4 results on '"Ma, Thong"'
Search Results
2. Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy.
- Author
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Pucha, Krishna A., Ma, Thong C., York, William, Kang, Un Jung, Kaufmann, Horacio, Kapogiannis, Dimitrios, and Palma, Jose-Alberto
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MULTIPLE system atrophy , *EXTRACELLULAR vesicles , *RAPAMYCIN , *SERUM , *MTOR inhibitors - Abstract
Impaired autophagy is a pathogenic mechanism in the synucleinopathies. Sirolimus, a potent mTOR inhibitor and autophagy activator, had no beneficial effects in a randomized placebo-controlled trial in patients with multiple system atrophy (MSA). Whether sirolimus effectively inhibited brain mTOR activity was unknown. We aimed to evaluate if patients with MSA treated with sirolimus had evidence of inhibited brain mTOR pathways by measuring neuron-derived serum extracellular vesicles (NEVs). Serum samples were collected from participants of the sirolimus-MSA trial, which randomized patients to sirolimus (2–6 mg/day) or placebo for 48 weeks. NEVs were immunoprecipitated with three antibodies-against neurons. Brain mTOR engagement was quantified as the change in the NEV phosphorylated mTOR (p-mTOR) to total-mTOR (tot-mTOR) ratio after 48 weeks of sirolimus. Samples from 27 patients [mean (±SD) age, 59.2±7 years, 15 (55.5%) men] were analyzed (19 sirolimus, 8 placebo). Treated- and placebo-patients had similar p-mTOR:tot-mTOR ratio at 24 (placebo: 0.248 ± 0.03, sirolimus: 0.289 ± 0.02; P = 0.305) and 48 weeks (placebo: 0.299 ± 0.05, sirolimus: 0.261 ± 0.03; P = 0.544). The tot-mTOR, p-mTOR, or their ratio levels were not associated with Unified MSA Rating Scale (UMSARS) worsening. These results are consistent with no brain mTOR engagement by oral sirolimus up to 6 mg/day. NEV-based biomarkers are a rational approach to investigating target engagement in clinical trials of brain-targeted therapeutics. • Sirolimus is an autophagy activator with neuroprotective effects in synucleinopathy models. • A placebo-controlled sirolimus trial in multiple system atrophy (MSA) showed no benefit. • Using blood samples from the trial participants, we isolated neuron-derived extracellular vesicles to measure mTOR biomarkers. • There were no differences in mTOR biomarkers in sirolimus-treated vs placebo patients. • Our results suggest that oral sirolimus did not engage the brain mTOR pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. Metformin therapy in a transgenic mouse model of Huntington's disease
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Ma, Thong C., Buescher, Jessica L., Oatis, Benjamin, Funk, Jason A., Nash, Andrew J., Carrier, Raeann L., and Hoyt, Kari R.
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HUNTINGTON disease , *AMINO acids , *GENETIC disorders , *CHOREA - Abstract
Abstract: Huntington''s disease (HD) is a hereditary neurodegenerative disease that leads to striatal degeneration and a severe movement disorder. We used a transgenic mouse model of HD (the R6/2 line with ∼150 glutamine repeats) to test a new therapy for this disease. We treated HD mice with metformin, a widely used anti-diabetes drug, in the drinking water (0, 2 or 5mg/ml) starting at 5 weeks of age. Metformin treatment significantly prolonged the survival time of male HD mice at the 2mg/ml dose (20.1% increase in lifespan) without affecting fasting blood glucose levels. This dose of metformin also decreased hind limb clasping time in 11-week-old mice. The higher dose did not prolong survival, and neither dose of metformin was effective in female HD mice. Collectively, our results suggest that metformin may be worth further investigation in additional HD models. [Copyright &y& Elsevier]
- Published
- 2007
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4. Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study.
