Parkinsonism-dementia Complex Research Articles

Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases.

Microglia play an important role in neuroinflammation and neurodegeneration. Here, we report an approach for generating microglia-containing cerebral organoids derived from human pluripotent stem cells involving the supplementation of growth factors (FGF, EGF, heparin) and 10% CO2 culture conditions. Usingthis platform, Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) cerebral organoids were generated from patient-derived induced pluripotent stem cells (iPSCs). These ALS-PDC-affected organoids had more reactive astrocytes and M1 microglia, and had fewer M2 microglia than their unaffected counterparts, leading to impaired microglia-mediated phagocytosis. RNA-seq analysis of ALS-PDC and control organoids indicated that the most significant changes were microglia- and astrocyte-related genes (IFITM1/2, TGF-β, and GFAP). The most significantly downregulated pathway was type I interferon signaling. Interferon-gamma supplementation increased IFITM expression, enhanced microglia-mediated phagocytosis, and reduced beta-amyloid accumulation in ALS-PDC-affected network. The results demonstrated the feasibility of using microglia-containing organoids for the study of neurodegenerative diseases.

APOE Alleles With Tau and Aβ Pathology in Patients With Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex in the Kii Peninsula.

To examine the association of the APOE ε4 and ε2 alleles with the pathologic features of patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex cases in the Kii peninsula of Japan (Kii ALS/PDC). We analyzed APOE variants in 18 autopsy patients with ALS/PDC, consisting of 9, 8, and 1 patient with PDC, ALS, and PDC followed by ALS, respectively. Moreover, we revealed the relationship between APOE variants and Aβ and tau pathologies. The frequency of the ε4 allele was not different between patients with Kii ALS/PDC and control participants. APOE ε4 was associated with increased Aβ pathology (p = 0.005 by the χ 2 test), but not with increased tau pathology (p = 0.984). The frequency of the ε2 allele was apparently higher than that of control participants (p = 0.254). The APOE ε2 allele was associated with increased tau pathology (p = 0.009) and not with reduced Aβ pathology (p = 0.383) in patients with Kii ALS/PDC. Although there was no overrepresentation of the frequency of the ε4 or ε2 allele, our findings suggest that the ε2 allele is associated with increased tau pathology and not with reduced Aβ pathology in patients with Kii ALS/PDC.

Therapeutic Strategies and Metal-Induced Oxidative Stress: Application of Synchrotron Radiation Microbeam to Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan.

A series of extensive gene-environment studies on amyotrophic lateral sclerosis (ALS) and Parkinsonism–dementia complex (PDC) in Guam Island, USA, and the Kii Peninsula of Japan, including Auyu Jakai, West New Guinea, have led us to hypothesize that a prolonged low calcium (Ca) and magnesium (Mg) intake, especially over generation, may cause oxidative stress to motor and nigral neurons by an increased uptake of environment metallic elements, i.e., aluminum (Al), manganese (Mn), and iron (Fe). Otherwise, 5–10% of total ALS cases are familial ALS (fALS), of which 20% of the fALS cases linked to a point mutation of Cu/Zn superoxide dismutase (SOD1). In the vicinity of the Kii Peninsula, about 7% of the ALS cases are also linked to the SOD1 mutation. Using synchrotron radiation (SR) microbeam, conglomerate inclusion (SOD1 aggregates) within a spinal motor neuron of the fALS case in the vicinity revealed a loss of copper (Cu) in contrast to extremely high contents of Zinc (Zn) and Ca. That means an exceptionally low Cu/Zn ratio with an increased Ca content, indicating the abnormalities of the active site of SOD1 protein of the fALS. Furthermore, sALS in the southernmost high incidence areas of the Kii Peninsula showed a low Cu/Zn ratio within a motor neuron, suggesting a fragility of SOD1 proteins. From the perspective of gene–environment interactions, the above two research trends may show a common oxidative stress underlying the neuronal degenerative process of ALS/PDC in the Kii Peninsula of Japan. Therefore, it is a crucial point for the prospect of therapeutic strategy to clarify a role of transition metals in the oxidative process in both ALS/PDC, including ALS elsewhere in the world. This paper reviews a history of the genetic epidemiological studies, especially from the aspect of gene–environment interaction, on ALS/PDC in the Kii and Guam high incidence foci and the results of a series of analytical research on trace metallic elements within neurons of both sALS and fALS cases, especially using a synchrotron radiation (SR) microbeam of Spring-8 and Photon Factory of Japan. The SR microbeam is an ideal X-ray source, which supplies an extremely high brilliance (high-intensity photon) and tunability (energy variability) to investigate trace metallic elements contained in biological specimens at the cellular level, even more without any damages. This research will provide a valuable information about the mechanism of oxidative stress involved in neuronal cell death in ALS and related neurodegenerative disorders. To elucidate the physicochemical mechanism of the oxidative process in neuronal degeneration, it will shed a new light on the therapeutic strategies for ALS/PDC in near future.

