Your search for: 'author:("Wischik, Claude M.")' has returned 11 results. (0.015s) Save search

Authors: Wischik, Claude M.

Article Type: Obituary

DOI: 10.3233/JAD-2007-11102

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 3-5, 2007

Authors: Wischik, Claude M.

Article Type: Other

DOI: 10.3233/JAD-2007-11103

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 7-9, 2007

Authors: Bentham, Peter | Staff, Roger T. | Schelter, Bjoern O. | Shiells, Helen | Harrington, Charles R. | Wischik, Claude M.

Article Type: Short Communication

Abstract: One of the mutations in the microtubule-associated protein tau, P301S, is causative for dominantly inherited frontotemporal dementia characterized by extensive tau pathology for which no licensed treatment is available. Hydromethylthionine is a potent tau aggregation inhibitor. We report treatment of an asymptomatic carrier of the P301S mutation using hydromethylthionine over a 5-year period beginning at the mean age of onset of clinical decline in the family. During the period of treatment, the rates of progression of cerebral atrophy were reduced by 61%–66% in frontal and temporal lobes, and the patient remained clinically asymptomatic.

Keywords: Frontotemporal dementia, hydromethylthionine, leucomethylthioninium, microtubule-associated protein tau, P301S

DOI: 10.3233/JAD-210390

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1017-1023, 2021

Authors: Wischik, Claude M. | Schelter, Björn O. | Wischik, Damon J. | Storey, John M. D. | Harrington, Charles R.

Article Type: Review Article

Abstract: Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer’s disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro , or “prion-like processing”, that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical …trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD. Show more

Keywords: Alzheimer’s disease, clinical trials, paired helical filaments, prion-like processing, protein aggregation inhibitors, tau protein

DOI: 10.3233/JAD-170727

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1287-1303, 2018

Authors: Anschuetz, Anne | Schwab, Karima | Harrington, Charles R. | Wischik, Claude M. | Riedel, Gernot

Article Type: Systematic Review

Abstract: Background: A key aspect of synaptic dysfunction in Alzheimer’s disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity. Objective: The objective of this meta-analysis was to provide an update on the available literature and to further characterize patterns of presynaptic protein loss in AD. Methods: Systematic literature search was conducted for studies published between 2015–2022 which quantified presynaptic proteins in postmortem tissue from AD patients and healthy controls. Three-level random …effects meta-analyses of twenty-two identified studies was performed to characterize overall presynaptic protein loss and changes in specific regions, proteins, protein families, and functional categories. Results: Meta-analysis confirmed overall loss of presynaptic proteins in AD patients. Subgroup analysis revealed region specificity of protein loss, with largest effects in temporal and frontal cortex. Results concerning different groups of proteins were also highly variable. Strongest and most consistently affected was the family of synaptosome associated proteins, especially SNAP25. Among the most severely affected were proteins regulating dense core vesicle exocytosis and the synaptic vesicle cycle. Conclusions: Results confirm previous literature related to presynaptic protein loss in AD patients and provide further in-depth characterization of most affected proteins and presynaptic functions. Show more

Keywords: Alzheimer’s disease, meta-analysis, presynaptic terminals, synaptic vesicles

DOI: 10.3233/JAD-231034

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 145-162, 2024

Authors: Wischik, Claude M. | Staff, Roger T. | Wischik, Damon J. | Bentham, Peter | Murray, Alison D. | Storey, John M.D. | Kook, Karin A. | Harrington, Charles R.

