Endemic parkinsonism: clusters, biology and clinical features.

The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.

Lytico-bodig in Guam: Historical links between diet and illness during and after Spanish colonization.

This paper analyses documents on health and disease among Chamorro people during and after 333 years (1565-1898) of the Spanish claim to and occupation of Guam. Here, a complex neurodegenerative disease-known locally as lytico-bodig and medically as amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC)-reached hyperendemic proportions in the mid-twentieth century but then declined and is now disappearing. A tau-dominated polyproteinopathy, clinical phenotypes included amyotrophic lateral sclerosis (ALS or lytico), atypical parkinsonism with dementia (P-D or bodig), and dementia alone. A plausible etiology for lytico-bodig is consumption of flour derived from the incompletely detoxified seed of Cycas micronesica (fadang in Chamorro; Federico in Spanish), a poisonous gymnosperm that survives climatic extremes that can affect the island. Traditional methods for safe consumption appear to have been lost over the course of time since governors Francisco de Villalobos (1796-1862) and Felipe de la Corte (1855-1866) proposed banning consumption in view of its acute toxic effects. A death certificate issued in 1823 might suggest ALS/PDC in people dying with disability or impedidos, and premature aging and a short life was linked to food use of fadang in the mid-1850s (Guam Vital Statistics Report, 1823). During the Japanese occupation of Guam (1941-1944), Chamorro people took refuge in the jungle for months, where they relied on insufficiently processed fadang as a staple food. After World War II, traditional foods and medicines were subsequently replaced as islanders rapidly acculturated to North American life.

Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease.

Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease. ABBREVIATIONS: BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin.

The practical evaluation and management of patients with symptoms of a sore burning mouth.

There are many etiologic factors to consider in a patient who presents with symptoms or sensations of a sore burning mouth. These range from local causes within the oral cavity to underlying systemic disease, including psychologic factors. This paper aims to describe the different clinical presentations and to outline a systematic approach to the evaluation and management of such patients. The clinician will be directed to the relevant diagnosis by following the traditional medical model of taking a focused history, performing a thorough clinical examination, considering the potential differential diagnoses, and requesting pertinent and appropriate investigations. The various differential diagnoses and broad treatment options will also be discussed and outlined. This paper will not, however, discuss burning mouth syndrome (oral dysesthesia), which is a diagnosis of exclusion, whereby the oral mucosa is clinically normal and there are no identifiable medical or dental causes to account for the patient's symptoms.

A unique retinal epitheliopathy is associated with amyotrophic lateral sclerosis/Parkinsonism-Dementia complex of Guam.

BACKGROUND: The aim of this work was to examine whether a linear retinal pigment epitheliopathy is associated with the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. METHODS: A total of 918 Guamanian Chamorros, with and without amyotrophic lateral sclerosis/parkinsonism-dementia complex, were examined cross-sectionally for linear retinal pigment epitheliopathy (LRPE). Overall, 239 Guamanians, who were neurologically asymptomatic, were followed for up to 20 years to determine the risk of developing amyotrophic lateral sclerosis/parkinsonism-dementia complex. RESULTS: The epitheliopathy was present in 59.7% (117 of 196) patients with amyotrophic lateral sclerosis/parkinsonism-dementia complex, but in only 24.7% (178 of 722) of subjects who were neurologically asymptomatic (age- and sex-adjusted risk difference: 35.0%; 95% confidence interval [CI]: 27.5-42.6; p < 0.0001). Prospectively, 15 of 50 cases with epitheliopathy developed amyotrophic lateral sclerosis/parkinsonism-dementia complex, compared to 4 of 189 cases without epitheliopathy (age- and sex-adjusted hazard ratio: 13.1; 95% CI: 4.0-43.1; P < 0.0001). CONCLUSION: Amyotrophic lateral sclerosis/parkinsonism-dementia complex is associated with an LRPE and predicts future neurological disease. Identifying the cause of this retinopathy could provide an understanding about the pathogenesis of amyotrophic lateral sclerosis/parkinsonism-dementia complex and related diseases.

World Workshop on Oral Medicine VI: an international validation study of clinical competencies for advanced training in oral medicine.

