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).

Towards multicenter β-amyloid PET imaging in mouse models: A triple scanner head-to-head comparison.

Aim: β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments.

Assessment of [F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.

Purpose: [F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [F]PI-2620 PET quantification for assessing tau by regional distribution volumes (V). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative.

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.

Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [F]-PI-2620 tau-PET signal.

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer's disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression.

[F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

Objectives: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions.

Depletion and activation of microglia impact metabolic connectivity of the mouse brain.

Aim: We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG-PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated.

Assessment of perfusion deficit with early phases of [F]PI-2620 tau-PET versus [F]flutemetamol-amyloid-PET recordings.

Purpose: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan.

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.

A Severe Dementia Syndrome Caused by Intron Retention and Cryptic Splice Site Activation in and Exacerbated by Repeat Expansions.

Heterozygous pathogenic variants in the STIP1 homologous and U-box containing protein 1 () gene have been identified as causes of autosomal dominant inherited spinocerebellar ataxia type 48 (SCA48). SCA48 is characterized by an ataxic movement disorder that is often, but not always, accompanied by a cognitive affective syndrome. We report a severe early onset dementia syndrome that mimics frontotemporal dementia and is caused by the intronic splice donor variant c.

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.

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).

Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for Assessment of Progressive Supranuclear Palsy Tau Pathology With [ F]PI-2620.

Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). We applied [F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively.

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.

Detection Gap of Right-Asymmetric Neuronal Degeneration by CERAD Test Battery in Alzheimer's Disease.

: Asymmetric disease characteristics on neuroimaging are common in structural and functional imaging of neurodegenerative diseases, particularly in Alzheimer's disease (AD). However, a standardized clinical evaluation of asymmetric neuronal degeneration and its impact on clinical findings has only sporadically been investigated for F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET). This study aimed to evaluate the impact of lateralized neuronal degeneration on the detection of AD by detailed clinical testing.

Cognitive reserve hypothesis in frontotemporal dementia: A FDG-PET study.

Background And Objective: Reserve is defined as the ability to maintain cognitive functions relatively well at a given level of pathology. Early life experiences such as education are associated with lower dementia risk in general. However, whether more years of education guards against the impact of brain alterations also in frontotemporal dementia (FTD) has not been shown in a large patient collective.