Donanemab immunogenicity in participants with early symptomatic Alzheimer's disease.

Introduction: Donanemab is an immunoglobulin G1 antibody that targets an N-terminal truncated form of amyloid beta present in mature plaques. Treatment-emergent (TE) anti-drug antibodies (ADAs) were quantified in donanemab-treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed.

Methods: Data were pooled from the phase 2 TRAILBLAZER-ALZ (NCT03367403) and phase 3 TRAILBLAZER-ALZ 2 trials (NCT04437511).

The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6.

The TRAILBLAZER-ALZ 6 study (NCT05738486) evaluated the effect of different donanemab dosing regimens on amyloid-related imaging abnormalities with edema/sulcal effusions (ARIA-E). The modified titration arm met the primary outcome and significantly reduced ARIA-E frequency compared with the standard dosing while maintaining a similar pharmacodynamic effect on amyloid reduction at 24 weeks. Primary outcome and 52-week data were previously published.

TRAILBLAZER-ALZ 4: A phase 3 trial comparing donanemab with aducanumab on amyloid plaque clearance in early, symptomatic Alzheimer's disease.

Introduction: The phase 3, open-label TRAILBLAZER-ALZ 4 study compared the effect of donanemab versus aducanumab on amyloid plaque (AP) clearance in participants with early symptomatic Alzheimer's disease.

Methods: Participants (n = 148) were randomized 1:1 to receive intravenous donanemab (700 mg every 4 weeks for three doses, then 1400 mg every 4 weeks thereafter) or aducanumab (per label). AP was measured with florbetapir F 18 positron emission tomography.

Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction.

Introduction: TRAILBLAZER-ALZ 6 (NCT05738486) is a multicenter, double-blind, ongoing phase 3b study in early symptomatic Alzheimer's disease.

Methods: Participants (n = 843) were randomized 1:1:1:1 (standard + three alternative donanemab dosing arms). Primary outcome was relative risk reduction (RRR) of amyloid-related imaging abnormalities with edema/effusions (ARIA-E) at 24 weeks assessed with Bayesian logistic regression.

Amyloid-Related Imaging Abnormalities With Donanemab in Early Symptomatic Alzheimer Disease: Secondary Analysis of the TRAILBLAZER-ALZ and ALZ 2 Randomized Clinical Trials.

Importance: Amyloid-related imaging abnormalities (ARIA) are the major adverse event associated with amyloid-targeting immunotherapy. Identifying clinical features and individual risk factors for ARIA could facilitate effective prediction and prevention strategies.

Objective: To characterize ARIA in participants treated with donanemab.

Using Clinical Scales and Digital Measures to Explore Falls in Patients with Lewy Body Dementia.

Introduction: PRESENCE was a phase 2 clinical trial assessing the efficacy of mevidalen, a D1 receptor positive allosteric modulator, for symptomatic treatment of Lewy body dementia (LBD). Mevidalen demonstrated improvements in motor and non-motor features of LBD, global functioning, and actigraphy-measured activity and daytime sleep. Adverse events (AEs) of fall were numerically increased in mevidalen-treated participants.

Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial.

Background: Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype.

Objective: To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).

Methods: PRESENCE was a phase 2, 12-week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo.

Effects of Lasmiditan on Cardiovascular Parameters and Pharmacokinetics in Healthy Subjects Receiving Oral Doses of Propranolol.

Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with β-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions.

Drug-Induced Steatosis and Steatohepatitis: The Search for Novel Serum Biomarkers Among Potential Biomarkers for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.

Drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH) are two of several types of drug-induced liver injury (DILI). They can be caused by various drugs and may present as acute, potentially lethal disorders or as chronic slowly progressive liver injury. Despite the fact that they are distinct disorders, the slow progressive forms of DIS and DISH are often confused with or misdiagnosed as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are much more common and, by definition, not caused by drugs.

Consequences of constitutive deletion of melanin-concentrating hormone-1 receptors for feeding and foraging behaviors of mice.

In order to decipher the functional involvement of melanin-concentrating hormone 1 (MCH1) receptors in the control of feeding and foraging behaviors, mice with constitutive deletion of MCH1 receptors MCH1R -/- or knockout (KO) were studied and compared to age-matched littermate control mice (MCH1R +/+ or wildtype (WT)). Several challenges to food-motivated behaviors of food-restricted WT and KO mice were implemented. There were no differences between genotypes in the acquisition of a nose-poke response that produced food or in a discrimination between a response that produced food and one that did not.

Pitx3 deficient mice as a genetic animal model of co-morbid depressive disorder and parkinsonism.

Approximately 40-50% of all patients with Parkinson׳s disease (PD) show symptoms and signs of depressive disorders, for which neither pathogenic understanding nor rational treatment are available. Using Pit3x-deficient mice, a model for selective nigrostriatal dopaminergic neurodegeneration, we tested depression-related behaviors and acute stress responses to better understand how a nigrostriatal dopaminergic deficit increases the prevalence of depressive disorders in PD patients. Pitx3-deficient mice showed decreased sucrose consumption and preference in the two-bottle free-choice test of anhedonia.

Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression.

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one], was evaluated using ex vivo binding with autoradiography.

The 5-hydroxytryptamine2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat.

Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic "antidepressant-like" effects of a 5-HT(2A) receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT(2A) receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT(2A) receptor blockade may exert effects on impulsivity, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.

Impaired learning and memory in Pitx3 deficient aphakia mice: a genetic model for striatum-dependent cognitive symptoms in Parkinson's disease.

Disorders of the basal ganglia such as Parkinson's disease (PD) and Huntington's disease are commonly thought of primarily as motor disorders; however, the cognitive symptoms of these diseases such as executive dysfunction, learning, memory and attention deficits are prominent and often more disabling than the hallmark motor symptoms. Cognitive features of PD are often neglected in preclinical studies of PD, likely due to the lack of available animal models to study them. Aphakia mice, which are deficient in the transcription factor Pitx3, model the selective nigrostriatal DA loss in PD.

Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice.

Chronic hypercortisolemia is a hallmark of neuroendocrine and psychiatric disorders, such as Cushing's disease and depression. Whether cortisol directly contributes to the altered mood and anxiety symptoms seen in these diseases remains unclear. To address this, the authors have modeled hypercortisolemia by administering corticosterone in the drinking water of female Swiss Webster mice for 17 or 18 days (13 mg/kg).

3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. There is a need for genetic animal models of PD for screening and in vivo testing of novel restorative therapeutic agents. Although current genetic models of PD produce behavioral impairment and nigrostriatal dysfunction, they do not reproduce the loss of midbrain dopaminergic neurons and 3,4-dihydroxyphenylalanine (L-DOPA) reversible behavioral deficits.

Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice.

Dopaminergic (DA) neurons in the ventral midbrain nuclei, substantia nigra pars compacta (SNc, A9) and ventral tegmental area (VTA, A10), play important roles in the control of movement, emotion, cognition, and reward related behavior. Although several transcription factors have been shown to be critical for midbrain DA neuron development, there has been no report of factor(s) that differentially regulate individual DA neuronal groups. Based on its highly restricted expression in the SNc and VTA in the brain, we hypothesize that the homeobox transcription factor Pitx3 may critically regulate the development of ventral midbrain DA neurons.