OBJECTIVE: To explore international consensus for the validation of clinical competencies for advanced training in Oral Medicine. STUDY DESIGN: An electronic survey of clinical competencies was designed. The survey was sent to and completed by identified international stakeholders during a 10-week period. To be validated, an individual competency had to achieve 90% or greater consensus to keep it in its current format. RESULTS: Stakeholders from 31 countries responded. High consensus agreement was achieved with 93 of 101 (92%) competencies exceeding the benchmark for agreement. Only 8 warranted further attention and were reviewed by a focus group. No additional competencies were suggested. CONCLUSION: This is the first international validated study of clinical competencies for advanced training in Oral Medicine. These validated clinical competencies could provide a model for countries developing an advanced training curriculum for Oral Medicine and also inform review of existing curricula.

Defining neurodegeneration on Guam by targeted genomic sequencing.

OBJECTIVE: Amyotrophic lateral sclerosis/parkinsonism-dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic. METHODS: In this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros. RESULTS: Genes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations. INTERPRETATION: The findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi-incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam.

Genetic variability of the retromer cargo recognition complex in parkinsonism.

BACKGROUND: A pathogenic mutation (VPS35 p.D620N) within the retromer complex has been shown to segregate with late-onset Parkinson's disease (PD). Several studies have subsequently detected the mutation in patients with PD and not in controls. METHODS: Mutation screening of the coding regions of the retromer cargo recognition complex genes (VPS26A/B, VPS29, and VPS35) was carried out in patients with PD (n = 396), atypical parkinsonism (n = 229), and in 368 controls. RESULTS: Overall, we identified five rare nonsynonymous mutations in VPS26A and one in VPS35; none were observed in VPS26B or VPS29. Three VPS26A variants (p.K93E, p.M112V, and p.K297X), identified in patients with atypical parkinsonism, were not observed in controls from this study (n = 368) or from publically available data sets (n = 4,426). CONCLUSION: Our results support the hypothesis that rare variants in the retromer complex genes may be involved in the development of parkinsonism, although further studies are warranted before any solid conclusions can be drawn.

Historical perspectives and memories of progressive supranuclear palsy.

Parkinsonism recalls James Parkinson of London and his description of six patients with "paralysis agitans" in 1817, which neurologist Jean-Marie Charcot renamed Parkinson disease. Its variants, referred to as atypical parkinsonian disorders, are the subject of this issue of Seminars in Neurology through which we continue a journey toward understanding the pathogenesis of these diverse neurodegenerative diseases that are sometimes genetically determined, but are more often sporadic and without familial occurrence.

Clinically relevant patch test results in patients with burning mouth syndrome.

BACKGROUND: Patients with a sore or burning mouth associated with clinically normal oral mucosa present a difficult diagnostic challenge. OBJECTIVE: The objective of this study was to assess the value of patch testing in patients with burning mouth syndrome. METHODS: We retrospectively reviewed the results of patch testing to an oral series in patients with burning mouth syndrome seen at Mayo Clinic, Rochester, Minnesota, between January 2000 and April 2006. RESULTS: Of 195 consecutive patients with a burning or sore mouth, 75 had patch testing to an oral series, and 28 of these patients (37.3%) had allergic patch test reactions. The most common allergens were nickel sulfate hexahydrate 2.5%, balsam of Peru, and gold sodium thiosulfate 0.5%. On follow-up, 15 patients reported improvement, 4 removed or avoided the offending dental metal, and 6 avoided the dietary allergen. Thirteen patients did not improve; 6 avoided identified allergens, but without improvement; 1 removed dental metals without symptom change; and 5 avoided test-positive dietary allergens but without improvement. The remaining 7 nonresponders had nonrelevant patch test results or did not avoid allergens. CONCLUSIONS: Patch testing can identify patients who may be allergic to dental metals or dietary additives and who may benefit from removal or avoidance of these.

Complete resolution of advanced Mycoplasma pneumoniae encephalitis mimicking brain mass lesions: report of two pediatric cases and review of literature.

