Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts.

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline.

Combining cerebrospinal fluid and PI-2620 tau-PET for biomarker-based stratification of Alzheimer's disease and 4R-tauopathies.

Introduction: Recent advances in biomarker research have improved the diagnosis and monitoring of Alzheimer's disease (AD), but in vivo biomarker-based workflows to assess 4R-tauopathy (4RT) patients are currently missing. We suggest a novel biomarker-based algorithm to characterize AD and 4RTs.

Methods: We cross-sectionally assessed combinations of cerebrospinal fluid measures (CSF p-tau and t-tau) and F-PI-2620 tau-positron emission tomography (PET) in patients with AD (n = 64), clinically suspected 4RTs (progressive supranuclear palsy or corticobasal syndrome, n = 82) and healthy controls (n = 19).

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e.

Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

Purpose: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [F]PI-2620 tau-positron-emission-tomography (PET) imaging with [I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability.

Methods: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.

A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life.

Dopamine Transporter Availability in Early Parkinson's Disease is Dependent on Sunlight Exposure.

Background: Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the seasons. We, therefore, investigated seasonal and sunlight-dependent effects on DAT availability in early Parkinson's disease (PD) patients and healthy controls.

Methods: DAT single-photon emission computed tomography scans (n = 730) were gathered from the Parkinson's Progression Marker Initiative (PPMI) database.

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.

Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study.

Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).

Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD.

Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia).

Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study.

Background: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups.

Methods: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA).

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.

Additive value of [F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

Purpose: Early after [F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs.

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.

Tau deposition patterns are associated with functional connectivity in primary tauopathies.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 generation F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96).

Preclinical characterization of [F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase.

Purpose: Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24S-hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) is being pursued as a drug for treatment of seizures in developmental and epileptic encephalopathies. Herein, we describe the successful discovery and the preclinical validation of the novel radiolabeled CH24H ligand (3-[F]fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone ([F]T-008) and its tritiated analog, [H]T-008.

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.

Feasibility of short imaging protocols for [F]PI-2620 tau-PET in progressive supranuclear palsy.

Purpose: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [F]PI-2620 tau-PET imaging of PSP.

Methods: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs.

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

Background: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).

Objective: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.

Methods: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.