Abstract

In the 1950s, the incidence of amyotrophic lateral sclerosis (ALS, or Lytico) and parkinsonism-dementia complex (PDC, or Bodig) on the island of Guam was much higher than anywhere else in the world. From the late 1960s to the early 1980s, the incidence of both disorders has decreased. The objective of the present study was to ascertain whether the decreasing incidence continued until the end of the century (1999). The average annual incidence of ALS and PDC was calculated for each 5-year period from 1940 to 1999, utilizing registration records of all ALS and PDC cases on Guam during that period. The results of this study confirmed that the incidence of ALS declined steadily during the past 40 years. The incidence of PDC also declined until the late 1980s but, unlike ALS, showed a slight increase from 1980 to 1999. The rapid decrease in incidence is not likely to be due to genetic factors. Instead, it is most likely to be the results of radical socioeconomic, ethnographic, and ecologic changes brought about by the rapid westernization of Guam.

Received for publication April 27, 2001; accepted for publication July 31, 2002.

In 1952 Koerner (1) and a year later Arnold et al. (2) reported the high incidence of amyotrophic lateral sclerosis (ALS) among the Chamorros of Guam, which was confirmed and expanded on in subsequent investigations by Tillema and Wijnberg (3), Kurland and Mulder (4, 5), and Mulder et al. (6). Kurland and Mulder (4) estimated the incidence of ALS on Guam in 1954 to be between 50 and 100 times higher than in the rest of the world. In addition to the high incidence of ALS, Mulder et al. (6) reported 22 Guamanian patients with parkinsonism, several of whom also had dementia. Hirano et al. (7, 8) first described the clinical and neuropathologic features of parkinsonism with dementia and concluded that this was a unique disease, parkinsonism-dementia, or parkinsonism-dementia complex (PDC). Both ALS and PDC are progressive and eventually fatal, and they frequently occur together in the same individual and in families (915). More recently, Matsumoto et al. (16) reported that spinal cord neurofibrillary tangles are present in both ALS and PDC. Because of the very close association between ALS and PDC, in the remainder of this report, unless otherwise indicated, the term “disease” or “diseases” will be used interchangeably to refer to either ALS or PDC.

Guam is the largest of the Mariana Islands, with a landmass of 215 square miles (556.85 km2) (figure 1). The original Chamorro population of Guam is believed to have originated from the Malay Archipelago as early as 1527 BC (17). Their first encounter with Europeans was in 1521 when Magellan landed near the village of Umatac in southern Guam. The Chamorro population at that time was estimated at about 50,000 (18). During the following 250 years, the indigenous population has undergone periodic but significant genetic change. Spanish-Chamorro wars (1675–1693), two strong typhoons (1621 and 1693), and infectious diseases introduced by Europeans, including a smallpox epidemic, decimated the island’s inhabitants (figure 2), so that by 1783 there were only 1,500 living Chamorros (18). This population decrease necessitated the introduction of Filipino laborers, many of whom remained on Guam, contributing to the development of a new gene pool. The continuous intermarriage of Chamorro women with Filipino male laborers, Spanish, Filipino, and Mexican soldiers in the Spanish occupying army, and various groups of privateers, whalers, and pirates resulted in hybridization of the original Chamorro gene pool, forming a neo-Chamorro population with a new gene pool by the end of the 19th century (17). This population remained relatively stable genetically and increased during the 20th century (figure 2).

Since the mid-1950s, Koerner (1) and Kurland and Mulder (5), among others, noted a high degree of familial occurrence of ALS and PDC. However, although familial aggregation suggested hereditary transmission, no definitive inheritance pattern could be established.

In 1956, the National Institutes of Health established the Guam Research Center as part of the National Institute of Neurological Disorders and Stroke (NINDS) to investigate the clinical, epidemiologic, and genetic aspects of these diseases. In 1958, two prospective studies were initiated. The first study aimed to investigate genetic factors in ALS and PDC by constructing pedigrees of all ALS and PDC patients (10, 11). The second study (Patient-Control Registry) aimed to ascertain whether the relatives of patients had a higher risk of developing the disease than did relatives of controls or the Chamorro population at large (1215). Other ALS and PDC registries were established later (19, 20).

