This randomized clinical trial evaluates the safety and efficacy of the monoclonal anti-tau antibody semorinemab in individuals with prodromal to mild Alzheimer disease.
Background The role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer’s disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [18F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months. Methods Our analyses incorporated data from 67 participants, including cognitively normal controls (n = 10) and β-amyloid (Aβ)-positive individuals ([18F] florbetapir Aβ PET) with prodromal (n = 26), mild (n = 16), or moderate (n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([18F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month period. Associations between baseline [18F]GTP1 tau PET indices and longitudinal cognitive performance were assessed via univariate (Spearman correlations) and multivariate (linear mixed effects models) approaches. The utility of potential prognostic tau PET cut points was assessed with ROC curves. Results Univariate analyses indicated that greater baseline [18F]GTP1 tau PET signal was associated with faster rates of subsequent decline on the MMSE, CDR, and ADAS-Cog13 across regions of interest (ROIs). In multivariate analyses adjusted for baseline age, cognitive performance, cortical volume, and Aβ PET SUVR, the prognostic performance of [18F]GTP1 SUVR was most robust in the whole cortical gray ROI. When AD participants were dichotomized into low versus high tau subgroups based on baseline [18F]GTP1 PET standardized uptake value ratios (SUVR) in the temporal (cutoff = 1.325) or whole cortical gray (cutoff = 1.245) ROIs, high tau subgroups demonstrated significantly more decline on the MMSE, CDR, and ADAS-Cog13. Conclusions Our results suggest that [18F]GTP1 tau PET represents a prognostic biomarker in AD and are consistent with data from other tau PET tracers. Tau PET imaging may have utility for identifying AD patients at risk for more rapid cognitive decline and for stratification and/or enrichment of participant selection in AD clinical trials. Trial registration ClinicalTrials.gov NCT02640092. Registered on December 28, 2015
Background White matter hyperintensities (WMH) on MRI are commonly seen in Alzheimer’s disease (AD) and thought to represent co‐morbid microvascular ischemic disease. However, the relationship between WMH and tau pathology in AD remains incompletely understood. We explored this question using screening/baseline data from a Phase 2 study of the anti‐tau antibody semorinemab (Tauriel; NCT03289143), which included both MRI and [18F]GTP1 tau PET imaging. Method Participants in the Tauriel study are aged 50‐80, meet criteria for AD dementia or mild cognitive impairment (MCI), have MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, evidence of significant amyloid pathology, and significant episodic memory impairment (RBANS delayed memory index < 85), and undergo screening MRIs, with WMH quantified using the Fazekas scale. Analyses were performed on a subset of participants (n=381) who received baseline [18F]GTP1 tau PET scans. Relationships between WMH, [18F]GTP1 SUVR in an AD‐specific temporal lobe ROI, age, and cognitive scales were assessed graphically and quantified using Pearson correlations, Cohen’s D, t‐tests, and multiple linear regression. Result Tauriel participants had Fazekas scores of zero (n=161), one (n=208), or two (n=12). Per the Figure, participants with Fazekas scores > 0 tended to be older (Cohen’s D=0.69, p < 0.001) and have lower temporal [18F]GTP1 SUVR (Cohen’s D=0.35, p<0.001). The relationship between temporal [18F]GTP1 SUVR and baseline ADAS‐Cog13 (r=0.39, p<0.001) remained significant after adjusting for Fazekas score and age via multiple regression (p<0.001). Conclusion Given the circumscribed range of disease severity seen in prodromal‐to‐mild AD participants at screening/baseline in the Tauriel study, the relationships between MRI WMH and [18F]GTP1 tau PET suggest that these pathologies have additive and independent contributions to cognition that may be age‐related. Clinical trials of anti‐tau therapeutics in similar patient populations may need to account for cerebrovascular co‐morbidities in patient selection and/or efficacy analyses.
Background In prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer’s disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD. Method We analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression. Result Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p’s<0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p’s<0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR. Conclusion Amongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline.
Background:The Tauriel Study (NCT03289143) was a Phase 2 randomized, doubleblind, placebo-controlled, parallel-group clinical trial that assessed the safety and efficacy of semorinemab in patients with prodromal-to-mild Alzheimer's disease over 73 weeks. We sought to assess the longitudinal performance of tau PET imaging and to determine the relationships between the multiple imaging and cognitive endpoints that were collected. Method: Cognitive testing, [ 18 F]GTP1 PET, and volumetric MRI imaging were performed at baseline, Week 49 and Week 73. Relationships between imaging and cognitive endpoints were assessed with Spearman correlations. Standardized change from baseline among imaging and cognitive endpoints were compared using Cohen's D. Result: 375 participants had evaluable [18F]GTP1 tau PET scans at baseline. On average, [18F]GTP1 SUVR in a temporal metaROI (mean = 1.56, SD = 0.28) was significantly higher than SUVR in whole cortical gray matter (mean = 1.33, SD = 0.25). In spite of the heterogenous localization of baseline [18F]GTP1 signal within and across subjects, longitudinal changes in tau PET were spatially more uniform: whole cortical gray SUVR and temporal meta ROI performed similarly at Week 73 in terms of standardized longitudinal change (Cohen's D = 0.61 and 0.65, respectively). Furthermore, correlations between local baseline SUVR, as parcellated across cortical Hammers Atlas ROIs, and change from baseline to week 73 were low (Avg Spearman r = 0.14, range = [-0.34, 0.37]). Conclusion:The Tauriel trial successfully enrolled a prodromal-to-mild AD patient population that progressed on both clinical and imaging endpoints that were statistically sensitive to detect potential treatment effects. However, correlations between changes in imaging and cognitive endpoints were low. Longer observation periods may further elucidate the associations between imaging and clinical endpoints.
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