Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Protein profiling of extracellular vesicles from iPSC-derived astrocytes of patients with ALS/PDC in Kii peninsula.

BACKGROUND: Amyotrophic lateral sclerosis/Parkinsonism-dementia complex in Kii peninsula, Japan (Kii ALS/PDC), is an endemic neurodegenerative disease whose causes and pathogenesis remain unknown. However, astrocytes in autopsied cases of Kii ALS/PDC show characteristic lesions. In addition, relationships between extracellular vesicles (EVs) and neurodegenerative diseases are increasingly apparent. Therefore, we focused on proteins in EVs derived from Kii ALS/PDC astrocytes in the present study. METHODS: Induced pluripotent stem cells (iPSCs) derived from three healthy controls (HCs) and three patients with Kii ALS/PDC were differentiated into astrocytes. EVs in the culture medium of astrocytes were collected and subjected to quantitative proteome analysis. RESULTS: Our proteome analysis reveals that EV-containing proteins derived from astrocytes of patients with Kii ALS/PDC show distinctive patterns compared with those of HCs. Moreover, EVs derived from Kii ALS/PDC astrocytes display increased proteins related to proteostasis and decreased proteins related to anti-inflammation. DISCUSSION: Proteins contained in EVs from astrocytes unveil protective support to neurons and may reflect the molecular pathomechanism of Kii ALS/PDC; accordingly, they may be potential biomarker candidates of Kii ALS/PDC.

An immigrant family with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex.

OBJECTIVES: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a unique endemic on Guam island of the USA, the Kii Peninsula of Japan, and Papua state of Indonesia. The pathomechanism of ALS/PDC remains to be solved, although interaction between some environmental factors and genetic background is plausible. This is the first autopsy-proven immigrant family of ALS/PDC of the Kii Peninsula. METHODS: A daughter and her father immigrated to the high incident area from outside the Kii Peninsula. The father developed ALS 18 years later after immigration, and his daughter also developed ALS 65 years after immigration. They showed pure ALS phenotype without parkinsonism and dementia. RESULTS: The daughter was diagnosed neuropathologically with Kii ALS/PDC with multiple proteinopathies: tauopathy, α-synucleinopathy, and TDP-43 proteinopathy. Gene analysis of familial ALS-related genes, including C9orf72, showed no mutation. DISCUSSION: The findings in an immigrant family established that certain environmental factors play a critical role in the pathogenesis of Kii ALS/PDC.

Amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Hohara focus of the Kii Peninsula: A multiple proteinopathy?

The high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) has been previously known in the Kii Peninsula of Japan and in Guam. Recently, the accumulation of various proteins, such as tau, trans-activation response DNA binding protein 43 kDa (TDP-43), and alpha-synuclein (αSyn), was reported in the brains of patients with ALS/PDC in Guam. To confirm whether similar findings are present in Kii ALS/PDC, we neuropathologically examined the brains and spinal cords of 18 patients with ALS/PDC (clinical diagnoses: eight ALS and 10 PDC) in Hohara Village, which is the eastern focus of Kii ALS. The average age at death was 71.6 years, and 16 patients (88.9%) had a family history of ALS/PDC. Autopsy specimens were immunohistochemically examined with antibodies against four major proteins. Neurofibrillary tangles, including ghost tangles, and tau-positive astrocytes were distributed widely in all of the brains examined, and TDP-43-positive neuronal cytoplasmic inclusions were observed mainly in the limbic system. Synuclein pathology was present in 14 patients (77.8%). These patients were classified into three pathological subtypes according to the most prominent proteinopathy: the tauopathy-dominant type, the TDP-43 proteinopathy-dominant type, and the synucleinopathy-dominant type. Five patients with severe tau deposition showed clinical features of atypical parkinsonism and dementia with or without motor neuron disease. Eight patients were predominated by phosphorylated TDP-43 inclusions and clinically showed ALS, and five patients were predominated by synuclein pathology and clinically showed signs of PDC. Based on the common characteristic tau pathology, three subtypes seemed to be pathologically continuous on a spectrum of a single disease. Thus, we conclude that ALS/PDC in the Hohara focus of the Kii Peninsula is a single disease characterized neuropathologically by a multiple proteinopathy, even though the clinical manifestations of the three subtypes differed from each other. It remains unclear whether the coexistence of the three proteinopathies was incidental or pathogenetically related.

Neuropsychological study of amyotrophic lateral sclerosis and parkinsonism-dementia complex in Kii peninsula, Japan.

