Browsing by Author "Siemers, Eric"

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    Assessing quality of life in Alzheimer's disease: Implications for clinical trials
    (Elsevier, 2016-12-13) Kahle-Wrobleski, Kristin; Ye, Wenyu; Hake, Ann Marie; Siemers, Eric; Chen, Yun-Fei; Liu-Seifert, Hong; Department of Psychiatry, IU School of Medicine
    Introduction Characterization of the quality of life (QOL) in Alzheimer's disease (AD) scale within the context of a clinical trial may inform its applicability in future trials. Methods Using data from 1322 patients enrolled in two phase-III studies (EXPEDITION 1 [NCT00905372] and 2 [NCT00904683]) of intravenous solanezumab in outpatients with mild AD dementia, correlations between patient- and caregiver-assessed QOL and between QOL and clinical outcome measures were examined. Longitudinal effects of solanezumab over 80 weeks were explored, controlling for patient and caregiver baseline characteristics. Results Caregivers rated patients' QOL worse than did patients themselves. Patients' QOL was correlated, albeit modestly, with clinical/health measures. Patients' QOL changed minimally over 80 weeks, although a treatment effect of solanezumab on QOL was detected. Discussion Further investigations are needed to determine the optimal measures with which to quantify and qualify QOL of patients with mild AD.
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    Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer’s Disease
    (IOS, 2015-07) Liu-Seifert, Hong; Siemers, Eric; Price, Karen; Han, Baoguang; Selzler, Katherine J.; Henley, David; Sundell, Karen; Aisen, Paul; Cummings, Jeffrey; Raskin, Joel; Mohs, Richard; Department of Neurological Surgery, IU School of Medicine
    Abstract Background: The temporal relationship of cognitive deficit and functional impairment in Alzheimer’s disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. Objective: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. Methods: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. Results: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. Conclusions: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.
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    Sabirnetug (ACU193) Lowers CSF Levels of Synaptic Biomarkers in INTERCEPT‐AD Phase 1 Study in Early AD
    (Wiley, 2025-01-09) Cline, Erika N.; Johnson, Elizabeth; Sundell, Karen; Antwi-Berko, Daniel; Koel-Simmerlink, Marleen J. A.; Teunissen, Charlotte; Siemers, Eric; Zhang, Hao; Hyland, Maddelyn; Sethuraman, Gopalan; Vanderstichele, Hugo; Kaplow, June; Dean, Robert A.; Jerecic, Jasna; Pathology and Laboratory Medicine, School of Medicine
    Background: Sabirnetug (ACU193) is a humanized IgG2 antibody targeting soluble, synaptotoxic amyloid β oligomers (AβOs). AβOs accumulate in Alzheimer’s disease (AD) and induce pre‐ and post‐synaptic changes, resulting in dendritic spine loss, neuronal degeneration, and release of synaptic proteins into the CSF. Recently, we reported that three administrations of sabirnetug in an early AD population (INTERCEPT‐AD Phase 1 study, NCT04931459) significantly lowered CSF levels of the post‐synaptic protein neurogranin as well as pTau181. Here, we present data on additional CSF synaptic biomarkers and AD plasma biomarkers measured in INTERCEPT‐AD. Method: INTERCEPT‐AD was a randomized, placebo‐controlled study with two parts: single ascending dose (SAD) randomized in a 6:2 ratio to sabirnetug (2, 10, 25, 60 mg/kg) or placebo and multiple ascending dose (MAD) randomized 8:2 to sabirnetug (three administrations at 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) or placebo. Biomarkers were measured blinded in CSF and EDTA‐plasma, before and after drug administration, by Amsterdam UMC. Result: CSF levels of vesicle‐associated membrane protein 2 (VAMP2), a protein involved in pre‐ and post‐synaptic vesicle trafficking, were significantly normalized (lowered) in sabirnetug treated participants relative to placebo in all three MAD cohorts. Levels of the pre‐synaptic protein neuronal pentraxin 2 (NPTX2), which acts on post‐synaptic excitatory synapses, regulates complement activity, and lowers with cognitive decline, trended lower with sabirnetug than placebo. Plasma levels of GFAP, pTau181, and pTau217 trended towards normalization (lowering) of AD‐dependent changes in the 60 mg/kg Q4W cohort. Conclusion: In INTERCEPT‐AD, three administrations of sabirnetug lowered CSF levels of both pre‐ and post‐synaptic proteins, consistent with sabirnetug’s proposed mechanism of action to inhibit AβO synaptic binding. VAMP2 appeared most sensitive to sabirnetug in this study, lowering significantly in all three MAD cohorts; other markers previously reported to have a statistically significant response to sabirnetug ‐ neurogranin and pTau181 ‐ did so at the highest dose. No statistically significant changes in plasma biomarkers were observed in this short study. Long‐term changes in biomarker levels and their relationship to clinical efficacy will be evaluated in the 18‐month ALTITUDE‐AD phase 2 study of sabirnetug beginning in the first half of 2024.
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    Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease
    (2018-01) Honig, Lawrence S.; Vellas, Bruno; Woodward, Michael; Boada, Mercè; Bullock, Roger; Borrie, Michael; Hager, Klaus; Andreasen, Niels; Scarpini, Elio; Liu‑Seifert, Hong; Case, Michael; Dean, Robert A.; Hake, Ann; Sundell, Karen; Hoffmann, Vicki Poole; Carlson, Christopher; Khanna, Rashna; Mintun, Mark; DeMattos, Ronald; Selzler, Katherine J.; Siemers, Eric; Pathology and Laboratory Medicine, School of Medicine
    BACKGROUND Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer’s disease did not significantly affect cognitive decline.