Source:             Askthedoctor-mailinglist
Date:                 13 januari 2002
Orig. source:    Neurology, volume 58, pages 90-97.
Orig. date:        9 januari 2002

PD and Guam. Why Guam?

Fifty years ago, on  the island of Guam, in the Western Pacific, an unusual
disorder was described among the native people of  Guam, the Chamorros. The
disease affected up to 10% of the native people of Guam. Some of the
patients developed a disease that is similar to Amyotrophic Lateral
Sclerosis (Lou Gehrig disease). Some of the native people developed a
disease that is similar to PD.  It differed from PD in that it occurred at a
younger age, almost all of the patients developed a dementia, and, at
autopsy, Lewy bodies the hallmark of PD, were not found in the brain.
Finally some of the native people developed a disease that was a combination
of ALS and PD.

Because of the similarity of the disease to ALS and PD, the disease has been
studied for 50 years. Although much useful information has emerged from
these studies, today, we still do not know why the disease occurs, why it
affects only the native people of Guam, and what the relationship of the
Guam disease is to ALS and PD in the rest of the world.

The following article was modified to make it more readable to laypeople.

Clinical Features and Changing Patterns of neurodegenerative disorders on
Guam, 1997-2000

D. Galasko, MD

Abstract

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.

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 AD.

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  or represents a late-life syndrome more closely allied to PDC.

==================

High-prevalence ALS was characterized among Chamorros, the native
inhabitants of Guam, in the early 1950s and Parkinson-dementia complex (PDC)
was described a few years later. During the next 30 years, the prevalence of
ALS decreased markedly and that of PDC to a lesser extent, and the age at
onset of both disorders increased.

ALS and PDC among Chamorros are of interest for many reasons. The
neuropathology of these disorders consists of widespread neurofibrillary
tangles (NFT) that are morphologically and biochemically identical to those
found in AD, with minimal or no accompanying amyloid deposition.

The etiology and high prevalence of these disorders on Guam has not been
explained. The rapid shifts in prevalence and age at onset since the 1950s,
particularly for ALS, suggest that environmental factors are important.

Over the years, investigations have focused on putative environmental
factors such as ingestion of toxins released during the preparation of flour
from local cycads, or neurotoxicity related to the unusual mineral content
of the water on Guam or to aluminum. Evidence for a casual role for any of
these factors is inconclusive.

Genetic risk may be important because cases cluster among families to an
extent, but do not follow an obvious pattern of inheritance. An interaction
between genetic predisposition, environmental exposure, and aging may be
necessary for ALS or PDC to develop.

Late-life dementia among elderly Chamorros has received little study.
Although dementia may be the presenting feature in patients with PDC,
prominent parkinsonian signs are typically found at the time of first
examination or within a few years of onset. A survey of individuals aged 40
and over in three villages in Guam in the late1980s noted that many older
patients had dementia without parkinsonism, and the term “Marianas dementia”
has been coined.

However, Chamorros with late-life dementia have not received systematic or
detailed study using current clinical research methods to evaluate dementia.
During more than four decades of studies, research teams on Guam have used
different approaches for clinical assessment and have not focused on ALS,
PDC, and dementia simultaneously.

Many of these studies predated modern research methods to assess mental
status and formal criteria for dementia. Although high-incidence ALS and PDC
were reported to have disappeared on Guam in the early 1980s, both
conditions continue to be encountered. Beginning in April 1997, we performed
standarized medical, neurologic, and psychometric evaluations of patients on
Guam to characterize the clinical features of patients with ALS,
parkinsonism, and dementia. This report describes clinical patterns of
late-life neurologic disorders among a series of patients evaluated during
these 36 months.

During the 3-year period, 228 Chamorro patients underwent detailed
evaluation. In addition another 14 subjects were diagnosed and also
underwent detailed evaluation. Another 410 Chamorros were assessed as normal
after undergoing screening, of whom 321 were aged 60 or older and 182 were
aged 70 or older.