BACKGROUND: The Kii peninsula of Japan is one of the foci of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in the world. The purpose of this study is to clarify the neuropsychological features of the patients with ALS/PDC of the Kii peninsula (Kii ALS/PDC). METHODS: The medical interview was done on 13 patients with Kii ALS/PDC, 12 patients with Alzheimer's disease, 10 patients with progressive supranuclear palsy, 10 patients with frontotemporal lobar degeneration and 10 patients with dementia with Lewy bodies. These patients and their carer/spouse were asked to report any history of abulia-apathy, hallucination, personality change and other variety of symptoms. Patients also underwent brain magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and neuropsychological tests comprising the Mini Mental State Examination, Raven's Colored Progressive Matrices, verbal fluency, and Paired-Associate Word Learning Test and some of them were assessed with the Frontal Assessment Battery (FAB). RESULTS: All patients with Kii ALS/PDC had cognitive dysfunction including abulia-apathy, bradyphrenia, hallucination, decrease of extraversion, disorientation, and delayed reaction time. Brain MRI showed atrophy of the frontal and/or temporal lobes, and SPECT revealed a decrease in cerebral blood flow of the frontal and/or temporal lobes in all patients with Kii ALS/PDC. Disorientation, difficulty in word recall, delayed reaction time, and low FAB score were recognized in Kii ALS/PDC patients with cognitive dysfunction. CONCLUSIONS: The core neuropsychological features of the patients with Kii ALS/PDC were characterized by marked abulia-apathy, bradyphrenia, and hallucination.

SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.

Tau Filaments from Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) adopt the CTE Fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

VPS35 mutation in Japanese patients with typical Parkinson's disease.

Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late-onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor-predominant PD.

An increase in ALS incidence on the Kii Peninsula, 1960-2009: a possible link to change in drinking water source.

We investigated changes in the incidence of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto area (K. area) in the Kii Peninsula, Japan in 1960-2009. Probable and definite ALS cases diagnosed using El Escorial criteria were collected during a five-decade period: period I-V, 1960-2009. Forty-three ALS patients matched the selection criteria in the overall K. area, including three patients on Oshima, a small island opposite the mainland K. area. The age- and gender-adjusted incidence of ALS in the overall K. area (standardized for the 2005 Japanese population) decreased from 5.47/100,000 (95% CI 1.86-9.08) in period I to 0.61/100,000 (95% CI-0.28-1.50) in period III, and then increased to 4.39/100,000 (95% CI 1.70-7.07) in period V. On Oshima, the age- and gender-adjusted incidence of ALS was 9.45/100,000 (95% CI-7.39-26.29) in period V. The present research indicates an increase of ALS incidence in the K. area, especially on Oshima. A limitation of this study was the small population.

Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population.

Our objective was to elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS) with OPTN mutations in the Japanese population. Mutational analysis of OPTN was conducted in 18 FALS pedigrees in whom mutations in other causative genes have been excluded and in 218 SALS patients by direct nucleotide sequence analysis. Novel non-synonymous variants identified in ALS patients were further screened in 271 controls. Results showed that although no mutations were identified in the FALS pedigrees, a novel heterozygous non-synonymous variant c.481G > A (p.V161M) was identified in one SALS patient, who originated from the southernmost part of the Kii Peninsula. The mutation was not present in 271 controls. As the clinical feature, the patient carrying V161M showed predominantly upper motor neuron signs with slow progression. This study suggests that mutations in OPTN are not the main cause of ALS in the Japanese population.

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

BACKGROUND AND OBJECTIVES: 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). METHODS: 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 Aß and tau pathologies. RESULTS: The frequency of the ε4 allele was not different between patients with Kii ALS/PDC and control participants. APOE ε4 was associated with increased Aß 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 Aß pathology (p = 0.383) in patients with Kii ALS/PDC. DISCUSSION: 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 Aß pathology in patients with Kii ALS/PDC.

PLA2G6 variant in Parkinson's disease.

PLA2G6 was reported recently as the causative gene for PARK14-linked autosomal recessive early-onset dystonia-parkinsonism. In a recent study in Singapore, heterozygous PLA2G6 p.P806R (c.2417C>G) mutation in exon 17 was reported to be a possible Parkinson's disease (PD)-related mutation. To determine the significance of the PLA2G6 mutation, we conducted an association study by performing direct sequencing of PLA2G6 exon 17 in 379 Japanese sporadic PD patients and 310 controls in the Japanese general population. In this group, we found 12 patients (12/379=3.16%) and 10 controls (10/310=3.23%) with a heterozygous p.P806R mutation (P=0.96, χ(2)=0.0019). Therefore, our large case-controlled study suggests that PLA2G6 p.P806R is not a disease-associated polymorphism in PD. Moreover, we performed direct sequencing of all exons and exon-intron boundaries of PLA2G6 in 116 Japanese patients with sporadic PD. Two single heterozygous variants (p.R301C or p.D331N) were found (both frequencies: 1/379 patients vs 0/310 controls) and the roles of their variants were unclear. Finally, combined with the previous report, our findings emphasize that PLA2G6 mutations are unlikely to be the major causes or risk factors of PD at least in Asian populations. However, further large studies in various populations are needed because patients with PLA2G6 mutations can show heterogeneous clinical features.