Article Type: Short Communication

Abstract: Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks …relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: −5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD. Show more

Keywords: Alzheimer's disease, controlled clinical trial, intervention studies, methylthioninium, safety, tau protein

DOI: 10.3233/JAD-142874

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 705-720, 2015

Authors: Hernandes-Alejandro, Mario | Montaño, Sarita | Harrington, Charles R. | Wischik, Claude M. | Salas-Casas, Andrés | Cortes-Reynosa, Pedro | Pérez Salazar, Eduardo | Cazares-Apatiga, Javier | Apatiga-Perez, Ricardo | Ontiveros Torres, Miguel Ángel | Perry, George | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer’s disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs). Objective: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD. Methods: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot …and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein. Results: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein. Conclusion: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development. Show more

Keywords: Alzheimer’s disease, matrix metalloproteinase-9, molecular dynamics simulation, protein-protein docking, tau protein

DOI: 10.3233/JAD-200146

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 553-569, 2020

Authors: Schelter, Bjoern O. | Shiells, Helen | Baddeley, Thomas C. | Rubino, Christopher M. | Ganesan, Harish | Hammel, Jeffrey | Vuksanovic, Vesna | Staff, Roger T. | Murray, Alison D. | Bracoud, Luc | Riedel, Gernot | Gauthier, Serge | Jia, Jianping | Bentham, Peter | Kook, Karin | Storey, John M.D. | Harrington, Charles R. | Wischik, Claude M.

Article Type: Research Article

Abstract: Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response relationships for steady state plasma levels …in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit. Conclusions: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer’s disease, clinical trials, drug interaction, leucomethylthioninium, population pharmacokinetics, hydromethylthionine

DOI: 10.3233/JAD-190772

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 931-946, 2019

Authors: Wilcock, Gordon K. | Gauthier, Serge | Frisoni, Giovanni B. | Jia, Jianping | Hardlund, Jiri H. | Moebius, Hans J. | Bentham, Peter | Kook, Karin A. | Schelter, Bjoern O. | Wischik, Damon J. | Davis, Charles S. | Staff, Roger T. | Vuksanovic, Vesna | Ahearn, Trevor | Bracoud, Luc | Shamsi, Kohkan | Marek, Ken | Seibyl, John | Riedel, Gernot | Storey, John M.D. | Harrington, Charles R. | Wischik, Claude M.

Article Type: Research Article

Abstract: Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n  = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n  = 79) versus 4 mg twice a day as randomized (n  = 396), and 4 mg twice a day as monotherapy (n  = 76) …versus 4 mg twice a day as add-on therapy (n  = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p  < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis. Show more

Keywords: ADAS-cog, Alzheimer’s disease, amyloid protein, clinical trial, cohort study, methylthioninium, tau protein, treatment

DOI: 10.3233/JAD-170560

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 435-457, 2018

Authors: Flores-Rodríguez, Paola | Harrington, Charles R. | Wischik, Claude M. | Ibarra-Bracamontes, Vanessa | Zarco, Natanael | Navarrete, Araceli | Martínez-Maldonado, Alejandra | Guadarrama-Ortíz, Parménides | Villanueva-Fierro, Ignacio | Ontiveros-Torres, Miguel Angel | Perry, George | Alonso, Alejandra D. | Floran-Garduño, Benjamin | Segovia, José | Luna-Muñoz, José

Article Type: Research Article

Abstract: It has been reported that the main function of tau protein is to stabilize microtubules and promote the movement of organelles through the axon in neurons. In Alzheimer’s disease, tau protein is the major constituent of the paired helical filament, and it undergoes post-translational modifications including hyperphosphorylation and truncation. Whether other functions of tau protein are involved in Alzheimer’s disease is less clear. We used SH-SY5Y human neuroblastoma cells as an in vitro model to further study the functions of tau protein. We detected phosphorylated tau protein as small dense dots in the cell nucleus, which strongly colocalize with intranuclear …speckle structures that were also labelled with an antibody to SC35, a protein involved in nuclear RNA splicing. We have shown further that tau protein, phosphorylated at the sites recognized by pT231, TG-3, and AD2 antibodies, is closely associated with cell division. Different functions may be characteristic of phosphorylation at specific sites. Our findings suggest that the presence of tau protein is involved in separation of sister chromatids in anaphase, and that tau protein also participates in maintaining the integrity of the DNA (pT231, prophase) and chromosomes during cell division (TG-3). Show more

Keywords: Alzheimer’s disease, cell cycle, phospho-tau protein, SC35, SH-SY5Y, staurosporine

DOI: 10.3233/JAD-190155

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 631-645, 2019