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease.

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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

ABSTRACT 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.

Kampō medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex): Postscript and Historical Footnote.

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) is a disappearing neurodegenerative disease in three former high-incidence foci of the U.S. territory of Guam, Papua-Indonesia (New Guinea) and Kii Peninsula, Honshu Island, Japan (Muro disease). We report additional data that associate medicinal use of cycad seed to Muro disease in the southern Kozagawa focus of ALS/PDC. In the other two ALS/PDC-affected populations, cycad seed was used as a traditional topical medicine in New Guinea and Guam and, additionally, for food on Guam.

Etiology of Retinal and Cerebellar Pathology in Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex.

PurposeTo reexamine the etiology of a unique retinal pathology (linear and vermiform sub-retinal tubular structures) described among subjects with and without neurodegenerative disease in former high-incidence foci of Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in Guam (USA) and the Kii peninsula of Honshu island (Japan).MethodsAnalysis of published and unpublished reports of 1) ALS/PDC and the retinal and cerebellar pathology associated therewith and 2) exogenous neurotoxic factors associated with ALS/PDC and the developing retina and cerebellum.ResultsALS/PDC retinal and cerebellar pathology matches persistent retinal and cerebellar dysplasia found in laboratory animals given single in utero or postnatal systemic treatment with cycasin, the principal neurotoxic component in the seed of cycad plants traditionally used for food (Guam) or oral medicine (Kii-Japan), both of which have been linked to the human neurodegenerative disease.ConclusionALS/PDC-associated retinal and cerebellar dysplasia could arise from in utero exposure to methylazoxymethanol, the genotoxic metabolite of cycasin that results from maternal ingestion of this azoxyglucoside. These results support the environmental toxic etiology of retinal and brain pathology in ALS/PDC.

Brain Transcriptome Analysis Links Deficiencies of Stress-Responsive Proteins to the Pathomechanism of Kii ALS/PDC.

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient brains. We prepared frozen brains from three individuals without neurodegenerative diseases, three patients with Alzheimer’s disease, and 21 patients with Kii ALS/PDC, and then acquired microarray data from cerebral gray and white matter tissues. Microarray results revealed that expression levels of genes associated with heat shock proteins, DNA binding/damage, and senescence were significantly altered in patients with ALS/PDC compared with healthy individuals. The RNA expression pattern observed for ALS-type brains was similar to that of PDC-type brains. Additionally, pathway and network analyses indicated that the molecular mechanism underlying ALS/PDC may be associated with oxidative phosphorylation of mitochondria, ribosomes, and the synaptic vesicle cycle; in particular, upstream regulators of these mechanisms may be found in synapses and during synaptic trafficking. Furthermore, phenotypic differences between ALS-type and PDC-type were observed, based on HLA haplotypes. In conclusion, determining the relationship between stress-responsive proteins, synaptic dysfunction, and the pathogenesis of ALS/PDC in the Kii peninsula may provide new understanding of this mysterious disease.

Kampō medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex).

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) is a disappearing neurodegenerative disease in three former high-incidence foci of Guam-USA, Papua-Indonesia and Kii Peninsula, Honshu Island, Japan. The latter includes two distinct ALS/PDC-affected regions (Hohara and Kozagawa), where the disorder is known as Muro disease. In Hohara, oral exposure to plant (cycad) neurotoxins used in traditional medical practice has been linked previously to Muro disease. We report new observations that link Kampō medicine to Muro disease in the southern Kozagawa focus. Oral exposure to cycad seed toxins is associated with all three foci of Western Pacific ALS/PDC.

