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Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage
Villarreal S, Zhao F, Hyde LA, Holder D, Forest T, Sondey M, Chen X, Sur C et al.. Journal of Alzheimer's disease : JAD, 2017-01-01
Topic: Drug trials: efficacy and safety
Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice. Animals were treated with verubecestat or controls including the anti-Aβ antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Aβ40 and Aβ42 by >90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Aβ treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aβ antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aβ immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials.
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APA 7th
Villarreal, S., Zhao, F., Hyde, L. A., Holder, D., Forest, T., Sondey, M., et al. (2017). Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage. Journal of Alzheimer's disease : JAD. https://doi.org/10.3233/jad-170056
Vancouver
Villarreal S, Zhao F, Hyde LA, Holder D, Forest T, Sondey M, et al. Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage. Journal of Alzheimer's disease : JAD. 2017. doi:10.3233/jad-170056. PMID: 28800329.
BibTeX
@article{villarreal2017-28800329,
author = {Villarreal, S. and Zhao, F. and Hyde, L. A. and Holder, D. and Forest, T. and Sondey, M. and Chen, X. and Sur, C. and others},
title = {{Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage}},
journal = {Journal of Alzheimer's disease : JAD},
year = {2017},
doi = {10.3233/jad-170056},
pmid = {28800329},
url = {https://doi.org/10.3233/jad-170056}
}
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Key findings
- The ARIA-H profile of verubecestat-treated mice was not significantly different than controls.
- Anti-Aβ treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aβ antibody treatment did not impact plaque status.
- Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load.
- Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aβ immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls.
- The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 57/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for sample size, effect reported and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 33 of the 58 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Alzheimer's disease : JAD) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “tg2576”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28800329) |
| Free to read | 2 / 2 | Free to read |
| Points | 33 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 33 of the 58 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
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