During 1997 through 2000, 10 Chamorro patients with ALS were evaluated,
representing a markedly lower frequency of ALS than in the 1950s and 1960s.
Their mean age at onset was 55 and sex distribution was fairly even. 90
Chamorro patients were identified as having PDC and a further 11 as having
PD without dementia. The mean age at onset for PDC was 68.1 and that of PD
was about 5 years younger. 83 individuals were diagnosed as having dementia,
which almost always presented with forgetfulness. Ten of these had a
coexisting condition that could contribute to dementia, such as stroke. The
mean age at onset of symptoms was 74.9, and women exceeded men by almost
3:1.

Although we have not performed population-based surveys or village-wide
examinations, we have made extensive efforts to identify and evaluate
patients with neurologic symptoms of interest throughout Guam. These efforts
include obtaining acceptance of our study by patients and caregivers as well
as by community, religious, and political leaders; establishing good
relationships with physicians, nurses, and social service providers;
ensuring that our assessment team included Chamorros; and carrying out the
majority of assessments via home visits.

We cannot claim to have identified every patient with ALS and PDC during
this interval, and our data presumably represent an underestimate.
Nonetheless, we think that the number of missed cases was small.
For brevity, this discussion will outline key findings from selected
published studies over the years, considering ALS and PDC separately,
without examining the details or possible limitations of each study.

In surveys in the early 1950s, the prevalence of ALS among Chamorros on Guam
was estimated to be more than 140 per 100,000. The incidence rates of ALS
decreased markedly from 1945 to 1985. For example, in analyses of patients
identified from 1945-1972, the average annual incidence rates decreased for
men from over 50:l00,000 for 1945 through 1959, to 20 to 30:100,000 for 1965
through 1972. A parallel decrease was noted for women, from about 30:100,000
in the 1950s to 12 to 20:100,000 in 1965 through 1972.

The reported disappearance of high-incidence ALS during the early 1980s has
been suggested to be possibly attributable to less effective case finding.
Analyses of data available from 1980 through 1989 suggested that the
incidence of ALS in Chamorros remained much lower than in earlier decades,
estimated at about 7.5:100,000.

Previous descriptions of Guam ALS noted that it resembled classic ALS in its
onset and combination of upper and lower motor neuron findings. Dysarthria
and bulbar palsy occurred in about one-third of patients. The documented age
at onset varied widely, from 20 to 70. There was a shift in mean age at
onset from 48 to 53 during 1950 through 1979, and in the 1970s no patients
had onset of ALS before age 30. We have found a further increase in age At
onset (to age 56), and only two patients with onset before age 40.

From 1950 through 1979, the incidence rates of ALS were about; twice as high
in men than in women, but since the early 1980s, these rates have appeared
to be more even.  Parkinsonism or dementia occur in only about 5 to 10% of
patients who present with ALS. Non-Chamorros on Guam rarely develop ALS.
Nine cases were documented from 1962 to 1977 in male Filipino immigrants to
Guam.

From 1997 to 2000, we have diagnosed 7 new patients with ALS: five
Chamorros, one Filipino, and one Caucasian long-term resident of Guam.
Overall, this represents a much lower incidence rate among Chamorros, who
currently number about 50,000 on Guam, than that typical of the 1950s and
1960s. ALS has thus decreased markedly among Chamorros, but has not
completely disappeared. The rapid and dramatic decline in the incidence of
ALS over a period of fewer than 50 years is easiest to reconcile with an
environmental factor that contributed to the disease in the past but
operates much less strongly, if at all, at present.

In the 1950s and 60s, PDC was about as common as ALS in Chamorros.
PDC now greatly exceeds ALS: we have evaluated about 9  times as many cases
of PDC compared with ALS. The clinical picture of PDC typically includes
both parkinsonism and dementia. The mean age at onset of PDC increased in
successive studies over 1950 to 1979, from 55 to 59 years in men and 51 to
59 years in women. Patients evaluated from 1997 to 2000 have shown a
continuation of this trend, with a further rise of mean age at onset, to 68.
PDC was previously noted to be two to three times more common in men than
women. We have found that PDC remains almost twice as common among men
than women.

