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Authors: Rafii, Michael S.

Article Type: Review Article

Abstract: In 2013, the Food and Drug Administration released draft guidance on drug development for early-stage Alzheimer's disease (AD). This guidance builds on the understanding that AD is a progressive disease with symptoms appearing long after neurodegeneration has begun. Preclinical AD relies on the conceptual distinction made between the presence of AD pathological processes and clinically observable symptoms. With the advent of new biomarkers that allow for presymptomatic detection of AD pathology, there now exists an opportunity to design and conduct clinical trials of putative disease-modifying drugs in the earliest stages of the disease when they are thought to have the …greatest chance of success. As such, there are four clinical trials planned or underway for the secondary prevention of AD. Show more

Keywords: Clinical trials, preclinical Alzheimer's disease

DOI: 10.3233/JAD-141482

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S545-S549, 2014

Authors: Rafii, Michael S. | Donohue, Michael C. | Matthews, Dawn C. | Muranevici, Gabriela | Ness, Seth | O’Bryant, Sid E. | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Adults with Down syndrome (DS) are at very high risk for Alzheimer’s disease (AD). Neurofilament light (NF-L) has emerged as a potential blood-based biomarker of neurodegeneration due to AD. Objective: To understand the relationship between plasma NF-L with age, brain amyloid, and tau pathology, neurodegeneration as well as cognitive and functional performance. Methods: We analyzed imaging data as well as cognitive measures in relation to plasma NF-L in adults with DS, ages 30 to 60 who were enrolled in the Down Syndrome Biomarker Initiative. Results: We found significant correlations between NF-L plasma concentrations and amyloid pathology (r  = 0.73, p … = 0.007, pa  = 0.041) and significant inverse correlations with regional glucose metabolism in 5 of 6 regions examined, which were Anterior cingulate (r  = –0.55, p  = 0.067, pa  = 0.067), Posterior cingulate r  = –0.90, p  < 0.001, pa  < 0.001), Lateral Temporal (r  = –0.78, p  = 0.004, pa  = 0.012), Frontal cortex (r  = –0.90, p  < 0.001, p pa  < 0.001), Parietal cortex (r  = –0.82, p  = 0.002, pa  = 0.008), Precuneus (r  = –0.73, pa = 0.010, pa  = 0.020), and with hippocampal volume (r  = –0.52, p  = 0.084, pa  = 0.084); and an inverse correlation with direct measures of cognition: CAMCOG (r  = –0.66 p  = 0.022, pa  = 0.066) and positive correlation with CANTAB Paired Associates Learning (PAL) error rate (r  = 0.68, p  = 0.015, pa  = 0.060). Finally, we found inverse relationships with informant-based functional measures (r  = –0.57, p  = 0.059, pa  = 0.084) and OMQ-PF (r  = –0.74, p  = 0.008, pa  = 0.041). Conclusion: Plasma NF-L is associated with progressive neurodegeneration as well as with declines in cognitive and functional measures in adults with DS. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, blood, Down syndrome, neurofilament light, plasma, tau

DOI: 10.3233/JAD-190322

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 131-138, 2019

Authors: Rafii, Michael S. | Skotko, Brian G. | McDonough, Mary Ellen | Pulsifer, Margaret | Evans, Casey | Doran, Eric | Muranevici, Gabriela | Kesslak, Patrick | Abushakra, Susan | Lott, Ira T. | for the ELND005-DS Study Group

Article Type: Research Article

Abstract: Background: ELND005 (scyllo -Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were …randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, Down syndrome, Myo-inositol

DOI: 10.3233/JAD-160965

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 401-411, 2017

Authors: Rafii, Michael S. | Lukic, Ana S. | Andrews, Randolph D. | Brewer, James | Rissman, Robert A. | Strother, Stephen C. | Wernick, Miles N. | Pennington, Craig | Mobley, William C. | Ness, Seth | Matthews, Dawn C. | for the Down Syndrome Biomarker Initiative and the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer’s disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations. Objectives: 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI. Methods: Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility …of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18 F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures. Results: All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures. Conclusions: Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, Down syndrome, Tau PET, volumetric MRI

DOI: 10.3233/JAD-170390

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 439-450, 2017

Authors: Petersen, Melissa E. | Rafii, Michael S. | Zhang, Fan | Hall, James | Julovich, David | Ances, Beau M. | Schupf, Nicole | Krinsky-McHale, Sharon J. | Mapstone, Mark | Silverman, Wayne | Lott, Ira | Klunk, William | Head, Elizabeth | Christian, Brad | Foroud, Tatiana | Lai, Florence | Diana Rosas, H. | Zaman, Shahid | Wang, Mei-Cheng | Tycko, Benjamin | Lee, Joseph H. | Handen, Benjamin | Hartley, Sigan | Fortea, Juan | O’Bryant, Sid | for the Alzheimer’s Biomarker Consortium –Down Syndrome (ABC-DS)

Article Type: Research Article

Abstract: Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD); however, the application of such biomarkers has been limited among the DS population. Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. Methods: Plasma samples were analyzed from n  = 305 (n  = 225 cognitively stable (CS); n  = 44 MCI-DS; n … = 36 DS–AD) participants enrolled in the Alzheimer’s Biomarker Consortium —Down Syndrome. Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs. Show more

Keywords: Neurofilament light chain, proteomics, sensitivity, specificity, total-tau, trisomy 21

DOI: 10.3233/JAD-201167

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 671-681, 2021