Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We here report biomagnification (the increasing accumulation of bioactive, often deleterious molecules through higher trophic levels of a food chain) of the neurotoxic nonprotein amino acid beta-methylamino-l-alanine (BMAA) in the Guam ecosystem. Free-living cyanobacteria produce 0.3 microg/g BMAA, but produce 2-37 microg/g as symbionts in the coralloid roots of cycad trees. BMAA is concentrated in the developing reproductive tissues of the cycad Cycas micronesica, averaging 9 microg/g in the fleshy seed sarcotesta and a mean of 1,161 microg/g BMAA in the outermost seed layer. Flying foxes (Pteropus mariannus), which forage on the seeds, accumulate a mean of 3,556 microg/g BMAA. Flying foxes are a prized food item of the indigenous Chamorro people who boil them in coconut cream and eat them whole. Chamorros who die of amyotrophic lateral sclerosis/parkinsonism-dementia complex (AL-SPDC), a neurodegenerative disease with symptoms similar to amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease, have an average of 6.6 microg/g BMAA in their brain tissues. The biomagnification of BMAA through the Guam ecosystem fits a classic triangle of increasing concentrations of toxic compounds up the food chain. This may explain why the incidence of ALS-PDC among the Chamorro was 50-100 times the incidence of amyotrophic lateral sclerosis elsewhere. Biomagnification of cyanobacterial BMAA may not be unique to Guam; our discovery of BMAA in the brain tissue from Alzheimer's patients from Canada suggests alternative ecological pathways for the bioaccumulation of BMAA in aquatic or terrestrial ecosystems.
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PMID:Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. 1461 59

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimer's disease (AD), and is thus considered a tauopathy. Following reports of alpha-synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of alpha-synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinson's disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of alpha-synuclein in the cerebellum of Guamanian PDC patients. Numerous alpha-synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing alpha-synuclein pathology in the amygdala. The average density of alpha-synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this alpha-synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar alpha-synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the alpha-synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes.
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PMID:Occurrence of alpha-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex. 1502 81

In Guadeloupe, there is an abnormally high frequency of atypical parkinsonism. Only one-third of the patients that develop parkinsonian symptoms were reported to present the classical features of idiopathic Parkinson disease and one-third a syndrome resembling progressive supranuclear palsy (PSP). The others were unclassifiable, according to established criteria. We carried out a cross-sectional study of 160 parkinsonian patients to: (i) define more precisely the clinical phenotypes of the PSP-like syndrome and the parkinsonism that was considered unclassifiable in comparison with previously known disorders; (ii) define the neuropsychological and brain imaging features of these patients; (iii) evaluate to what extent a candidate aetiological factor, the mitochondrial complex I inhibitor annonacin contained in the fruit and leaves of the tropical plant Annona muricata (soursop) plays a role in the neurological syndrome. Neuropsychological tests and MRI were used to classify the patients into those with Parkinson's disease (31%), Guadeloupean PSP-like syndrome (32%), Guadeloupean parkinsonism-dementia complex (PDC, 31%) and other parkinsonism-related disorders (6%). Patients with a PSP-like syndrome developed levodopa-resistant parkinsonism, associated with early postural instability and supranuclear oculomotor dysfunction. They differed, however, from classical PSP patients by the frequency of tremor (>50%), dysautonomia (50%) and the occurrence of hallucinations (59%). PDC patients had levodopa-resistant parkinsonism associated with frontosubcortical dementia, 52% of these patients had hallucinations, but, importantly, none had oculomotor dysfunction. The pattern of neuropsychological deficits was similar in both subgroups. Cerebral atrophy was seen in the majority of the PSP-like and PDC patients, with enlargement of the third ventricle and marked T2-hypointensity in the basal ganglia, particularly the substantia nigra. Consumption of soursop was significantly greater in both PSP-like and PDC patients than in controls and Parkinson's disease patients. In conclusion, atypical Guadeloupean parkinsonism comprises two forms of parkinsonism and dementia that differ clinically by the presence of oculomotor signs, but have similar cognitive profiles and neuroimaging features, suggesting that they may constitute a single disease entity, and both were similarly exposed to annonaceous neurotoxins, notably annonacin.
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PMID:Atypical parkinsonism in Guadeloupe: a common risk factor for two closely related phenotypes? 1730 92

Of all the molecules reported to have toxicological effects, BMAA (beta-methylamino alanine) stands out as having the most checkered past. In the late 1960's it was reported to be a toxic component of the cycad flour consumed by Chamorros on Guam which caused the high incidence of amyotrophic lateral sclerosis (ALS) in Guam, that was associated with a Parkinson's disease-like dementia complex (ALS-PDC). However, because ALS-PDC is a slow onset disease, manifesting itself as long as 30 years following exposure to the putative neurotoxin, and only acute toxic effects of BMAA were observed in animal studies, interest in BMAA waned. A seminal study by Spencer et al., in 1987 showing neurological impairments with long-term BMAA-fed monkeys revived the hypothesis that BMAA could cause ALS-PDC. However, the amounts of BMAA used in that study were viewed as being the equivalent of a person consuming their body weight of cycad flour every day. Again, the BMAA hypothesis was discarded. Recently a third iteration of the BMAA hypothesis has been proposed. It is based on the discovery of a novel dietary source of BMAA via biomagnification of BMAA in flying foxes, once consumed in great amounts by Chamorros. Also, reports that BMAA can be incorporated into plant and animal proteins, a heretofore unrecognized dietary source of BMAA, further solidified this new hypothesis. However, once again this hypothesis has its detractors and it remains controversial. This manuscript critically evaluates in vivo studies directed at establishing an animal model of BMAA-induced ALS-PDC and their implications for this hypothesis.
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PMID:Animal models of BMAA neurotoxicity: a critical review. 1819 17

