Kwang-Ming Chen

Amyotrophic lateral sclerosis and parkinsonism‐dementia on Guam A 30‐year evaluation of clinical and neuropathologic trends

We reviewed the records of 279 Guamanian Chamorro patients with amyotrophic lateral sclerosis (ALS) and 293 patients with parkinsonism-dementia (PD), who had onset of symptoms between 1950 and 1979, to determine if there were changes in the clinical and neuropathologic features that might clarify the declining incidence rates in the past decade. There were no major temporal changes in the frequencies of physical findings or histopathologic features, but in the past three decades, an increase in age at onset was observed for both ALS and PD. There was also a shorter duration of illness in ALS and a longer duration in PD. Good correlation was found between the clinical and pathologic findings for both ALS and PD throughout this period.

Odor identification deficit of the parkinsonism‐dementia complex of Guam Equivalence to that of Alzheimer's and idiopathic Parkinson's disease

Olfactory dysfunction is among the first signs of Alzheimers disease (AD), idiopathic Parkinsons disease (PD), and the parkinsonism-dementia complex (PDC) of Guam. We have recently demonstrated that the odor identification and detection deficits of patients with PD are equivalent to those of patients with mild AD when subtle differences in cognitive function are statistically controlled for by analysis of covariance. In contrast, patients with progressive supranuclear palsy (PSP) and patients with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism evidence olfactory function much more similar to that of normal controls. In the present study, we administered the University of Pennsylvania Smell Identification Test and the Picture Identification Test to 24 patients with early signs of the PDC of Guam and statistically compared their test scores to those of 24 early-stage AD and 24 early-stage PD patients of similar age and gender from the United States mainland. Although the PDC group evidenced slightly more difficulty in identifying pictures than did the other 2 groups, the odor identification deficit associated with this disorder was of the same magnitude as that observed in AD and PD, suggesting that olfactory testing cannot be used to distinguish among these 3 diseases and that the olfactory dysfunction of these disorders may reflect a common neurologic substrate.

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.

Distinct pathological features of the gallyas- and tau-positive glia in the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam.

We examined 50 patients with parkinsonism-dementia complex of Guam (Guam PDC). 10 Guamanian patients with amyotrophic lateral sclerosis (ALS), 5 patients with combined PDC and ALS (PDC-ALS), and 20 non-PDC non-ALS Guamanians, who had been autopsied between 1979 and 1982, paying special attention to glial inclusions. Gallyas-positive and tau-immunopositive intracytoplasmic inclusions were observed in many of the glial cells, in addition to extensive neurofibrillary tangles (NFTs) in the brains of Guam PDC and PDC-ALS patients. Granular hazy inclusions were seen in the astrocytes, and some crescent/coiled inclusions were observed in the oligodendroglia. Many granular hazy inclusions were observed in the amygdaloid nucleus, inferior olivary nucleus, and lateral funiculus of the spinal cord. The crescent/coiled inclusions were observed predominantly in the anterior nucleus of the thalamus, motor cortex, midbrain tegmentum, pyramids of the medulla oblongata, and lateral funiculus of the spinal cord. The granular hazy inclusions have never been reported previously, and the topographic distribution of the crescent/coiled inclusions in Guam PDC and PDC-ALS differs from those reported previously in other NFT-forming diseases. These findings indicate that Guam PDC and PDC-ALS involve not only neurons but also glia, and that their morphological and topographic differences from other NFT-forming diseases may provide further insights into their distinct etiopathogenesis, and thus prove useful for diagnosis.

The neostriatum and nucleus accumbens in parkinsonism-dementia complex of Guam : a pathological comparison with Alzheimer's disease and progressive supranuclear palsy

The neostriatum, nucleus accumbens and basal nucleus of Meynert (bnM) in the parkinsonismdementia complex of Guam (Guam PDC) were examined immunohistologically, ultrastructurally, quantitatively and topographically, and the results were compared with those in Alzheimers 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.

Parkinsonism‐dementia in a Filipino migrant A clinicopathologic case report

A 69-year-old male Filipino migrant developed a clinical syndrome and neuropathologic changes indistinguishable from parkinsonism-dementia (PD). The patient originally migrated from the Ilocos region of the Philippine Islands to Hawaii and then to Guam, where he remained for 26 years before neurologic symptoms began. This is the first case of clinically and neuropathologically verified PD in a non-Chamorro and supports the notion that long-term continuous exposure to the Guamanian environment increases the risk of developing disease.

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 μm 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.

Parkinsonism, dementia and vertical gaze palsy in a Guamanian with atypical neuroglial degeneration

Abstract A 58-year-old Chamorro female patient, who died in 1993, was examined clinicopathologically. At the age of 51, she suffered from hemiparkinsonism, then bradykinesia, rigidity without tremor, and dementia. Extrapyramidal symptoms developed, and at the age of 57, vertical gaze palsy was noted. The clinical diagnosis was parkinsonism-dementia complex (PDC) with vertical gaze palsy. The brain showed atrophy in the frontal and temporal lobes, and the atrophy was accentuated in the dentate gyrus, Ammon’s horn and parahippocampal gyrus. The basal ganglia, thalamus and midbrain were moderately atrophic. The substantia nigra and locus ceruleus were completely depigmented. Numerous neurofibrillary tangles (NFTs) were seen in the subiculum and amygdaloid nucleus. Many NFTs were evident in the parahippocampal gyrus, lateral occipitotemporal gyrus, insula, Sommer sector, basal nucleus of Meynert, lateral nucleus of the thalamus, subthalamic nucleus and brain stem, and several were observed in the globus pallidus and hypothalamus. The Sommer sector, substantia nigra, locus ceruleus and basal nucleus of Meynert showed severe loss of neurons, and a moderate loss of neurons was exhibited by the globus pallidus. These findings were apparently consistent with those associated with PDC. However, in this patient, severe neuronal loss was seen in the subthalamic nucleus and lateral nucleus of the thalamus, and grumose degeneration, which has not previously been reported in PDC, was seen in the dentate nucleus. In addition, many tufted astrocytes, which have been reported to occur in progressive supranuclear palsy (PSP) and postencephalitic parkinsonism, but scarcely observed in PDC, were present. Furthermore, astrocytic plaques, which have been considered as a specific finding of corticobasal degeneration (CBD), were observed in the cerebral cortex. On the other hand, granular hazy astrocytic inclusions, previously reported to occur in PDC, were not seen. Chromatolytic neurons were not observed. The question thus arises as to whether it is appropriate to consider this patient as having suffered from a combination of PDC, PSP and CBD. From the view points of absence of granular hazy astrocytic inclusions and chromatolytic neurons, and of tufted astrocytes in the neostriatum, it is conceivable that this patient is a case of a new disease entity.