During the past two decades, there have been reports of changes in incidence rates, the age at onset, the sex ratio, and the duration of ALS and PDC (21, 22). The present report is an effort to identify all cases of ALS and PDC reported on Guam since the 1940s and to calculate their average annual incidence rates for the 60-year period, 1940–1999.

MATERIALS AND METHODS

Case ascertainment

From 1956 to 1982, the staff of the NINDS Research Center on Guam (Research Center) evaluated all new cases of ALS and PDC and recorded them in case registries. New cases of ALS and PDC were identified through visits of the staff to each village, house-to-house surveys, and an island-wide referral network. The latter involved the Guam Memorial Hospital, private religious hospitals, local physicians, neurologists, public health nurses, local village officials, and until the mid-1980s specially trained local medical practitioners. Quite often patients themselves or their relatives identified and referred new cases. After a patient underwent neurologic evaluation, received a definitive diagnosis of ALS or PDC, and was registered with the Research Center, he or she had a follow-up clinical and neurologic reexamination every 3–6 months. The case registry also included individuals who were diagnosed as having ALS or PDC prior to 1956 through review of hospital and church records, death certificates, and neurologic and neuropathologic examination records. The NINDS Research Center was closed in 1983. However, ALS and PDC research was renewed in the late 1980s under extramural grants from the National Institutes of Health. After 1995, new cases of ALS and PDC were ascertained by the current Guam Clinical Core team. Cases with onset from 1983 to 1995 were identified from a variety of sources (23). These included NINDS files, a Registry of cases from 1989 to 1994 (Dr. L. T. Kurland, Principal Investigator), and death certificates on Guam. The Lytico-Bodig Association on Guam provided assistance to patients during this period and made its registry available, and records of home nursing services were reviewed with the cooperation of the University of Guam and the Guam Department of Public Health. Finally, members of the Clinical Core team systematically inquired at senior centers whether attendees or family members knew of siblings, other relatives, neighbors, or friends with Lytico-Bodig. If they did, the names were checked against the sources mentioned above. Patients with Lytico-Bodig may have escaped our ascertainment if families elected to take care of them without alerting any of these sources, or if patients were not brought to medical attention. Detailed descriptions of case ascertainment and case diagnostic criteria are given elsewhere (23).

From 1940 to 1999, there were 929 ALS or PDC cases on Guam. Of these, 436 (278 males and 158 females) were diagnosed as ALS and 493 (312 males and 181 females) diagnosed as PDC (figure 3).

Population estimates

The average annual Chamorro population of Guam by age (<20 or ≥20 years), by sex, by 5-year age groups, and by 5-year periods from 1940 to 1999 was extracted from the US Census of Guam for the years 1940, 1950, 1960, 1970, 1980, 1990, and 2000 (24) and from birth and death records published in the 1991, 1992, 1993, 1994, and 1995 issues of the Annual Statistical Reports of the Guam Department of Public Health and Social Services (25). Figure 2 shows how, from the latter part of the 19th century to the end of the 20th century, the Chamorro population of Guam increased. The census data indicate a decrease in the number of both men and women during 1975–1985. It is not clear whether this is a result of changing census methods, an unusually high rate of emigration, or changes in the ethnic self-identification of Guamanians in answering the census questionnaires. The adult (≥20 years) population increased steadily, while the under-20-year group increased through 1970–1979 and then decreased for the next two decades. After 1990, the under-20-year group was for the first time smaller than the adult group.