Effect of tetracycline family of antibiotics on actin aggregation, resulting in the formation of Hirano bodies responsible for neuropathological disorders

Actin, an ATPase superfamily protein, regulates some vital biological functions like cell locomotion, cytokinesis, synaptic plasticity and cell signaling in higher eukaryotes, and is dependent on the dynamics of actin polymerization process. Impaired regulation of actin polymerization has been implicated in the formation and deposition of rod-like paracrystalline structures called as Hirano bodies in neuronal cells of patients suffering from Alzheimer’s disease, Pick’s disease, Guam amyotrophic lateral sclerosis and parkinsonism–dementia complex. Aggregation of actin forming amorphous deposition in the brain cells is also associated with chronic alcoholism and aging of the neurons. In the current article, we propose the breaking of the highly amorphous and dysregulated actin aggregates using generic compounds like tetracycline, oxytetracycline, doxycycline and minocycline which are used as antibiotics against tuberculosis and infection caused due to various Gram-negative bacteria. We have investigated the effect and affinity of binding of these four compounds to that of actin aggregates using 90° light scattering, size exclusion chromatography, dynamic light scattering, circular dichroism, scanning electron microscopy, transmission electron microscopy imaging and kinetic analysis. The isothermal calorimetric measurements showed that the binding constant for the cycline family molecules used in this study range from 9.8 E4 M−1 to 1.3 E4 M−1. To understand the in vivo effect, we also studied the effect of these drugs on Saccharomyces cerevisiae Δend3 mutant cells. Our data suggest that these generic compounds can plausibly be used for the treatment of various neurodegenerative diseases occurring due to Hirano body formation in brain cells.Communicated by Ramaswamy H. Sarma

Impact of C9orf72 on Japanese Patients with Amytrophic Lateral Sclerosis (ALS)/Frontotemporal Dementia (FTD)

In 2011, C9orf72 hexanucleotide (GGGGCC) repeat expansion (HRE) in intron 1 was reported as the most common cause of sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population. In the Japanese population, the C9orf72 repeat expansion was found to account for 0.2% cases of sporadic ALS and 2.6% of familial ALS. Notably, among individuals in the Kii peninsula which has recorded high incidence of ALS or ALS/PDC (parkinsonism-dementia complex), the frequency of C9orf72 repeat expansion was 20% (3/15) indicating high prevalence. It is important to obtain detailed family history of ALS and FTD to understand the cause of the diseases including the C9orf72 mutation.

Hypothesis: Etiologic and Molecular Mechanistic Leads for Sporadic Neurodegenerative Diseases Based on Experience With Western Pacific ALS/PDC.

Seventy years of research on Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia Complex (ALS/PDC) have provided invaluable data on the etiology, molecular pathogenesis and latency of this disappearing, largely environmental neurodegenerative disease. ALS/PDC is linked to genotoxic chemicals (notably methylazoxymethanol, MAM) derived from seed of the cycad plant (Cycas spp.) that were used as a traditional food and/or medicine in all three disease-affected Western Pacific populations. MAM, nitrosamines and hydrazines generate methyl free radicals that damage DNA (in the form of O6-methylguanine lesions) that can induce mutations in cycling cells and degenerative changes in post-mitotic cells, notably neurons. This paper explores exposures to naturally occurring and manmade sources of nitrosamines and hydrazines in association with sporadic forms of ALS (with or without frontotemporal degeneration), progressive supranuclear palsy, and Alzheimer disease. Research approaches are suggested to examine whether these associations might have etiological significance.Lay SummaryUnknown environmental exposures are thought to be risk factors for non-inherited forms of certain progressive brain diseases, such as sporadic forms of amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer's disease (sAD). Related progressive and fatal brain disorders coalesce in a single neurodegenerative disease of largely environmental origin (ALS-Parkinsonism-dementia Complex) that has affected three genetically distinct populations residing in islands of the Western Pacific region. Prolonged study of this prototypical neurodegenerative disease has provided invaluable information on the probable environmental cause (specific chemical genotoxins) and molecular mechanisms (unrepaired nerve cell DNA-damage) by which brain degeneration begins, evolves and, years or decades later, clinical signs appear, and progress. This information is used as a foundation to explore whether chemically related genotoxins (nitrosamines, hydrazines) are possible risk factors for sALS, sPSP, and sAD. Methods to test this hypothesis in the field and laboratory are proposed.

