Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.

Introduction: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.

Methods: The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22].

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease.

Introduction: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.

Methods: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.

Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature.

Nighttime Sleep and Daytime Sleepiness Improved With Pimavanserin During Treatment of Parkinson's Disease Psychosis.

Introduction: Impaired nocturnal sleep and excessive daytime sleepiness are common problems for patients with Parkinson's disease, and patients with Parkinson's disease with sleep dysfunction are 5 times more likely to experience psychotic symptoms. Pimavanserin, a 5-HT2A inverse agonist approved to treat Parkinson's disease psychosis, may improve sleep quality in patients with Parkinson's disease experiencing sleep disturbances.

Methods: Scales for Outcomes in Parkinson's Disease nighttime sleep (SCOPA-NS) and SCOPA-daytime sleepiness (DS) data obtained during 2 double-blind placebo-controlled studies of pimavanserin in persons with Parkinson's disease psychosis were evaluated.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia.

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.

Neuropsychiatric symptom clusters targeted for treatment at earlier versus later stages of dementia.

Objective: To characterize clusters of neuropsychiatric symptoms targeted for tracking the disease course in people with dementia, in relation to stage.

Methods: Baseline symptoms from 2922 subjects from two datasets (one clinic based, one online) were aggregated. Common neuropsychiatric symptoms identified by patients/carers as targets of treatment using a dementia SymptomGuide™ were selected.

Regional distribution of sodium-dependent excitatory amino acid transporters in rat spinal cord.

Background/objective: The excitatory amino acid transporters (EAATs), or sodium-dependent glutamate transporters, provide the primary mechanism for glutamate removal from the synaptic cleft. EAAT distribution has been determined in the rat brain, but it is only partially characterized in the spinal cord.

Methods: The regional anatomic distribution of EAATs in spinal cord was assessed by radioligand autoradiography throughout cervical, thoracic, and lumbar cord levels in female Sprague-Dawley rats.

Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome.

Amyloid-beta (Abeta) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of Abeta clearance on the development of tau pathology. Here we show that Abeta immunotherapy reduces not only extracellular Abeta plaques but also intracellular Abeta accumulation and most notably leads to the clearance of early tau pathology.

Assessment of behavior in animal models of spinal cord injury.

There has been a significant increase in the amount of research directed at understanding pathologic and behavioral consequences of spinal cord injury (SCI), and attempts to promote recovery of function. Several different approaches can be used to induce SCI; each has particular strengths and weaknesses. Ultimately, behavior is an extremely relevant outcome measure for determining the functional consequences of the initial injury, spontaneous recovery of function, and the efficacy of therapeutic interventions that are developed.

Spatial learning is delayed and brain-derived neurotrophic factor mRNA expression inhibited by administration of MK-801 in rats.

Brain-derived neurotrophic factor (BDNF) is involved in activity-dependent plasticity and interacts with the neurotransmitter glutamate. Glutamate N-methl-D-aspartate (NMDA) receptor activation increases BDNF expression, while BDNF facilitates NMDA activity, with both involved in spatial learning. Administration of the NMDA receptor antagonist MK-801 can impair this leaning.

Immunization with a vaccine that combines the expression of MUC1 and B7 co-stimulatory molecules prolongs the survival of mice and delays the appearance of mouse mammary tumors.

Human epithelial mucin (MUC1) is expressed by many carcinomas, including breast cancer cells. This breast cancer-associated antigen has been widely used for immunotherapy, despite the fact that cellular immune responses to MUC1 are impaired in breast cancer patients and MUC1 transgenic animals. Previously, we found that immunogenicity to MUC1 was also impaired in BALB/c mice injected with a mammary tumor cell line (410.

Exercise increases the vulnerability of rat hippocampal neurons to kainate lesion.

Available evidence suggests that regular, moderate-intensity exercise has beneficial effects on neural health, perhaps including neuroprotection. To evaluate this idea further, we compared the severity of kainate-induced neuronal loss in exercised versus sedentary female rats. Stereological estimations of neuron number revealed that rats in the exercise condition exhibited significantly greater neuron loss in hippocampal region CA2/3, suggesting that high levels of physical activity may increase neuronal vulnerability to excitotoxicity.

Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid.

The role of adjuvant on the T(h)1 and T(h)2 immune responses to Abeta-immunotherapy (Abeta(42 )peptide) was examined in wild-type mice. Fine epitope analysis with overlapping oligomers of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The 6-20 peptide was recognized only weakly by antisera from mice administrated with Abeta(42) peptide formulated in complete Freund's adjuvant (CFA), alum or TiterMax Gold (TMG).

Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum.

Brain-derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise-dependent gene upregulation of this neurotrophin.

Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain.

Granulovacuolar degeneration (GVD) is a diagnostic neuropathological feature of Alzheimer's disease (AD). In some neurons, apoptosis has been hypothesized to be a primary mechanism causing neuronal cell death in AD. In this study we investigated CA1 neurons with GVD in AD and Down's syndrome (DS) brain.