It is not clear whether the decrease in the proportion of younger Chamorros represents a continuing decline of the birth rate or the repatriation of adult Chamorros living off the Island. Besides the changes in the Guamanian Chamorro population during the past 40 years, there has also been a dramatic change in the ethnic composition of Guamanian residents. In the 1960 US Census, 34,762 Guamanians were recorded as Chamorros and 32,282 as non-Chamorros (table 1). In the 2000 US Census, the Chamorro population increased to 57,297 and the non-Chamorro population to 97,508. The total number and ethnic composition of non-Chamorros changed because of temporary or permanent immigration to Guam, which was part of the overall speedy economic modernization of the island and associated sociocultural changes. These changes also brought about a population movement from the traditional horticultural southern districts to the industrial-, business-, and service economy-based central and northern districts. Among the districts shown in figure 1, Hagatna (Agana), Asan-Maina, Piti, Sinajana, and Tamuning lost population during the past 40 years, while the rest of the districts gained population.

Statistical methods

The long-term trends in incidence of ALS and PDC were smoothed using a local likelihood procedure (26). To adjust for changing age distributions in the Chamorro population from 1940 to 1999, we adjusted the incidence for each 5-year epoch to an arbitrary standard population (the 1990 US Census population), by multiplying the number of individuals in each age group of the standard population by the age-specific incidence of ALS and PDC in the population of Guam (27). This allows rates to be easily compared with those reported from other population-based studies.

RESULTS

Table 2 presents the average incidence of ALS per 100,000 individuals, per 5-year period by sex and 5-year age group. Table 3 presents similar information on PDC. The curves in figure 4 depict the information in table 2 and table 3, and they have been smoothed (26). The symbols in the graph of figure 4 indicate the average annual incidence for each 5-year period. In both males and females, the incidence of ALS peaked in 1950–1954. Starting in the late 1950s, the incidence of ALS in both males and females declined steadily, and at the same time the difference in rates between males and females decreased until 1980–1984, when the rates for males and females were 5/100,000 and 4/100,000, respectively (table 2). The incidence of PDC in males peaked during 1960–1964 and then declined steadily until 1980–1984, followed by a slight increase (table 3; figure 4). The incidence of PDC in females continued to increase until 1970–1974, and then it too declined sharply until 1980–1984 and leveled off (figure 4). After 1980, the incidence of ALS in both males and females stabilized around 3/100,000, while the incidence of PDC gradually increased to 19/100,000 in males and 18/100,000 in females. From 1980 to 1999, there were 21 (10 male and 11 female) new cases of ALS and 127 (67 male and 60 female) new cases of PDC (figure 3).

DISCUSSION

The incidence of ALS and PDC on Guam changed during the past 60 years. Both disorders peaked between 1950 and 1960 and then declined. For ALS, the decline has continued steadily, with the incidence falling below 3/100,000 per year for males and females by 1999.

The incidence of PDC started to decrease in the early 1960s in males and in the late 1970s in females. However, unlike ALS, it increased slightly in both males and females after 1980, decreasing again in females after 1990. The sex ratio of both disorders has changed, from a male excess during the 1950s and 1960s to comparable rates in males and females by 1980.

It is not clear what brought about the fluctuations in the incidence of ALS and PDC during the past 50 years. Some possible explanations were discussed above, but others remain speculative. For example, the incidence of ALS and PDC before 1940 is not known. Patients with ALS or “paralysis” were identified in US Naval medical records and death certificates from 1902 to 1940. The accuracy of diagnosis and completeness of ascertainment are unclear. The NINDS Research Center on Guam was not established until 1956, and PDC was not identified as a unique disease until 1961 (7, 8); therefore, the apparently higher rates from 1955 to 1964, relative to 1945–1954, could reflect more intensive case finding. Similarly, it is not clear whether the low incidence during 1980–1989 is genuine or a result of the closing of the Center. Another factor that may have contributed to decreased reporting of new cases during this period is the advent of sufficient numbers of medical facilities and clinicians on the island who could diagnose and treat patients with ALS and PDC in the absence of the Center.

