Abnormal cytoskeletal pathology peculiar to corticobasal degeneration is different from that of Alzheimer's disease or progressive supranuclear palsy

1994 ◽  
Vol 88 (4) ◽  
pp. 379-383 ◽  
Author(s):  
Toshiki Uchihara ◽  
Kazuko Mitani ◽  
Hiroshi Mori ◽  
Hiromi Kondo ◽  
Masahito Yamada ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progressive Supranuclear Palsy ◽  
Corticobasal Degeneration

scholarly journals Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2398-2405 ◽  
Author(s):  
Shinsuke Ishigaki ◽  
Yuichi Riku ◽  
Yusuke Fujioka ◽  
Kuniyuki Endo ◽  
Nobuyuki Iwade ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alzheimer Disease ◽  
Progressive Supranuclear Palsy ◽  
Corticobasal Degeneration ◽  
Pick's Disease ◽  
Pick’S Disease ◽  
Subsequent Increase ◽  
Fused In Sarcoma ◽  
Wide Range

Abstract Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer’s disease, or Pick’s disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer’s disease or Pick’s disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

scholarly journals Progressive Supranuclear Palsy: A Review of Co-existing Neurodegeneration

2008 ◽  
Vol 35 (5) ◽  
pp. 602-608 ◽  
Author(s):  
J Keith-Rokosh ◽  
L C Ang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neurodegenerative Diseases ◽  
Progressive Supranuclear Palsy ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Pathological Changes ◽  
Subcortical Regions ◽  
Argyrophilic Grains

Objectives:The neuropathological findings of 32 progressive supranuclear palsy (PSP) cases over a period of 17 years were reviewed.Results:Of the 26 cases with adequate clinical data, 20 patients either presented with cognitive dysfunction or developed a cognitive impairment subsequently during the course of the disease. Co-existing changes of argyrophilic grains and corticobasal degeneration (CBD) were found in 28% and 32% of the cases respectively. Alzheimer-related pathology was found in 69% of cases but only 18.75% of cases fulfilled the consortium to establish a registry for Alzheimer's disease (CERAD) criteria for either definite or probable Alzheimer's disease. Lewy bodies were noted in four cases (12.5%), all in the subcortical regions. Only seven cases of PSP showed no pathological evidence of other co-existing neurodegenerative diseases. The severity of the cerebrovascular pathology in this cohort was insufficient to explain any clinical symptomatology.Conclusions:As in previous studies, this study has demonstrated the frequent co-existence of pathological changes usually noted in other neurodegenerative diseases in PSP. Whether these coexisting pathological changes contribute to the cognitive impairment in PSP remains uncertain.

scholarly journals 18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3477-3494 ◽  
Author(s):  
David N Soleimani-Meigooni ◽  
Leonardo Iaccarino ◽  
Renaud La Joie ◽  
Suzanne Baker ◽  
Viktoriya Bourakova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Lobar Degeneration ◽  
Neurofibrillary Tangle ◽  
Corticobasal Degeneration ◽  
Braak Stage ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Normal Controls

Abstract Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34–76); eight female; median PET-to-autopsy interval of 30 months (range 4–59 months)]. Eight patients had primary Alzheimer’s disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80–100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer’s disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer’s disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer’s disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer’s (Braak VI) pathology. However, patients with earlier Braak stages (Braak I–IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer’s disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.

scholarly journals Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies

2021 ◽  
Vol 3 (4) ◽  
Author(s):  
Toshiki Tezuka ◽  
Keisuke Takahata ◽  
Morinobu Seki ◽  
Hajime Tabuchi ◽  
Yuki Momota ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progressive Supranuclear Palsy ◽  
Standardized Uptake Value ◽  
Corticobasal Degeneration ◽  
Post Injection ◽  
Healthy Controls ◽  
Tau Pathology ◽  
Tau Pet

Abstract Tau aggregates represent a key pathologic feature of Alzheimer’s disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer’s disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer’s disease tauopathies compared with Alzheimer’s disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer’s disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [18F]PI-2620 PET (Image acquisition at 60–90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer’s disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer’s disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer’s disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer’s disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60–90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer’s disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer’s disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer’s disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer’s disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

scholarly journals Asparagine residue 368 is involved in Alzheimer's disease tau strain–specific aggregation

2020 ◽  
Vol 295 (41) ◽  
pp. 13996-14014
Author(s):  
Shotaro Shimonaka ◽  
Shin-Ei Matsumoto ◽  
Montasir Elahi ◽  
Koichi Ishiguro ◽  
Masato Hasegawa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Progressive Supranuclear Palsy ◽  
Corticobasal Degeneration ◽  
Terminal Region ◽  
Partial Deletion ◽  
Tau Aggregation ◽  
Asparagine Residue

In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed “tau strains”) and acts as an aggregation “seed” templating the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the C-terminal region (243–406 amino acids (aa)) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited via templated aggregation are still unknown. Here, we sought to identify the key sequences of seed-dependent aggregation. To identify sequences for which deletion reduces tau aggregation, SH-SY5Y cells expressing a series of 10 partial deletion (Del 1–10, covering 244–400 aa) mutants of tau-CTF24 (243–441 aa) were treated with tau seeds prepared from a different tauopathy patient's brain (Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration) or recombinant tau, and then seed-dependent tau aggregation was assessed biochemically. We found that the Del 8 mutant lacking 353–368 aa showed significantly decreased aggregation in both cellular and in vitro models. Furthermore, to identify the minimum sequence responsible for tau aggregation, we systematically repeated cellular tau aggregation assays for the delineation of shorter deletion sites and revealed that Asn-368 mutation suppressed tau aggregation triggered by an AD tau seed, but not using other tauopathy seeds. Our study suggested that 353–368 aa is a novel aggregation-responsible sequence other than PHF6 and PHF6*, and within this sequence, the Asn-368 residue plays a role in strain-specific tau aggregation in different tauopathies.

scholarly journals Azul de Metileno na Paralisia Supranuclear Progressiva, uma possibilidade?

2020 ◽  
Vol 28 ◽  
pp. 1-18
Author(s):  
Celmir de Oliveira Vilaça ◽  
Bruno Lima Pessoa ◽  
Marco Orsini ◽  
Carlos Henrique Melo Reis ◽  
Marco Antonio Alves Azizi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Methylene Blue ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Tau Protein ◽  
Corticobasal Degeneration

Objetivo: Discutir a hipótese do uso do azul de metileno na Paralisia Supranuclear Progressiva. Método: Revisão não sistemática empregando as palavras-chaves “methylene blue” associada aos termos “tauopathies, “tau protein”, “Alzheimer’s Disease”, “Frontotemporal Dementia”, “Progressive Supranuclear Palsy” e “Corticobasal Degeneration”. Discussão: Foram utilizados 45 artigos, todos em inglês para a confecção deste artigo. Conclusão: O uso de inibidores de agregação proteica como o azul de metileno representa importante área de pesquisa para tratamento das tauopatias. Trabalhos realizados com o uso do azul de metileno em tauopatias como a Doença de Alzheimer e a demência frontotemporal sugerem a possibilidade de seu uso na Paralisia Supranuclear Progressiva.

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