Mycoplasma pneumoniae is a well-known cause of atypical pneumonia. CNS involvement is a relatively frequent extrapulmonary manifestation, most commonly manifesting as encephalitis in the pediatric population. We present two unusual cases of M. pneumoniae encephalitis that presented with symptoms and imaging findings suggesting mass occupying lesions, and worsening altered mental status. Biopsy of the lesions was necessary in both cases to aid with diagnosis. Histopathologic features excluded neoplasm, and established the diagnosis of encephalitis, but did not point toward its etiology. The only finding that indicated M. pneumoniae as the most likely pathogen was serum IgM positivity in the absence of any other identifiable infectious source, and complete neurologic recovery following specific anti-mycoplasmal treatment. The patients were successfully treated with antibiotics and steroids, with the second case also requiring intravenous immunoglobulin and anti-epileptics. The clinical presentation and histopathologic findings suggested an immune-mediated pathogenesis, but acute disseminated encephalomyelitis was excluded due to extensive gray matter involvement. Disease resolution despite status epilepticus and herniation in case 2 is a novel finding of the study. Current principles of diagnosis and management of encephalitis as the presenting manifestation of mycoplasmal infection are discussed.

The ALS/PDC syndrome of Guam: potential biomarkers for an enigmatic disorder.

The ALS/parkinsonism-dementia complex of Guam is a long latency disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. It is remarkably similar to a syndrome localized to the Kii Peninsula of Japan. There are as yet no identified pathological features that will clearly distinguish the Guam or Kii ALS/PDC syndrome from other degenerative neurological disorders. At present, ALS/PDC of Guam and the Kii Peninsula can be confirmed only by postmortem examination. The most prominent pathological hallmark is the widespread occurrence of neurofibrillary tangles which express the same balance of 3R and 4R tau that is found in Alzheimer disease. They both show an increased prevalence of a peculiar retinal disorder termed linear retinal pigmentary epitheliopathy. The disorders are both highly familial. Several environmental factors have been proposed but no supportive evidence for an environmental or dietary factor has been found. Genome searches have so far failed to identify causative genes although two single nuclear polymorphisms related to MAPT that increase the risk of the Guam syndrome have been located. The two syndromes are clearly unique, and clues as to their causation could be beneficial in understanding the etiology of similar, but much more prevalent disorders in North America, Europe and Asia. Identification of biomarkers for premortem diagnosis would be helpful in management as well as in revealing the true etiology.

TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations.

The transactive response (TAR) DNA binding protein 43 (TDP-43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS-related disorders. In this study, we examined abnormal TDP-43 pathology in 13 sporadic ALS (SALS), six familial ALS (FALS) with and without Cu/Zn superoxide dismutase (SOD1) mutations (SOD1-FALS and non-SOD1-FALS), Guam ALS, two frontotemporal lobar degeneration with MND/ALS (FTLD-MND/ALS), one FTLD with ubiquitin-only-immunoreactive inclusions (FTLD-U) and two progressive supranuclear palsy (PSP). Sections from the spinal cord were processed for immunohistochemistry using antibodies against TDP-43, ubiquitin, p62, cystatin C, phosphorylated tau protein (P-tau; AT8), alpha-synuclein and phosphorylated neurofilament protein (P-NF). In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62-immunoreactive (IR) neuronal inclusions co-localized with TDP-43. In three out of four SOD1-FALS and one of two non-SOD1-FALS cases, TDP-43-IR inclusions were absent despite the presence of p62 and/or ubiquitin-IR inclusions. However, a single TDP-43-IR neuronal inclusion co-localized with p62 and ubiquitin in one SOD1-FALS (His48Gln) case. Except for one neuron in a Guam case, all TDP-43-IR neuronal inclusions were negative for P-tau (AT8). TDP-43-IR glial inclusions and neurites were also demonstrated. The TDP-43 is a consistent component of the ubiquitinated inclusions in SALS and Guam ALS, but TDP-43-IR inclusions are absent or scarce in SOD1-FALS.

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).

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.

The ALS/PDC syndrome of Guam and the cycad hypothesis.

There is a high incidence on Guam of a severe tauopathy known as the Parkinson- dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.