Neurotheranostics: The Next Frontier for Health Span.

With an aging U.S. population, advancements in the treatment of Alzheimer disease (AD) and other neurodegenerative diseases are key to the maximization of health span.

Imaging Biomarkers for Central Nervous System Drug Development and Future Clinical Utility: Lessons from Neurodegenerative Disorders.

Diseases of the central nervous system are common and often chronic conditions associated with significant morbidity. In particular, neurodegenerative disorders including Alzheimer and Parkinson disease constitute a major health and socioeconomic challenge, with an increasing incidence in many industrialized countries with aging populations. Recent work has established the primary role of abnormal protein accumulation and the spread of disease-specific deposits in brain as a factor in neurotoxicity and disruption of functional networks.

A Visual Interpretation Algorithm for Assessing Brain Tauopathy with F-MK-6240 PET.

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition.

Statistical Considerations in the Design of Clinical Trials Targeting Prodromal Parkinson Disease.

Clinical trials testing interventions for prodromal Parkinson disease (PD) hold particular promise for preserving neuronal function and thereby slowing or even forestalling progression to overt PD. Selection of the appropriate target population and outcome measures presents challenges unique to prodromal PD. We propose 3 clinical trial designs, spanning phase 2a, phase 2b, and phase 3 development, that might serve as templates for prodromal PD trials.

F-PI-2620 Tau PET Improves the Imaging Diagnosis of Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the F-labeled tau PET tracer 2-(2-([F]fluoro)pyridin-4-yl)-9-pyrrolo[2,3-:4,5-']dipyridine (F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP.

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.

Early detection of amyloid load using F-florbetaben PET.

Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using F-florbetaben PET. Quantitative thresholds for the early (SUVR) and established (SUVR) Aβ deposition were developed, and the topography of early Aβ deposition was assessed.

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.

Evaluation of Dosimetry, Quantitative Methods, and Test-Retest Variability of F-PI-2620 PET for the Assessment of Tau Deposits in the Human Brain.

F-PI-2620 is a next-generation tau PET tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry, and quantitative methods of F-PI-2620 in the human brain. Full kinetic modeling to quantify tau load was investigated.

Tau PET imaging with F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study.

F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this first-in-humans study was to evaluate the ability of F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess the safety and tolerability of this new tau PET tracer.

[F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer's disease.

Objective: Neurofibrillary tangles (NFTs), consisting of intracellular aggregates of the tau protein, are a pathological hallmark of Alzheimer's disease (AD). Here we report the identification and initial characterization of Genentech Tau Probe 1 ([F]GTP1), a small-molecule PET probe for imaging tau pathology in AD patients.

Methods: Autoradiography using human brain tissues from AD donors and protein binding panels were used to determine [F]GTP1 binding characteristics.

Imaging histamine H3 receptors with [ F]FMH3: Test-retest and occupancy studies in the non-human primate.

A positron emission tomography (PET) radioligand, [ F]FMH3, has been developed to interrogate histamine receptor subtype 3 (H3R), where dysfunction at this site is linked with obesity, sleep abnormality, and cognitive disorders. [ F]FMH3 was evaluated for imaging central H3R sites in non-human primates through test-retest (TRT) and dose-receptor occupancy studies with two selective H3R antagonists in order to support clinical investigations. Two adult female baboons underwent [ F]FMH3 PET brain scans in the HR+, at repeated baseline (n = 7) and following administration of escalating doses of ABT-239 (0.

Signs and Artifacts in Amyloid PET.

Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasingly important to achieve the correct diagnosis as soon as possible. In challenging presentations of dementia, such as patients with clinically atypical features or early-age onset of mild cognitive impairment, amyloid PET is a valuable tool in determining the diagnosis of Alzheimer dementia.

Brain intrinsic network connectivity in individuals with frequent tanning behavior.

Background: Emergent studies suggest a bidirectional relationship between brain functioning and the skin. This neurocutaneous connection may be responsible for the reward response to tanning and, thus, may contribute to excessive tanning behavior. To date, however, this association has not yet been examined.

Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F 18.

Alzheimer disease (AD) is characterized by β-amyloid (Aβ) plaques and tau neurofibrillary tangles. There are several PET imaging biomarkers for Aβ including C-PiB and F-florbetapir. Recently, PET tracers for tau neurofibrillary tangles have become available and have shown utility in detection and monitoring of neurofibrillary pathology over time.

Kinetic Modeling of the Tau PET Tracer F-AV-1451 in Human Healthy Volunteers and Alzheimer Disease Subjects.

F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects.

Cerebellar Amyloid-β Plaques: How Frequent Are They, and Do They Influence 18F-Florbetaben SUV Ratios?

Unlabelled: SUV ratios (SUVRs) are used for relative quantification of F-florbetaben scans. The cerebellar cortex can be used as a reference region for quantification. However, cerebellar amyloid-β (Aβ) plaques may be present in Alzheimer disease (AD).

A novel thermoregulatory role for PDE10A in mouse and human adipocytes.

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the novel radioligand [(18)F]-AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice.

Dopamine efflux in response to ultraviolet radiation in addicted sunbed users.

Compulsive tanning despite awareness of ultraviolet radiation (UVR) carcinogenicity may represent an "addictive" behavior. Many addictive disorders are associated with alterations in dopamine (D2/D3) receptor binding and dopamine reactivity in the brain's reward pathway. To determine if compulsive tanners exhibited neurobiologic responses similar to other addictive disorders, this study assessed basal striatal D2/D3 binding and UVR-induced striatal dopamine efflux in ten addicted and ten infrequent tanners.