Parkinsonism-dementia Complex Of Guam Research Articles

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.

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.

Two distribution patterns of TDP-43-immunopositve inclusions in amyotrophic lateral sclerosis of Guam: Comparison with parkinsonism-dementia complex of Guam and classic ALS

Two distribution patterns of TDP-43-immunopositve inclusions in amyotrophic lateral sclerosis of Guam: Comparison with parkinsonism-dementia complex of Guam and classic ALS

'Hummingbird' Sign in a Patient with Guam Parkinsonism-Dementia Complex.

We present a case of a 71-year-old male Chamorro patient from Guam who presented with progressive supranuclear palsy (PSP)-Richardson’s syndrome. Considering his strong family history of parkinsonism and a PSP phenotype, he was clinically diagnosed with Guam parkinsonism-dementia complex (PDC). Magnetic resonance imaging (MRI) of the brain revealed prominent midbrain atrophy with preserved pontine volume, forming the ‘hummingbird’ sign, which has not been described before in Guam PDC. Molecular analysis of the chromosome 9 open reading frame 72 gene (C9orf72) showed only 6 GGGGCC repeats. We discuss the clinico-pathological similarities and differences between PSP and Guam PDC, and highlight the topography of neuropathological changes seen in Guam PDC to explain the appearance of the ‘hummingbird’ sign on MRI.

Hippocampal sclerosis in the parkinsonism-dementia complex of Guam: quantitative examination of neurons, neurofibrillary tangles, and TDP-43 immunoreactivity in CA1.

The cornu ammonis 1 (CA1) area in the hippocampus of the parkinsonism-dementia complex (PDC) of Guam was examined quantitatively with special references to the number of neurons, intraneuronal (i) and extracellular (e) neurofibirillary tangles (NFTs), and TDP-43 (43-kDa trans-activation-responsive region DNA-binding protein)-immunopositive structures, in 24 Chamorro patients with PDC of Guam and seven control Chamorro Guamanians (both groups having no ischemic or anoxic complications). The results were that: (i) in the patients with mildly involved PDC, total numbers of neurons, iNFTs and eNFTs were almost the same as those of neurons of controls; (ii) in patients severely involved, total numbers of neurons, iNFTs and eNFTs decreased markedly; (iii) the decrease of the number of pyramidal neurons in CA1 with positive nuclear TDP-43 was intimately correlated with the decrease in total neuron numbers; (iv) whereas the numbers of neurons and TDP-43-immunopositive intracytoplasmic aggregation in the CA1 area were inversely correlated; and (v) depression of nuclear TDP-43 immuonostainability was not affected by the presence or absence of NFTs. In conclusion, hippocampal sclerosis exists in PDC; there is a possibility of elimination of eNFTs which appeared in the CA1 in patients with PDC and loss of the neurons correlates with disappearance of nuclear TDP-43, but not with appearance of intraneurocytoplasmic TDP-43 aggregation or iNFTs.

Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

The neurotoxin beta-N-methylamino-l-alanine (BMAA) was first identified as a “toxin of interest” in regard to the amyotrophic lateral sclerosis–Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resemble those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease.

Olfactory dysfunction in Parkinson disease

Olfactory dysfunction is among the earliest nonmotor features of Parkinson disease (PD). Such dysfunction is present in approximately 90% of early-stage PD cases and can precede the onset of motor symptoms by years. The mechanisms responsible for olfactory dysfunction are currently unknown. As equivalent deficits are observed in Alzheimer disease, Down syndrome, and the Parkinson-dementia complex of Guam, a common pathological substrate may be involved. Given that olfactory loss occurs to a lesser extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy, olfactory testing can be useful in differential diagnosis. The olfactory dysfunction in PD and a number of related diseases with smell loss correlates with decreased numbers of neurons in structures such as the locus coeruleus, the raphe nuclei, and the nucleus basalis of Meynart. These neuroanatomical findings, together with evidence for involvement of the autonomic nervous system in numerous PD-related symptoms, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to the olfactory loss. This Review discusses the current understanding of olfactory dysfunction in PD, including factors that may be related to its cause.