It is not plausible that a deleterious gene or genes were almost lost from the Chamorro population, especially since the new Chamorro hybrid population has remained relatively stable during the past 60 years. However, even had there been enough genetic admixture between Chamorros and immigrants to bring about a gene frequency change, much more generational time would be needed to bring about the observed changes in incidence. Likewise, outmigration over the past 50 years would have required a highly disproportional number of those leaving Guam to have carried the defective gene with them. Earlier genetic studies showed that purely environmental, Mendelian dominant, and Mendelian recessive hypotheses in the etiology of ALS and PDC could be rejected, although a two-allele major locus hypothesis was possible (11). Even under a two-allele hypothesis, the model predicted that environmental exposures were needed for a genetically susceptible individual to develop ALS, PDC, or both. Therefore, genetic changes alone could not have caused such a great decrease in incidence in such a short time.

Another possibility is that the high incidence of ALS and PDC on Guam reflected a peculiar age distribution of the Chamorro population. To examine this, we age adjusted the Guam ALS and PDC incidence data by using the 1990 US population as a standard (27). The adjusted age-specific rates for ALS and PDC were invariably higher than were the unadjusted rates, because the US population had a higher proportion of individuals aged 55 or more years compared with the Chamorros.

Environmental factors underlying ALS and PDC could have changed enough in the past 50 years to affect disease rates. Post World War II and particularly in the late 1960s, there have been rapid and radical socioeconomic, ethnographic, and ecologic changes on Guam, brought about mainly by modernization and westernization. By the mid- 1970s, Guam changed from an isolated, hotel-free, restaurant-free, rural, western Pacific island that depended in large part on homegrown foods and fishing for subsistence to a fast food diet. Traditional Guamanian foods, which included predominantly fresh vegetables, fruits, and fish, were replaced with a diet similar to that of the mainland United States (28). Present day Chamorro foods have high levels of fat, and beverages have high levels of sugar and a low nutrient content. Fruits are for the most part canned in heavy syrup (28, 29). During the same period, Chamorros have obtained US citizenship and have become more dependent on employment at US military bases, luxury seaside hotels, and other tourist industry-related occupations. In addition, the switch to a cash economy resulted in the relocation of many Guamanians nearer to their place of employment. The modernization process, together with the building of a modern road network, multilevel commercial buildings, typhoon- and earthquake-resistant homes with concrete foundations, deep well water supplies, modern sewage disposal facilities, an expanded telephone and electric network, and a commercial and tourist airport, had all been completed by the end of the 20th century. Modernization could have minimized or eliminated some, or all, of the exogenous risk factors that contribute to ALS or PDC. Changes in place of residence, construction of modern housing, different nutritional practices (28, 29), elimination of food and water supplies associated with toxins, and toxic exposures all may have contributed. Finally, the role of women in the Guamanian society changed considerably during the past 40 years. Many have found work in the retail centers and offices of the central and northern districts of the island, and fewer are involved with domestic responsibilities and the preparation of native food specialties. Although the modernization of the Island is the most facile explanation for the lowering of environmental risks, it is possible that the decrease in the incidence of ALS and PDC may have been brought about by triggering factors unrelated to modernization, which existed in the past but were eliminated more recently.

During the past 40 years, the non-Chamorro Guamanian population increased much more rapidly than did the native Chamorro population (table 1), which included changes in its ethnic composition. More significantly, however, there has been a significant outmigration of Chamorros from the southern districts of the island, which traditionally had the highest incidences of ALS and PDC, to the central and northern districts (figure 1), which originally had moderate or low rates of disease.

The present results confirm and extend earlier reports (21) that the incidence of both ALS and PDC has decreased dramatically during the past 40 years. The incidence of ALS continued to decline in the past 20 years, but that of PDC showed a moderate increase during the past 15 years and has leveled off. It is possible that PDC represents a phenotype that can be triggered by a lower degree of exposure to exogenous factors than ALS, accounting for the slight divergence of incidence of these conditions in recent years. The decrease in incidence is likely due primarily to epigenetic risk factors rather than to changes in the gene pool of the Chamorro population. Investigations into the etiology of ALS and PDC on Guam continue.

