Palatability and Swallowability of Pimavanserin When Mixed with Selected Food Vehicles: An Exploratory Open-Label Crossover Study.

Dysphagia (difficulty swallowing) affects up to 13% of persons 65 years and older and 51% of older persons in nursing homes and can contribute to reduced adherence to oral medications. This was an exploratory, single-center, open-label, randomized, crossover study in healthy older adult participants. Primary objectives were evaluation of palatability (taste) and swallowability of the contents of pimavanserin 34 mg capsules mixed with selected soft foods or a liquid nutritional supplement.

Safety, Tolerability, and Pharmacokinetics of the β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Verubecestat (MK-8931) in Healthy Elderly Male and Female Subjects.

β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of β-amyloid peptides, which are implicated in the etiology of Alzheimer's disease. The safety and pharmacokinetics of the BACE1 inhibitor verubecestat have previously been studied in young adults aged 19-45 years. In this randomized, placebo-controlled, phase I study (protocol MK-8931-006), we investigated the safety, tolerability, and pharmacokinetics of a single dose (100 mg) or multiple doses (30, 80, and 120 mg) once daily for 28 days of verubecestat in healthy elderly subjects.

Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study.

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated.

Brain Imaging of Alzheimer Dementia Patients and Elderly Controls with F-MK-6240, a PET Tracer Targeting Neurofibrillary Tangles.

F-MK-6240 (F-labeled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective, subnanomolar-affinity PET tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of F-MK-6240 in healthy elderly (HE) subjects, subjects with clinically probable Alzheimer disease (AD), and subjects with amnestic mild cognitive impairment were characterized in a study that is, to our knowledge, the first to be performed on humans. Dynamic PET scans of up to 150 min were performed on 4 cognitively normal HE subjects, 4 AD subjects, and 2 amnestic mild cognitive impairment subjects after a bolus injection of 152-169 MBq of F-MK-6240 to evaluate tracer kinetics and distribution in brain.

Multiple comorbid neuropathologies in the setting of Alzheimer's disease neuropathology and implications for drug development.

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients.

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys.

Structures and Rotational Barriers of a Diiodobinorsnoutane: Energetic Preference for Gauche Conformation.

The diiodobinorsnoutane, bi(5-iodopentacyclo[4.3.0.

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man.

Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist.

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter.

Introduction: Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability.

Effect of tubing condensate on non-invasive positive pressure ventilators tested under simulated clinical conditions.

Rationale: Water condensate in the humidifier tubing can affect bi-level ventilation by narrowing tube diameter and increasing airflow resistance. We investigated room temperature and tubing type as ways to reduce condensate and its effect on bi-level triggering and pressure delivery. In this bench study, the aim was to test the hypothesis that a relationship exists between room temperature and tubing condensate.

TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97.

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP7) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster, and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+) (ATPases associated with multiple cellular activities) ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown.

VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death.

Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The disease is characterized neuropathologically by frontal and temporal lobar atrophy, neuron loss and gliosis, and ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen in other sporadic and familial FTLD-U entities. The major component of the ubiquitinated inclusions of FTLD with VCP mutation is TDP-43 (TAR DNA-binding protein of 43 kDa).

Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies.

Accumulation of hyperphosphorylated, ubiquitinated and N-terminally truncated TAR DNA-binding protein (TDP-43) is the pathological hallmark lesion in most familial and sporadic forms of FTLD-U and ALS, which can be subsumed as TDP-43 proteinopathies. In order to get more insight into the role of abnormal phosphorylation in the disease process, the identification of specific phosphorylation sites and the generation of phosphorylation-specific antibodies are mandatory. Here, we developed and characterized novel rat monoclonal antibodies (1D3 and 7A9) raised against phosphorylated S409/410 of TDP-43.

Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies.

Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.

Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.

Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred.

Distinct antemortem profiles in patients with pathologically defined frontotemporal dementia.

Background: Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases.

Objective: To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease.

Design: Retrospective clinical-pathologic survey.

TDP-43: a novel neurodegenerative proteinopathy.

Over the past decade, it has become clear that there is a significant overlap in the clinical spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). The identification of TDP-43 as the major disease protein in the pathology of both frontotemporal lobar degeneration with ubiquitin inclusions and ALS provides the first molecular link for these diseases. Pathological TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved to generate carboxy-terminal fragments in affected brain regions.

TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions.

Background: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U).

Objective: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43).

Design: Retrospective clinical-pathologic study.

Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations.

Background: Patients with frontotemporal dementia due to mutation of progranulin may have a distinct phenotype.

Objective: To identify distinct clinical and pathologic features of patients with frontotemporal dementia who have mutations of progranulin (GRN).

Design: Retrospective clinical-pathologic study.

TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions.

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND.

Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.

Objective: Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies.

Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy.

Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations.

Generation and reactions of Pentacyclo[4.3.0.0(2,4).0(3,8).0(5,7)]non-4-ene.

The highly pyramidalized alkene, pentacyclo[4.3.0.

TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations.

Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a major disease protein in the ubiquitin-positive inclusions of sporadic and familial FTLD-U.