TDP-43 pathology may occur in the BRI2 gene-related dementias

The ubiquitously expressed TAR DNA-binding protein-43 (TDP-43), involved in transcription and alternative splicing, is a major disease protein in frontotemporal lobar degeneration and amyotrophic lateral sclerosis [8]. TDP43-positive inclusions may also be detected in other neurodegenerative diseases, including Alzheimer’s disease (AD), Lewy body disorders, corticobasal degeneration and the parkinsonism–dementia complex of Guam (PDCG) [8]. In 2009, Schwab et al. [12] reported TDP-43 pathology including neuronal cytoplasmic inclusions (NCIs), dystrophic neurites and occasional positivity in neurofibrillary tangle (NFT) fibres in a case with familial British dementia (FBD). FBD and familial Danish dementia (FDD), also known as BRI2 gene-related dementias [3], are inherited cerebral amyloid diseases, in which the relevant 34 aminoacid-long amyloid peptides, ABri in FBD and ADan in FDD, are cleaved from the C-terminus of the mutated BRI2 precursor proteins [13, 14]. Although ABri and ADan show no homology to amyloid-beta, the neuropathology of FBD and FDD with amyloid and diffuse plaques, cerebral amyloid angiopathy and NFT pathology [5, 6] is remarkably similar to that of AD. As the study of Schwab et al. [12] investigated one case, the frequency of TDP-43 pathology in FBD remains unknown. This prompted us to screen sections of formalinfixed, paraffin embedded tissue from the hippocampal formation, temporal and frontal cortex and amygdala for TDP-43 pathology in five FBD and four FDD cases (mean age at death 62.2 and 53.5 years, respectively), using two non-phosphorylation dependent (Abnova, ProteinTech) and one phosphorylation dependent (pS409/410; Cosmo Bio Co.) antibodies. We found rare TDP-43-positive NCIs in the CA1 hippocampal subregion in one of the FBD cases (Fig. 1), but all the FDD cases were negative. TDP-43 pathology, most commonly in a limbic distribution, is relatively frequent in AD, although a ‘diffuse type’ with widespread TDP-43 inclusions is also known [1]. TDP-43 pathology may be present in up to 60% of the AD cases when pTDP-43 antibodies are used and the amygdala is also screened [2]. Similar to the majority of AD cases, the TDP-43 pathology showed a limbic distribution in the FBD case reported by Schwab et al. [12] and the rare TDP-43-positive NCIs were found in the hippocampus in one of our five FBD cases, supporting the notion that mesial temporal lobe structures are particularly susceptible to TDP-43 pathology [2]. Although we have investigated the largest available cohort of cases, it is not possible to accurately estimate the frequency of associated TDP-43 pathology in FBD. If data from the study of Schwab et al. [12] and from our study are pooled (six cases), one can estimate that up to one-third of the FBD cases may have at least some TDP-43 pathology. No such pathology has so far been observed in FDD. The cause and mechanism of TDP-43 proteinopathies occurring in association with a number of neurodegenerative diseases is unknown [8]. As in AD, tau pathology is severe and the amyloid plaque load is high in limbic structures in FBD, which could indicate that similar cellular mechanisms are involved in initiating neurodegeneration including TDP-43 pathology in both AD and FBD. Our observation of TDP-43 inclusions in the hippocampal formation affected by prion amyloid plaques and extensive NFT pathology in hereditary prion disease with Y163X T. Lashley J. L. Holton T. Revesz (&) Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK e-mail: T.Revesz@ion.ucl.ac.uk

AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies

Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. AMP-activated protein kinase (AMPK) is a metabolic sensor expressed in most mammalian cell types. In the brain, AMPK controls neuronal maintenance and is overactivated during metabolic stress. Here, we show that activated AMPK (p-AMPK) is abnormally accumulated in cerebral neurons in 3R+4R and 3R tauopathies, such as Alzheimer's disease (AD), tangle-predominant dementia, Guam Parkinson dementia complex, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease. In AD brains, p-AMPK accumulation decorated neuropil threads and dystrophic neurites surrounding amyloid plaques, and appeared in more than 90% of neurons bearing pre-tangles and tangles. Granular p-AMPK immunoreactivity was also observed in several tauopathies in apparently unaffected neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. Less p-AMPK pathology was observed in PSP and CBD, where minimal p-AMPK accumulation was also found in tangle-positive glial cells. p-AMPK was not found in purified PHFs, indicating that p-AMPK did not co-aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Thus, activated AMPK abnormally accumulated in tangle- and pre-tangle-bearing neurons in all major tauopathies. By controlling tau phosphorylation, AMPK might regulate neurodegeneration and therefore could represent a novel common determinant in tauopathies.