Parkinsonism-dementia complex, and endemic disease on the island of Guam. I. - Clinical features. By Asao Hirano, Leonard T. Kurland, Robert S. Krooth and Simmons Lessell. Brain 1961; 84: 642–661; with Parkinsonism-dementia complex, and endemic disease on the island of Guam. II. - Pathological features. By Asao Hirano, Nathan Malamud and Leonard Kurland. Brain 1961; 84: 662–679.

Parkinsonism-dementia complex, and endemic disease on the island of Guam. I. - Clinical features. By Asao Hirano, Leonard T. Kurland, Robert S. Krooth and Simmons Lessell. Brain 1961; 84: 642–661; with Parkinsonism-dementia complex, and endemic disease on the island of Guam. II. - Pathological features. By Asao Hirano, Nathan Malamud and Leonard Kurland. Brain 1961; 84: 662–679.

\u03b2-N-methylamino-L-alanine (BMAA) suppresses cell cycle progression of non-neuronal cells

β-N-methylamino-L-alanine (BMAA), a natural non-proteinaceous amino acid, is a neurotoxin produced by a wide range of cyanobacteria living in various environments. BMAA is a candidate environmental risk factor for neurodegenerative diseases such as amyotrophic lateral sclerosis and Parkinson-dementia complex. Although BMAA is known to exhibit weak neuronal excitotoxicity via glutamate receptors, the underlying mechanism of toxicity has yet to be fully elucidated. To examine the glutamate receptor-independent toxicity of BMAA, we investigated the effects of BMAA in non-neuronal cell lines. BMAA potently suppressed the cell cycle progression of NIH3T3 cells at the G1/S checkpoint without inducing plasma membrane damage, apoptosis, or overproduction of reactive oxygen species, which were previously reported for neurons and neuroblastoma cells treated with BMAA. We found no evidence that activation of glutamate receptors was involved in the suppression of the G1/S transition by BMAA. Our results indicate that BMAA affects cellular functions, such as the division of non-neuronal cells, through glutamate receptor-independent mechanisms.

Spatial Patterns of the Tau-Immunoreactive Inclusions in Eight Different Tauopathies are Consistent with the Spread of Pathogenic Tau

Background: Tauopathies are a major group of neurodegenerative disorders characterised by the presence of tau-immunoreactive inclusions in the cytoplasm of neurons and glia. The spread of pathogenic tau along neuroanatomical pathways may play a significant role in the pathogenesis of neurodegenerative disorders. It is hypothesised that such a spread of tau along neuroanatomical pathways would give rise to a characteristic spatial pattern of the tau-immunoreactive neuronal cytoplasmic inclusions (NCI) in affected tissue. Methods: The aim of this study was to investigate this hypothesis by comparing the spatial patterns of NCI in regions of the cerebral cortex in eight different tauopathies: Alzheimer’s disease, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, frontotemporal dementia with parkinsonism linked to chromosome 17, Guam parkinsonism-dementia complex, Pick’s disease, and progressive supranuclear palsy. Results: Regardless of disorder, tau isoform, or inclusion morphology, the NCI were most frequently aggregated into clusters, which were regularly distributed parallel to the pia mater. In many regions, the regularly distributed clusters of NCI range in size (400–800 µm) approximating to the dimension of cell columns associated with the cortico-cortical pathways. Conclusion: The presence of regularly distributed clusters of NCI in the cortex of all eight tauopathies suggests an association between the pathology and the cortico-cortical pathways and is consistent with the pathogenic spread of tau along these connections. Hence, treatments designed to protect the cortex from this spread may be applicable across many tauopathies.