ACKNOWLEDGMENTS

This study was supported by grant AG 14382 from the National Institute on Aging.

The authors are indebted to the earlier investigators of ALS and PDC on Guam, whose contributions are cited in the References section; they especially are indebted to the late Dr. Leonard Kurland, who was actively involved in ALS and PDC research on Guam for almost half a century and who made available to them some of the data from the 1980s. They also want to thank Dr. Kathleen M. Fox who organized, cataloged, and archived some of the earlier ALS and PDC scientific data and Dr. Rebecca Pobocik for providing them with valuable information on the dietary changes among Guamanians.

Reprint requests to Dr. Chris C. Plato, Department of Neurosciences, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0624 (e-mail: drccplato@mindspring.com).

FIGURE 1. The island of Guam and the western Pacific Ocean. (From the 2000 US Census of Guam).

FIGURE 1. The island of Guam and the western Pacific Ocean. (From the 2000 US Census of Guam).

FIGURE 2. Fluctuations in the population of Guam from 1668 to 2000. Data were compiled from various historical reports and official census records.

FIGURE 2. Fluctuations in the population of Guam from 1668 to 2000. Data were compiled from various historical reports and official census records.

FIGURE 3. Number of new cases of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), during each 5-year period, among male and female Guamanian Chamorros, from 1940 to 1999.

FIGURE 3. Number of new cases of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), during each 5-year period, among male and female Guamanian Chamorros, from 1940 to 1999.

FIGURE 4. Average annual incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) per 100,000 male and female Guamanian Chamorros per 5-year period from 1940 to 1999. Lines smoothed.

FIGURE 4. Average annual incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) per 100,000 male and female Guamanian Chamorros per 5-year period from 1940 to 1999. Lines smoothed.

TABLE 1.

Total number and ethnic composition of the population of Guam in 1960 and in 2000 according to the US Census

Ethnic group Population in 1960  Population in 2000 
No.  No. 
Chamorro 34,762 51.9  57,297 37.0 
Filipino 8,580 12.8  40,729 26.3 
White 20,724 30.9  10,592 6.8 
Micronesian    11,094 7.2 
Other Asian    10,299 6.7 
Other/unspecified 2,978 4.4  24,794 16.0 
      
Total 67,044 100.0  154,805 100.0 
Ethnic group Population in 1960  Population in 2000 
No.  No. 
Chamorro 34,762 51.9  57,297 37.0 
Filipino 8,580 12.8  40,729 26.3 
White 20,724 30.9  10,592 6.8 
Micronesian    11,094 7.2 
Other Asian    10,299 6.7 
Other/unspecified 2,978 4.4  24,794 16.0 
      
Total 67,044 100.0  154,805 100.0 
TABLE 2.

Sex- and age-specific 5-year average annual incidence rates (per 100,000 population) for Guamanian Chamorro ALS* patients from 1940 to 1999

