Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study.

Positron emission tomography (PET) is frequently used to obtain target occupancy (%TO) of central nervous system (CNS) drug candidates during clinical development. Obtaining %TO with PET can be particularly powerful when the %TO associated with efficacy is known for a protein target. Using the radiotracer [F]AV-133, the relationship between plasma concentration (PK) and %TO of NBI-750142, an experimental inhibitor of the vesicular monoamine transporter type 2 (VMAT2) was obtained in both nonhuman primate (NHP) and human.

Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease.

Introduction: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models.

In Vivo Head-to-Head Comparison of [F]GTP1 with [F]MK-6240 and [F]PI-2620 in Alzheimer Disease.

Alzheimer disease (AD) is characterized by the accumulation of tau neurofibrillary tangles that can be labeled with PET tracers. Multiple tau PET tracers have been used in clinical studies, including [F]GTP1, [F]PI-2620, and [F]MK-6240. Standardized harmonization scales for comparing tau PET signals across tracers are currently under development and can be informed by comparisons of signals between tracers in both target and off-target regions of the brain.

The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases.

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson's disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls.

Trial of Prasinezumab in Early-Stage Parkinson's Disease.

Background: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease.

Methods: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks.

Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study.

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials.

Binding characteristics of [F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET.

The novel tau-PET tracer [F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated.

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome.

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR) in knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR expression in humans with FXS exposed to NAMs might help in that effort.

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Clinical evaluation of [F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer's disease.

Purpose: The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer's disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer's disease to age-matched healthy controls.

Early-phase [F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

Purpose: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [F]PI-2620 as a potential substitute for [F]fluorodeoxyglucose ([F]FDG).

Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.

Objective: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.

Methods: The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.

F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study.

Objective: F-flortaucipir (formerly F-AV1451 or F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).

Methods: Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β ( C-PiB or F-florbetapir) and tau ( F-flortaucipir).

A randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early Parkinson's disease.

Background: Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD.

Methods: Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.

Clinical utility of DaTscan™ imaging in the evaluation of patients with parkinsonism: a US perspective.

Single photon emission computed tomography (SPECT) with Ioflupane I123 injection (DaTscan™) was approved by the Food and Drug Administration in 2011 for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. While brain SPECT imaging using DaTscan is a covered service under Medicare policy, there is a lack of consensus on its role in routine clinical practice in the US. Areas covered: To address this issue, an expert group of US-based movement disorders neurologists convened to discuss the clinical utility of DaTscan in movement disorders practices within the US.

Change in PDE10 across early Huntington disease assessed by [18F]MNI-659 and PET imaging.

Objective: To evaluate whether striatal [(18)F]MNI-659 PET imaging of phosphodiesterase 10A (PDE10) serves as a sensitive and reliable biomarker of striatal neurodegeneration in a longitudinal cohort of participants with early Huntington disease (HD).

Methods: A cohort of participants with HD, including both participants premanifest or manifest with motor signs, underwent clinical assessments, genetic determination, and 2 [(18)F]MNI-659 PET imaging sessions approximately 1 year apart. Eleven healthy control (HC) participants underwent clinical assessments and [(18)F]MNI-659 PET imaging once.

Impact of Depression on Progression of Impairment and Disability in Early Parkinson's Disease.

Background: Depression is one of the most common nonmotor symptoms associated with Parkinson's disease (PD), yet the impact of depression on progression of disease is unclear.

Objective: The aim of this study was to prospectively characterize the relationship between depressive symptoms and measures of disease progression in a large sample of patients with early, medically treated PD.

Methods: Baseline and longitudinal Beck Depression Inventory (BDI) scores from participants in the NINDS Exploratory Trials in PD Long Term Study 1 were correlated with changes in multiple measures of disease severity over 5 years.

The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease.

Importance: In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need.

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

Clinical comparison of 99mTc exametazime and 123I Ioflupane SPECT in patients with chronic mild traumatic brain injury.

Background: This study evaluated the clinical interpretations of single photon emission computed tomography (SPECT) using a cerebral blood flow and a dopamine transporter tracer in patients with chronic mild traumatic brain injury (TBI). The goal was to determine how these two different scan might be used and compared to each other in this patient population.

Methods And Findings: Twenty-five patients with persistent symptoms after a mild TBI underwent SPECT with both (99m)Tc exametazime to measure cerebral blood flow (CBF) and (123)I ioflupane to measure dopamine transporter (DAT) binding.

Kinetic modeling, test-retest, and dosimetry of 123I-MNI-420 in humans.

Unlabelled: In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of (123)I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain.

Methods: Nine healthy human subjects were enrolled in this study; 7 completed (123)I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating (123)I-MNI-420 biodistribution and dosimetry.