between calcium and manganese.
These findings suggest a possible process of metal-induced soft tissue calcification with interaction of other di- and/or trivalent cations such as aluminum, manganese in CNS tissue of these degenerative CNS diseases.     

Seeking environmental causes of neurodegenerative disease and envisioning primary prevention

Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer’s disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of disease-affected individuals and communities, the results of which can provide an invaluable guide to steer cogent epidemiological and laboratory-based research.     

Age-, gender-, and socioeconomic status-specific incidence of Parkinson's disease and parkinsonism in North East Scotland: The PINE study

There have been few high quality incidence studies of Parkinson's disease (PD). We measured age-, gender- and socioeconomic-specific incidence rates for parkinsonism and PD in north-east Scotland, and compared our results with those of previous high quality studies.Incident patients were identified prospectively over three years by several overlapping methods from primary care practices (total population 311,357). Parkinsonism was diagnosed if patients had two or more cardinal motor signs. Drug-induced parkinsonism was excluded. Patients had yearly follow-up to improve diagnostic accuracy.Incidence rates using clinical diagnosis at latest follow-up were calculated for all parkinsonism and for PD by age, gender and socioeconomic status. Meta-analysis with similar studies was performed.Of 377 patients identified at baseline with possible or probable parkinsonism, 363 were confirmed as incident patients after median follow-up of 26 months (mean age 74.8 years, SD 9.8; 61% men). The crude annual incidence of parkinsonism was 28.7 per 100,000 (95% confidence interval (CI) 25.7–31.8) and PD 17.9 per 100,000 (95% CI 15.5–20.4). PD was more common in men (age-adjusted male to female ratio 1.87:1, 95% CI 1.55–2.23) but there was no difference by socioeconomic status. Meta-analysis of 12 studies showed an incidence of PD (adjusted to the 1990 Scottish population) of 14.6 per 100,000 (95% CI 12.2–17.3) with considerable heterogeneity (I² 95%), partially explained by population size and recruitment duration.The incidence of PD was similar to other high quality studies. The incidence of PD was not affected by socioeconomic status.     

A two-fold difference in the age-adjusted prevalences of Parkinson''s disease between the island of Als and the Faroe Islands

With the aim of comparing the previously found high prevalence of idiopathic Parkinson's disease (PD) in the Faroe Islands with the prevalence of PD in an area of Denmark, we used the same case-finding methods for case ascertainment and the same strict criteria to diagnose PD on the island of Als. During the last year before the prevalence date (1 January 1998), we found in various registries from pharmacies, hospital, private neurologist and general practitioners 121 patients with suspected Parkinsonism out of 56,839 inhabitants on the island of Als. After exclusion of those who had other diseases, a total of 79 patients were left for further examinations. Among these we found 58 with PD. The overall prevalence of PD was estimated to be 102.0 and the age-adjusted prevalence to be 98.3 per 100,000 persons compared with 187.6 and 209.0 in the Faroe Islands. Compared with the previous results from the Faroe Islands (prevalence date 1 July 1995) we found an even lower mean age at onset of PD symptoms and at onset of treatment, a lower proportion of definite PD and a lower average dose of levodopa. We therefore conclude that the two-fold higher prevalence in the Faroe Islands than on the island of Als was not due to an early diagnosis and a higher ascertainment of cases with mild PD, which was suggested as being one possible explanation for our previous finding of a high prevalence of PD in the Faroe Islands.     

Increasing mortality from amyotrophic lateral sclerosis in Norway?

OBJECTIVE: To investigate a possible increase in incidence of ALS in Norway. METHODS: Death certificate data from all deaths in Norway in the period 1961 to 1994 for ALS, PD, and MG were obtained from Statistics Norway and related to population statistics. Data on ALS was obtained on sex, age, and place of death and compared with mortality data in PD and MG for the same period. Data were standardized using the 1990 population as standard population. Poisson regression was used to test for trends in mortality. The data from the death certificates were related to a clinical study performed on ALS in one of the counties during the same period. RESULTS: The annual mortality of ALS almost doubled during the period studied, rising from 1.38 to 2.54 per 100,000 inhabitants at the end of the study. The increased mortality appeared solely in the population older than 60 years of age, with a peak in mortality in the age group 80 to 84 years. The increase was larger in women than in men, and the ratio between the sexes was 1.32 (men-women, age-adjusted at the end of the study). The mortality in patients with PD showed a similar increase to that seen in ALS, whereas no increase in mortality was observed in patients with a diagnosis of MG. There were considerable differences in ALS mortality in different counties, but no clear regional trends were observed. CONCLUSION: The authors report increasing ALS mortality. Although the increase in mortality is restricted to the population aged 65 years or older, it cannot be explained by increasing age of the general population alone.     