Age (years) 1940–1944 1945–1949 1950–1954 1955–1959 1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1989 1990–1994 1995–1999 
Male             
20–24 30 22 18 19 20 
25–29 26 51 48 23 
30–34 64 124 209 21 38 17 17 
35–39 114 202 271 117 171 69 39 21 
40–44 45 279 321 139 203 157 129 24 13 
45–49 164 391 88 561 147 160 255 117 30 
50–54 222 272 502 204 385 234 160 58 25 24 
55–59 201 412 418 303 323 332 254 42 42 
60–64 114 222 657 408 68 236 171 43 
65–69 192 167 296 247 212 92 74 
>69 133 127 92 71 116 48 
All ages 32 67 73 57 50 30 24 17 
Female             
20–24 33 
25–29 41 58 55 18 
30–34 80 47 21 20 94 18 17 
35–39 38 98 87 52 71 85 38 
40–44 311 99 88 53 46 23 27 12 
45–49 182 286 176 124 139 76 27 58 
50–54 61 269 44 37 119 115 
55–59 213 263 214 135 120 108 153 48 21 
60–64 153 270 149 103 
65–69 71 124 63 64 98 34 
>69 48 
All ages 37 41 27 23 20 16 12 
Age (years) 1940–1944 1945–1949 1950–1954 1955–1959 1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1989 1990–1994 1995–1999 
Male             
20–24 30 22 18 19 20 
25–29 26 51 48 23 
30–34 64 124 209 21 38 17 17 
35–39 114 202 271 117 171 69 39 21 
40–44 45 279 321 139 203 157 129 24 13 
45–49 164 391 88 561 147 160 255 117 30 
50–54 222 272 502 204 385 234 160 58 25 24 
55–59 201 412 418 303 323 332 254 42 42 
60–64 114 222 657 408 68 236 171 43 
65–69 192 167 296 247 212 92 74 
>69 133 127 92 71 116 48 
All ages 32 67 73 57 50 30 24 17 
Female             
20–24 33 
25–29 41 58 55 18 
30–34 80 47 21 20 94 18 17 
35–39 38 98 87 52 71 85 38 
40–44 311 99 88 53 46 23 27 12 
45–49 182 286 176 124 139 76 27 58 
50–54 61 269 44 37 119 115 
55–59 213 263 214 135 120 108 153 48 21 
60–64 153 270 149 103 
65–69 71 124 63 64 98 34 
>69 48 
All ages 37 41 27 23 20 16 12 

* ALS, amyotrophic lateral sclerosis.

TABLE 3.

Sex- and age-specific 5-year average annual incidence rates (per 100,000 population) for Guamanian Chamorro PDC patients from 1940 to 1999

Age (years) 1940–1944 1945–1949 1950–1954 1955–1959 1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1989 1990–1994 1995–1999 
Male 
20–24 
25–29 
30–34 25 
35–39 38 67 30 57 23 
40–44 80 71 139 68 79 64 
45–49 55 220 120 110 192 198 29 26 
50–54 313 458 385 430 468 128 51 
55–59 488 848 914 379 211 253 42 64 26 51 
60–64 111 376 653 753 531 571 214 280 58 
65–69 370 635 184 490 809 200 173 405 270 
>69 127 426 92 161 71 405 97 143 280 423 
All ages 33 55 57 43 37 34 14 19 16 
Female 
20–24 
25–29 
30–34 21 20 
35–39 24 21 21 
40–44 39 29 26 23 20 23 
45–49 46 176 31 111 152 108 
50–54 44 110 132 89 115 23 
55–59 160 225 160 359 76 41 181 72 
60–64 77 270 171 297 462 213 231 151 26 
65–69 120 94 250 142 186 315 64 98 236 34 
>69 121 107 192 190 47 183 159 176 
All ages 16 23 20 28 26 18 17 
Age (years) 1940–1944 1945–1949 1950–1954 1955–1959 1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1989 1990–1994 1995–1999 
Male 
20–24 
25–29 
30–34 25 
35–39 38 67 30 57 23 
40–44 80 71 139 68 79 64 
45–49 55 220 120 110 192 198 29 26 
50–54 313 458 385 430 468 128 51 
55–59 488 848 914 379 211 253 42 64 26 51 
60–64 111 376 653 753 531 571 214 280 58 
65–69 370 635 184 490 809 200 173 405 270 
>69 127 426 92 161 71 405 97 143 280 423 
All ages 33 55 57 43 37 34 14 19 16 
Female 
20–24 
25–29 
30–34 21 20 
35–39 24 21 21 
40–44 39 29 26 23 20 23 
45–49 46 176 31 111 152 108 
50–54 44 110 132 89 115 23 
55–59 160 225 160 359 76 41 181 72 
60–64 77 270 171 297 462 213 231 151 26 
65–69 120 94 250 142 186 315 64 98 236 34 
>69 121 107 192 190 47 183 159 176 
All ages 16 23 20 28 26 18 17 

* PDC, parkinsonism-dementia complex.

† Deceased.

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