Guam ALS/PDC is a severe tangle forming disorder endemic to Guam with features overlapping such neurodegenerative disorders as Alzheimer disease (AD), Parkinson disease (PD), progressive supranuclear palsy (PSP), ALS, corticobasal degeneration (CBD) and pallido-ponto-nigral degeneration (PPND). Since the prevalence is declining, we examined brain tissue from 35 clinically diagnosed Chamorro patients with ALS/PDC and two Chamorro controls autopsied between 1946 and 2006, to determine if distinct variations in the pathology could be identified up to this time. Although the age at autopsy increased by 4.5-5 years per decade, we identified no qualitative differences in pathological deposits with antibodies against tau, ubiquitin, A beta, alpha-synuclein and TDP-43, indicating that these more recently identified proteins have been involved in the neuropathogenesis over the past 6 decades. Tau and TDP-43 positive neuronal, oligodendroglial and astrocytic inclusions involving multiple nerve fiber tracts occurred in both the ALS and PDC types, reinforcing the concept that these forms are part of the same disorder. The results obtained may help to define the commonality of the Guam disease with other tangle forming disorders and may help in monitoring the epidemiological changes that are taking place.
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PMID:Enduring involvement of tau, beta-amyloid, alpha-synuclein, ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC). 1884 96

The aim of this study is to investigate the changes of the pupil's light reflex (PLR) and mobility in Parkinson's disease (PD) patients with and without cognitive disorder. Twenty two (22) patients (ten males, twelve females, mean age: 72.7+/-7.3 years) with identified PD entered the study. The patients were examined with the Mini Mental State Examination (MMSE), the Wechsler II Memory Scale (WMS II) and the Hamilton Depression Scale (HAM-D17). Eleven (11) patients (five males, six females, mean age: 72.09+/-7.06 years) were free of any cognitive deficits and eleven (11) patients (five males, six females, mean age: 73.36+/-7.55 years) had cognitive disorder according to the aforementioned scales. None of the patients satisfied the DSM-IV-TR criteria for depression or anxiety disorder. The patients underwent a pupillometric study in both eyes with single flash stimuli of 24.6 candelas/m(2) intensity and 20 ms duration. The pupillometric parameters that were studied were: Latency for the onset of Constriction (T1), Baseline Pupil Radius (R1), Minimum Pupil Radius after the pupil reaction to light (R2), Amplitude (AMP, R1-R2), Time for maximum Miosis (T2), Maximum Constriction Velocity (VCmax) and Maximum Constriction Acceleration (ACmax). The pupillometric findings of each group were compared to those of an age and sex matched group of eleven healthy subjects. Furthermore, a comparison between the findings of the two groups was conducted. ACmax and VCmax were significantly lower in patients without (PD) and with coexisting cognitive impairment (PDC) compared to normal subjects (NC) (p<0.001). Patients with cognitive impairment (PDC) had significantly lower levels of ACmax, VCmax and AMP than patients without cognitive deficits (PD). Cognitive impairment in PD, which mainly reflects a central cholinergic deficit, may be a crucial pathogenetic factor for the decrease in the aforementioned pupillometric parameters. VCmax and ACmax can be considered as the most sensitive indicators of this central cholinergic deficiency.
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PMID:Pupillometric findings in patients with Parkinson's disease and cognitive disorder. 1904 1

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.
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PMID:Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates. 1956 4

Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS. Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attention since they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guam suggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein amino acid, beta-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found that BMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on the seeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAA occurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 microg/g, 5 mM) but not in control brains have rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding that BMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration 95 microg/g, 0.8mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts of cyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and that cyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues, were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al. have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALS and Alzheimer's disease (concentrations >100 microg/g) but not in the brains of non-neurological controls or Huntington's disease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inability to prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that develops depends on the polygenic background of the individual.
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PMID:Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. 1992 26

We propose a partial directed coherence (PCD) method based on a sparse multivariate autoregressive (mAR) model to investigate patterns of information flow in electroencephalography (EEG) recordings in Parkinson's disease (PD) patients performing a visually-guided motor task. The use of a sparsity constraint on the mAR matrix addresses issues such as sample size, model order selection and number of parameters to be estimated, particularly when the number of EEG channels used is large and the window size is small in order to capture dynamic changes. The proposed PDC-based information flow analysis demonstrated distinctly altered patterns of connectivity between PD patients off medication and healthy subjects, particularly with respect to net information outflow from the left sensorimotor (L Sm) region, which might indicate excessive spreading of activity in the diseased state. Disrupted patterns of connectivity in PD were partially restored by levodopa medication. In addition, PDC-based analysis proved to be more sensitive to temporally-dynamic connectivity changes as compared to traditional spectral analysis, which might be influenced primarily by large-scale changes. We suggest that the proposed sparse-PDC method is a suitable technique to investigate altered connectivity in Parkinson's disease.
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PMID:Partial directed coherence-based information flow in Parkinson's disease patients performing a visually-guided motor task. 1996 28

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.
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PMID:Sleep alterations in an environmental neurotoxin-induced model of parkinsonism. 2071 46


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