Parkinsonism is the usual presenting feature of PDC, with cognitive decline
accompanying it at onset or following within a few years. In about 30% of
patients, cognitive decline is reported to precede parkinsonism, but
parkinsonism typically follows within 1 to 2 years. The parkinsonism of PDC
shares many features with typical idiopathic PD. Findings are more often
symmetric than in idiopathic PD. Dysarthria, hypophonic speech, loss of
facial expression and of associated movements, and decreased blinking also
occur frequently.

Rest tremor affects about 30-40% of patients, whereas action or postural
tremor is common. Gait difficulty is extremely common. Some patients show
relatively early and severe gait difficulty. Patients with PDC respond to
some extent to L-dopa or dopaminergic agonists, though less dramatically
patients with idiopathic PD.

Although the environment on Guam has changed markedly, the neurologic
picture of PDC does not appear to have changed over the past 40 years. In
the past, in patients who presented with parkinsonism and preserved
cognitive abilities, dementia developed almost without fail within the next
5 years. Idiopathic PD has been noted to be rare among Chamorros. We have
identified a small group of patients with parkinsonism who have intact
cognitive and functional abilities for at least a few years.

Follow-up evaluation will enable us to determine whether these patients with
PD remain cognitively normal or have a high risk for developing dementia. We
have found that the dementia syndrome of PDC usually begins with symptoms of
forgetfulness and disorientation. Difficulty with calculation and problem
solving are also common, but language abilities generally are preserved
until later in the course.

Major depression is rare, but apathy or decreased initiative occurs
commonly, together with increased daytime drowsiness or sleep. Agitation and
aggressive behavior may occur as the dementia progresses. Pathologic changes
include widespread NFT in limbic, temporal, and neocortical regions and loss
of neurons and tangles in the substantia nigra. The diagnosis of PDC among
older patients than in the past raises questions about whether the disease
itself has changed.

Our continued neuropathologic studies have shown that our clinical diagnosis
of PDC is highly predictive of tangle pathology in a distribution consistent
with PDC. Over the past 3 years, we have identified 9  times more patients
with PDC compared with ALS, which differs markedly from the equal occurrence
of these disorders in the 1960s. An analysis of PDC on Guam, using all
available data from 1956-1985, yielded estimates of annual incidence over
this entire period of 62:100,000 for men and 19:100.000 for women. We have
systematically re-analyzed the age-adjusted 5-year incidence rates of PDC
from 1950-  1999, and found that PDC has steadily declined compared with the
peak incidence rates recorded in the 1950s and 1960s.

This trend in incidence rates is far less striking for PDC than for ALS on
Guam. A pure dementia syndrome has only recently been recognized in elderly
Chamorros, many years after the initial wave of research interest in ALS and
PDC. In 3 years we have evaluated more than 80 patients with pure dementia.
Pending further neuropathologic studies, we are using the term Mariana
dementia (referring to the Mariana island chain, which includes Guam),
recognizing that the syndrome is highly suggestive of AD. The mean age at
onset, 74, is older than that for PDC and is compatible with AD. In these
demented patients, women exceeded men by almost 3:1. This represents a
greater female-to-male imbalance than is usually seen in studies of AD.
Neuropathologic findings have been reported in only a small number of
patients with dementia. One report described two Chamorros with dementia
whose brains showed AD pathology.

Patterns of neurodegenerative disorders on Guam have changed over the past
40 years. The incidence of ALS has declined markedly, although new cases
continue to be identified. PDC appears to have declined to a much lesser
degree and its age at onset continues to increase. However, neither of these
disorders has disappeared, despite marked changes that have permeated and
deeply altered the lifestyle, diet, and culture of the Chamorros. The
interplay between genetic susceptibility and environmental changes could
explain the temporal trends affecting ALS and, to a smaller extent, PDC.

To explore these factors, we are conducting molecular genetic studies of ALS
and PDC. With gains in life expectancy on Guam and systematic assessment of
many elderly Chamorros, dementia is being diagnosed more often. PDC and
pure dementia may show considerable clinical overlap when patients reach
advanced stages.

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