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Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimers disease patients.
INTRODUCTION: The A/T/N (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimers disease (AD) diagnosis and can encompass additional changes such as inflammation (I). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. HIGHLIGHTS: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate
Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia
Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response
Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study
With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology
Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation
Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population
Variable Patterns of Continuous Morphine Infusions at End of Life
BackgroundContinuous morphine infusions (CMIs) treat pain and dyspnea at the end of life (EOL). CMIs may be initiated at an empiric rate and/or are rapidly escalated without proper titration.ObjectiveThe study objective was to evaluate CMI patterns at the EOL.MethodsThis single-center, retrospective chart review evaluated adult patients who died while receiving CMI at EOL. Patient demographics and opioid dosing information were extracted from an electronic medical record. Twenty-four hour IV morphine equivalent was calculated prior to CMI initiation and at the time of death.ResultsOf the 190 patient charts, 63.2% (n=120) received no bolus doses prior to CMI initiation. Mean 24-hour IV morphine equivalent prior to CMI initiation was 49.3 mg (range: 0-1200 mg, SD 384.9) and at time of death was 267.1 mg (12.0-5193.2 mg, SD 442.2), representing an increase of +442%. Mean CMI starting rate was 3.3 mg/hour (0.4-30.0 mg/hour, SD 3.6) with titration at time of death to a mean of 7.7 mg/hour (0.4-70.0 mg/hour, SD 9.4), representing an increase of +130%. Mean number of CMI rate adjustments was 2.5 (0-5, SD 3.3); and number of bolus doses administered between titrations was 4.2 (0-27, SD 4.8). Mean time from CMI initiation to death was 15.5 hours (0.05-126.9 hours, SD 21.7). There was a negative association between rate of infusion increase per hour and total number of hours on CMI (r=-0.2, p=0.0062).ConclusionsHospitalized patients at EOL had a much higher 24-hour IV morphine equivalents and CMI rates at time of death compared to CMI initiation. Variability was observed in the number of CMI rate adjustments and the number of bolus doses administered
Variable Patterns of Continuous Morphine Infusions at End of Life
Background: Continuous morphine infusions (CMIs) treat pain and dyspnea at the end of life (EOL). CMIs may be initiated at an empiric rate and/or are rapidly escalated without proper titration. Objective: The study objective was to evaluate CMI patterns at the EOL. Methods: This single-center, retrospective chart review evaluated adult patients who died while receiving CMI at EOL. Patient demographics and opioid dosing information were extracted from an electronic medical record. Twenty-four hour IV morphine equivalent was calculated prior to CMI initiation and at the time of death. Results: Of the 190 patient charts, 63.2% (n=120) received no bolus doses prior to CMI initiation. Mean 24-hour IV morphine equivalent prior to CMI initiation was 49.3 mg (range: 0–1200 mg, SD 384.9) and at time of death was 267.1 mg (12.0–5193.2 mg, SD 442.2), representing an increase of +442%. Mean CMI starting rate was 3.3 mg/hour (0.4–30.0 mg/hour, SD 3.6) with titration at time of death to a mean of 7.7 mg/hour (0.4–70.0 mg/hour, SD 9.4), representing an increase of +130%. Mean number of CMI rate adjustments was 2.5 (0–5, SD 3.3); and number of bolus doses administered between titrations was 4.2 (0–27, SD 4.8). Mean time from CMI initiation to death was 15.5 hours (0.05–126.9 hours, SD 21.7). There was a negative association between rate of infusion increase per hour and total number of hours on CMI (r=−0.2, p=0.0062). Conclusions: Hospitalized patients at EOL had a much higher 24-hour IV morphine equivalents and CMI rates at time of death compared to CMI initiation. Variability was observed in the number of CMI rate adjustments and the number of bolus doses administered