Cerebrovascular inflammation is associated with tau pathology in Guam parkinsonism dementia

Parkinsonism-dementia complex of Guam (Guam PDC)is a neurodegenerative disease with parkinsonism and early onset Alzheimer-like dementia. Guam PDC belongs to the family of neurodegenerative disorders, known as tauopathies, which are histopathologically characterized by abnormal deposition of microtubule-associated protein tau. While changes in the blood-brain barrier (BBB) in Alzheimer's disease are increasingly recognized, dysfunction of BBB in Guam PDC has not been extensively studied. In this study, we characterized cerebrovascular changes in the patients with Guam PDC. The brain tissue from ten post-mortem Guam PDC patients and six non-demented controls were assessed for structural and functional changes in BBB. Entorhinal cortex sections were immunostained for the markers of brain endothelial cells (claudin-5, occludin, and collagen IV) and inflammation (VCAM-1, ICAM-1, P-Selectin, and E-Selectin). The ultrastructure of brain capillaries was investigated by confocal microscopy and morphological changes and intensity alterations were evaluated. We found a significant decrease of tight junction proteins and the upregulation of adhesion molecules that correlated with the presence of neurofibrillary tangles. In addition, we showed the presence of CD3+-positive cells in the brain areas affected by pathological lesions. Our findings indicate that pathological lesions in Guam PDCare associated with inflammatory changes of brain capillaries and could mediate transmigration of cells to the brain parenchyma.

Dysfunction of Protein Quality Control in Parkinsonism-Dementia Complex of Guam.

Guam parkinsonism–dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders.

The Neurotoxic Effects of Cycads and Metals: A Review

The bioaccumulation of environmental toxins as possible risk factors in the etiology ofamyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) is studied inthree foci of the Western Pacific: Guam, the Kii Peninsula, and West Papua New Guinea. Theobjective of this study was to evaluate the best evidence on the exogenous causes of ALS/PDC, with emphasis on the role of cycads, iron, and manganese in the Western Pacific foci,by performing a systematic review of major electronic databases using predefined criteria, 68of which met the selection criteria. Two major environmental hypotheses are associated withthis enigmatic disease: the vegetal hypothesis, which focuses on the neurotoxic and genotoxicproperties of the cycad, and the mineral hypothesis, which focuses on the neurotoxic propertiesof metals. Although typically studied independently, environmental data suggests these twohypotheses may, in fact, converge. Epidemiologic research investigating the association betweenexposure to environmental toxins and ALS/PDC has proven inconclusive. Nevertheless,possible causal links indicate a need for more holistic research to not only better understandALS/PDC, but also glean new insights regarding the associated neurodegenerative diseases.

Sporadic Parkinsonism-Dementia Complex of Rhode Island with Unusually Abundant Glial TDP-43 Immunoreactivity

Sporadic Parkinsonism-Dementia Complex of Rhode Island with Unusually Abundant Glial TDP-43 Immunoreactivity

A novel liquid chromatography/mass spectrometry method for determination of neurotransmitters in brain tissue: Application to human tauopathies

Neurotransmitters, small molecules widely distributed in the central nervous system are essential in transmitting electrical signals across neurons via chemical communication. Dysregulation of these chemical signaling molecules is linked to numerous neurological diseases including tauopathies. In this study, a precise and reliable liquid chromatography method was established with tandem mass spectrometry detection for the simultaneous determination of aspartic acid, asparagine, glutamic acid, glutamine, γ-aminobutyric acid, N-acetyl-l-aspartic acid, pyroglutamic acid, acetylcholine and choline in human brain tissue. The method was successfully applied to the analysis of human brain tissues from three different tauopathies; corticobasal degeneration, progressive supranuclear palsy and parkinsonism-dementia complex of Guam. Neurotransmitters were analyzed on ultra-high performance chromatography (UHPLC) using an ethylene bridged hybrid amide column coupled with tandem mass spectrometry (MS/MS). Identification and quantification of neurotransmitters was carried out by ESI+ mass spectrometry detection. We optimized sample preparation to achieve simple and fast extraction of all nine analytes. Our method exhibited an excellent linearity for all analytes (all coefficients of determination >0.99), with inter-day and intra-day precision yielding relative standard deviations 3.2%–11.2% and an accuracy was in range of 92.6%–104.3%. The present study, using the above method, is the first to demonstrate significant alterations of brain neurotransmitters caused by pathological processes in the brain tissues of patient with three different tauopathies.