TRPM7 is not associated with amyotrophic lateral sclerosis-parkinsonism dementia complex in the Kii peninsula of Japan.

Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS/PDC) is a distinct neurodegenerative disorder characterized by ALS pathology with neurofibrillary tangles (NFTs) in the spinal cord and brain. Recent clinical studies have revealed a high incidence and a high familial occurrence of ALS/PDC in both Guam and the Kii peninsula of Japan, suggesting a strong genetic predisposition to this disorder. The T1482I variant (rs8042919) of TRPM7 gene which is suggested to play roles in regulating the cellular homeostasis of Ca(2+), Mg(2+), and trace metals, has recently been reported to be associated with Guamanian patients with ALS/PDC. To investigate whether TRPM7 is associated with Kii ALS/PDC, we conducted parametric linkage analyses of the TRPM7 locus in a large extended family with ALS/PDC. Linkage analysis did not reveal any evidence supporting the linkage to the TRPM7 locus. Resequencing of the entire coding region of TRPM7 did not reveal any pathogenic mutations in an affected individual in this family. The allele frequencies of the T1482I in affected individuals in this family or in those from other families are not significantly different from those in regional controls or those in HapMap-JPT samples. These results indicate that TRPM7 is not associated with ALS/PDC in the Kii peninsula of Japan.

Expression of Mutant Ubiquitin and Proteostasis Impairment in Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex Brains.

Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder that is endemic to the Kii peninsula of Japan. The disorder is clinically characterized by a variable combination of parkinsonism, dementia, and motor neuron symptoms. Despite extensive investigations, the etiology and pathogenesis of ALS/PDC remain unclear. At the neuropathological level, Kii ALS/PDC is characterized by neuronal loss and tau-dominant polyproteinopathy. Here, we report the accumulation of several proteins involved in protein homeostasis pathways, that is, the ubiquitin-proteasome system and the autophagy-lysosome pathway, in postmortem brain tissue from a number of Kii ALS/PDC cases (n = 4). Of particular interest is the presence of a mutant ubiquitin protein (UBB+1), which is indicative of disrupted ubiquitin homeostasis. The findings suggest that abnormal protein aggregation is linked to impaired protein homeostasis pathways in Kii 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.

Increased oxidative stress in patients with amyotrophic lateral sclerosis/Parkinsonism-dementia complex in the Kii peninsula, Japan.

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of the Kii peninsula (Kii ALS/PDC) is an endemic and a tauopathy, which shows clinical symptoms of amyotrophy, parkinsonism, and dementia. The objective of this study was to report the role of oxidative stress on Kii ALS/PDC using biochemical analysis. Urinary 8-hydroxydeoxyguanosine (8-OHdG)/creatinine ratio was analyzed in 11 patients with Kii ALS/PDC and 8 normal controls. The mean level of urinary 8-OHdG/creatinine ratio of the patients with Kii ALS/PDC was significantly higher than that of control subjects. Oxidative stress may be implicated in pathogenesis of Kii ALS/PDC.

[The Current State of Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan, 2019].

Recent papers of amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula, Japan (Kii ALS/PDC), published since 2015, were reviewed The studies included transition element of scalp hair analysis, dopaminergic PET study, review of life style changes in the high incident area, neurotoxic BMAA analysis, a clinical report of a migration case, comprehensive neuropathological study, cerebellar tau pathology, nitrative stress in the central nervous system study, optinurin pathology in the spinal cord, and tau PET study. Tau PET was advocated to be a new useful tool for diagnosis, even in the early stage of ALS/PDC with tauopathy. The etiology of Kii ALS/PDC remainds unknown. There are patients and healthy residents within the same environment in the high incidence foci, therefore it is difficult to explain this result by exposure to environmental factors alone. From the genetic viewpoint, rare-disease and rare-variant model may be applied to Kii ALS/PDC. Because there was an immigrant who was diagnosed neuropathologically, and a drastic decrease of the prevalence in the past several decades in the high incident area, it is feasible that Kii ALS/PDC is a multifactorial disease caused by both risk genes and environmental factors. Identifying risk genes and environmental factors for Kii ALS/PDC may contribute to the prevention of neurodegenerative diseases.

Tau imaging detects distinctive distribution of tau pathology in ALS/PDC on the Kii Peninsula.

OBJECTIVE: To characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand. METHODS: This is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP* ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed. RESULTS: A voxel-based comparison of [11C]PBB3 BP* ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP* ND images showed increased BP* ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP* ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (ß-amyloid) except one with marginal positivity. CONCLUSION: [11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.