Muro disease or ALS-parkinsonism-dementia complex of the Kii peninsula of Japan]

"Muro disease" is an endemic ALS in the Muro district that includes the southern coastal mountainous areas of the Kii peninsula of Japan. Epidemiological survey in 1960s disclosed extremely high incidence of ALS in two villages, Hohara and Kozagawa, and disappearance of high incidence by early 1980s was reported with its etiology unsolved. We resurveyed for neurodegenerative diseases in Hohara and found continuous high ALS incidence. We also found parkinsonism-dementia complex (PDC) verified neuropathologically. ALS and PDC frequently occurred in one individual simultaneously and affected many members in the same family, and neuropathological findings of ALS and PDC were similar to each other, showing a combination of upper and lower motor neuron involvements and many neurofibrillar tangles (NFTs) in the brainstem and cerebral cortex, resembling those of ALS/PDC on Guam. TDP-43 positive inclusions were found in the dentate gyrus of the hippocampus and spinal motor neurons in all cases examined. Age-adjusted incidence rates during 1950 and 2000 have showed that incidence of ALS was gradually declining for 50 years while that of PDC rose up steeply in 1990s. No particular environmental factors were confirmed and gene analyses of candidate genes of ALS, parkinsonism and dementia failed to reveal any mutations. Continuing high incidence and high rates of familial occurrence suggest that primary cause of Kii ALS/PDC may be genetic rather than environmental.     

Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam

We tested the brain tissues of the Chamorro people of Guam who died of amyotrophic lateral sclerosis/Parkinsonism dimentia complex (ALS/PDC) for the neurotoxin beta-methylamino-l-alanine (BMAA). We used validated high-pressure liquid chromatography and liquid chromatography-mass spectrometry analyses to test well-characterized archival tissues of the superior frontal gyrus from eight Chamorros from Guam and a comparison group of 15 Canadians. BMAA was found as a free amino acid in 83% of Chamorro ALS/PDC patients (3-10 microg/g) as a protein-associated amino acid in 100% of the Chamorro individuals (149-1190 microg/g). Both forms of BMAA were also found at comparable levels in two Canadians who died of progressive neurodegenerative disease. BMAA, which is produced by cyanobacteria, may be associated with some cases of neurodegenerative disease.     

Characterization of tau pathologies in gray and white matter of Guam parkinsonism-dementia complex

Guam parkinsonism-dementia complex (PDC) is a neurodegenerative tauopathy in ethnic Chamorro residents of the Mariana Islands that manifests clinically with parkinsonism as well as dementia and is characterized neuropathologically by prominent cortical neuron loss in association with extensive telencephalic neurofibrillary tau pathology. To further characterize cortical gray and white matter tau, alpha-synuclein and lipid peroxidation pathologies in Guam PDC, we examined the brains of 17 Chamorro PDC and control subjects using biochemical and immunohistological techniques. We observed insoluble tau pathology in both gray and white matter of PDC and Guam control cases, with frontal and temporal lobes being most severely affected. Using phosphorylation dependent anti-tau antibodies, abundant tau inclusions were detected by immunohistochemistry in both neuronal and glial cells of the neocortex, while less alpha-synuclein pathology was observed in more limited brain regions. Further, in sharp contrast to Alzheimer’s disease (AD), levels of the lipid peroxidation product 8, 12–iso-iPF_2α-VI isoprostane were not elevated in Guam PDC brains relative to controls. Thus, although the tau pathologies of Guam PDC share similarities with AD, the composite Guam PDC neuropathology profile of tau, alpha-synuclein and 8, 12-iso-iPF_2α-VI isoprostane reported here more closely resembles that seen in other tauopathies including frontotemporal dementias (FTDs), which may imply that Guam PDC and FTD tauopathies share underlying mechanisms of neurodegeneration.