TDP-43 pathology in familial British dementia

Trans-activation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. This has suggested defining a new class of diseases known as TDP-43 proteinopathies. However, it has been reported more recently that TDP-43 positive inclusions occur in other neurodegenerative disorders such as Alzheimer's disease, Dementia with Lewy Bodies and Parkinsonism dementia complex of Guam. Here we report the occurrence of TDP-43 inclusions in one other neurodegenerative disorder: familial British dementia. Using a variety of antibodies against phosphorylated and non-phosphorylated TDP-43 epitopes, we found intense accumulation occurred in the form of dystrophic neurites, neuronal cytoplasmic inclusions and was also occasionally associated with neurofibrillary tangles. Double immunostaining revealed that TDP-43 and tau aggregates were rarely directly colocalized, but co-existed in the same neurons as separate inclusions. Double staining with ubiquitin showed a direct colocalization with TDP-43. The phosphorylation-dependent TDP-43 antibodies proved superior to phosphorylation-independent antibodies in revealing pathological inclusions since the former did not stain non-phosphorylated TDP-43 in normal nuclei. Our results support the concept that TDP-43 pathology is not narrowly restricted, but is involved in the etiology of many neurodegenerative disorders.

Colocalization of Transactivation-Responsive DNA-Binding Protein 43 and Huntingtin in Inclusions of Huntington Disease

Transactivation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. Transactivation-responsive DNA-binding protein 43-immunostained inclusions have also been found in other neurodegenerative disorders including Alzheimer disease, dementia with Lewy bodies, and parkinsonism dementia complex of Guam. Here, we analyzed the occurrence of TDP-43 immunostaining in Huntington disease, which is characterized by inclusions containing mutated huntingtin. In all Huntington disease cases studied, TDP-43 was frequently colocalized with huntingtin in dystrophic neurites and various intracellular inclusions, but not in intranuclear inclusions; the latter were only stained with huntingtin and anti-ubiquitin antibodies. Two phosphorylation-dependent TDP-43 antibodies proved to be superior for detecting pathological inclusions because they did not stain nonphosphorylated TDP-43 in normal nuclei; staining of normal nuclei with phosphorylation-independent antibodies obscured the inclusions. Our results further add to the hypothesis that TDP-43 may be involved in the pathology of a variety of neurodegenerative disorders.

Lack of TAR‐DNA binding protein‐43 (TDP‐43) pathology in human prion diseases

AimsTAR-DNA binding protein-43 (TDP-43) is the major ubiquitinated protein in the aggregates in frontotemporal dementia with ubiquitin-positive, tau-negative inclusions and motor neurone disease. Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism–dementia complex. We therefore aimed to determine whether there is TDP-43 pathology in human prion diseases, which are characterised by variable deposition of prion protein (PrP) aggregates in the brain as amyloid plaques or more diffuse deposits.Material and methodsTDP-43, ubiquitin and PrP were analysed by immunohistochemistry and double-labelling immunofluorescence, in sporadic, acquired and inherited forms of human prion disease.ResultsMost PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin. No abnormal TDP-43 inclusions were identified in any type of prion disease case, and TDP-43 did not co-localize with ubiquitin-positive PrP plaques or with diffuse PrP aggregates.ConclusionsThese data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.

Frontal-Subcortical Dementias

Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction. Classic frontal-subcortical dementias include Huntington chorea, Parkinson disease dementia, progressive supranuclear palsy, thalamic degeneration, subcortical vascular dementia, multiple sclerosis, the acquired immunodeficiency syndrome dementia complex, depressive pseudodementia, and some other rare dementias like spinocerebellar degenerative syndromes, Hallervorden-Spatz disease, choreoacanthocytosis, idiopathic basal ganglia calcification, Guamanian parkinsonism-dementia complex, corticobasal degeneration multiple system atrophy, Wilson disease, metachromatic leukodystrophy, adrenoleukodystrophy, hypoparathyroidism, sarcoidosis, and other CNS inflammatory disorders. Anatomic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. However, most frontal-subcortical dementias show cortical atrophy in later stages, and cortical dementias have subcortical pathology at some point. In fact, the concept might be seen as a continuum, and only the 2 extremes would be represented by pure cortical or subcortical pathology. Anyway, subcortical disorders may still be more similar to one another than they are to AD. Possibly, frontal-subcortical and cortical dementias are the description of the prior main target of the disease process, ending up in both cases in a global dementia. Although the dichotomy cortical versus frontal-subcortical dementia is not strict, the 2 concepts still seem to have advantages.

TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity

TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity

Quantitative Proteomics Identifies Surfactant-Resistant α-Synuclein in Cerebral Cortex of Parkinsonism-Dementia Complex of Guam but Not Alzheimer's Disease or Progressive Supranuclear Palsy

Parkinsonism-dementia complex (PDC) remains a significant health burden to the Chamorro population. We tested the hypothesis that quantitative proteomics might provide fresh insight into this enigmatic illness by analyzing proteins resistant to surfactant extraction from patients with Alzheimer's disease (AD) or PDC and their matched controls using isobaric tags for relative and absolute quantification. In addition to the expected increase in abnormal frontal cortical Abeta peptides, tau, ubiquitin, and apolipoprotein E in AD, and tau in PDC, we identified alpha-synuclein (SNCA) as a major abnormal protein in PDC but not AD. We confirmed our isobaric tags for relative and absolute quantification findings by enzyme-linked immunosorbent assay in frontal and temporal cortices. We extended our assays to include a limited number of cases of progressive supranuclear palsy (PSP) and dementia with Lewy bodies; we observed increased abnormal tau but not SNCA in PSP, and abnormal SNCA in dementia with Lewy bodies that was quantitatively similar to PDC. Finally, soluble Abeta oligomers were selectively increased in AD but not PDC or PSP. These results show that frontal and temporal cortex in PDC is distinguished from AD and PSP by its accumulation of abnormal SNCA and suggest that PDC be considered a synucleinopathy as well as a tauopathy.

Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism-dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam.

TDP-43 is deposited in the Guam parkinsonism-dementia complex brains

TDP-43, a nuclear factor that functions in regulating transcription and alternative splicing, was recently identified as a component of the ubiquitin-positive, tau-negative inclusions specific for frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). In the present study, we carried out immunohistochemical and biochemical analyses of brains of Guamanians with the parkinsonism-dementia complex (G-PDC) using anti-TDP-43, anti-tau and anti-ubiquitin antibodies. Immunohistochemistry with anti-TDP-43 antibodies revealed various types of positive structures in the frontotemporal and hippocampal regions of G-PDC cases. Most of these structures were negative for tau. By immunoblot analysis with the TDP-43 antibody, an abnormal 45 kDa band, as well as a diffuse staining throughout the gel, was detected in the sarkosyl-insoluble fractions of G-PDC brains. Dephosphorylation has shown that abnormal phosphorylation takes place in the accumulated TDP-43 seen in FTLD-U and ALS. These results suggest that accumulation of TDP-43 is a common process in certain neurodegenerative disorders, including FTLD-U, ALS and G-PDC.

LRRK2 Expression in Normal and Pathologic Human Brain and in Human Cell Lines

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal-dominant late-onset Parkinson disease. We report that by reverse transcriptase-polymerase chain reaction, the mRNA of LRRK2 is expressed in soluble extracts of human brain, liver, and heart and in cultured human astrocytes, microglia, and oligodendroglia as well as in human neuroblastoma cell lines. We find by Western blotting using a polyclonal antibody of the leucine-rich repeat kinase 2 protein (Lrrk2) specific for C-terminal residues 2511-2527 that an apparent full-length protein and several of its fractions are expressed in soluble extracts of normal human brain. By immunocytochemistry, the antibody recognizes neurons, and more weakly astrocytes and microglia, in normal brain tissue. It intensely labels Lewy bodies in Parkinson disease and related neurodegenerative disorders. It also labels a subset of neurofibrillary tangles in Alzheimer disease and the Parkinsonism dementia complex of Guam (PDCG). It labels thorn-shaped astrocytes and oligodendroglial coiled bodies in PDCG; oligodendroglial inclusions in multiple system atrophy; Pick bodies in Pick disease; nuclear and cytoplasmic inclusions in Huntington disease; and intraneuronal and glial inclusions in amyotrophic lateral sclerosis. In summary, LRRK2 is constitutively expressed in neurons and also in glial cells of human brain. It strongly associates with pathological inclusions in several neurodegenerative disorders.