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Ma, Yihua, Farris, Carly M, Weber, Sandrina, Schade, Sebastian, Nguyen, Hieu, Pérez-Soriano, Alexandra, Giraldo, Darly M, Fernández, Manel, Soto, Marta, Cámara, Ana, Painous, Celia, Muñoz, Esteban, Valldeoriola, Francesc, Martí, Maria J, Clarimon, Jordi, Kallunki, Pekka, Ma, Thong Chi, Alcalay, Roy N, Gomes, Bárbara Fernandez, and Blennow, Kaj
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RAPID eye movement sleep , *LEWY body dementia , *PARKINSON'S disease , *BEHAVIOR disorders , *SLEEP disorders , *MULTIPLE system atrophy - Abstract
The pathological hallmarks of multiple system atrophy and Parkinson's disease are, respectively, misfolded-α-synuclein-laden glial cytoplasmic inclusions and Lewy bodies. CSF-soluble misfolded α-synuclein aggregates (seeds) are readily detected in people with Parkinson's disease by α-synuclein seed amplification assay (synSAA), but identification of seeds associated with multiple system atrophy for diagnostic purposes has proven elusive. We aimed to assess whether a novel synSAA could reliably distinguish seeds from Lewy bodies and glial cytoplasmic inclusions. In this multicentre cohort study, a novel synSAA that multiplies and detects seeds by fluorescence was used to analyse masked CSF and brain samples from participants with either clinically diagnosed or pathology-confirmed multiple system atrophy, Parkinson's disease, dementia with Lewy bodies, isolated rapid eye movement sleep behaviour disorder (IRBD), disorders that were not synucleinopathies, or healthy controls. Participants were from eight available cohorts from seven medical centres in four countries: New York Brain Bank, New York, USA (NYBB); University of Pennsylvania, Philadelphia, PA, USA (UPENN); Paracelsus-Elena-Klinik, Kassel, Germany (DeNoPa and KAMSA); Hospital Clinic Barcelona, Spain (BARMSA); Universität Tübingen, Tübingen, Germany (EKUT); Göteborgs Universitet, Göteborgs, Sweden (UGOT); and Karolinska Institutet, Stockholm, Sweden (KIMSA). Clinical cohorts were classified for expected diagnostic accuracy as either research (longitudinal follow-up visits) or real-life (single visit). Sensitivity and specificity were estimated according to pathological (gold standard) and clinical (reference standard) diagnoses. In 23 brain samples (from the NYBB cohort), those containing Lewy bodies were synSAA-positive and produced high fluorescence amplification patterns (defined as type 1); those containing glial cytoplasmic inclusions were synSAA-positive and produced intermediate fluorescence (defined as type 2); and those without α-synuclein pathology produced below-threshold fluorescence and were synSAA-negative. In 21 pathology-confirmed CSF samples (from the UPENN cohort), those with Lewy bodies were synSAA-positive type 1; those with glial cytoplasmic inclusions were synSAA-positive type 2; and those with four-repeat tauopathy were synSAA-negative. In the DeNoPa research cohort (which had no samples from people with multiple system atrophy), the novel synSAA had sensitivities of 95% (95% CI 88–99) for 80 participants with Parkinson's disease and 95% (76–100) for 21 participants with IRBD, and a specificity of 95% (86–99) for 60 healthy controls. Overall (combining BARMSA, EKUT, KAMSA, UGOT, and KIMSA cohorts that were enriched for cases of multiple system atrophy), the novel synSAA had 87% sensitivity for multiple system atrophy (95% CI 80–93) and specificity for type 2 seeds was 77% (67–85). For participants with multiple system atrophy just in research cohorts (BARMSA and EKUT), the novel synSAA had a sensitivity of 84% (95% CI 71–92) and a specificity for type 2 seeds of 87% (74–95), whereas cases from real-life cohorts (KAMSA, KIMSA, and UGOT) had a sensitivity of 91% (95% CI 80–97) but a decreased specificity for type 2 seeds of 68% (53–81). The novel synSAA produced amplification patterns that enabled the identification of underlying α-synuclein pathology, showing two levels of fluorescence that corresponded with different pathological hallmarks of synucleinopathy. The synSAA might be useful for early diagnosis of synucleinopathies in clinical trials, and potentially for clinical use, but additional formal validation work is needed. Michael J Fox Foundation for Parkinson's Research, Amprion. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
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