Antoine Leuzy

Lund University | LU · Clinical Memory Research Unit

Background and Objectives The neuropathological changes underlying Alzheimer´s disease (AD) start before overt cognitive symptoms arise, but it is not well-known how they relate to the first subtle cognitive changes. The objective for this study was to examine the independent associations of the AD hallmarks β-amyloid (Aβ), tau, and neurodegenerati...

Importance There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective To describe longitudinal [¹⁸F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the...

Neurodegenerative disorders such as Alzheimer's disease (AD) represent a mounting public health challenge. As these diseases are difficult to diagnose clinically, biomarkers of underlying pathophysiology are playing an ever-increasing role in research, clinical trials, and in the clinical work-up of patients. Though cerebrospinal fluid (CSF) and po...

The introduction of the AT(N) framework raised several issues in regards to the definition of T+. What brain regions should be sampled? Based on one or on multiple tracers? In this work, we developed a “universal” cortical tau mask for the AD continuum derived from all the major tau ligands. This “universal” cortical mask will serve as the common t...

Recent data suggest that blood biomarkers of amyloid‐β (Aβ) pathology (Aβ42/Aβ40), tau pathology (phosphorylated tau [P‐tau]) and neurodegeneration (neurofilament light [NfL]) in Alzheimer disease (AD) become abnormal very early in the disease course, albeit with different dynamics; Aβ42/Aβ40 starts to change first followed next by P‐tau and then b...

Several studies indicate that increases in cerebrospinal fluid (CSF) phosphorylated tau (P‐tau) in Alzheimer’s disease (AD) occur in response to very early amyloid‐β (Aβ) pathology and precede widespread tau aggregation. Thus far, however, there are no studies comparing different P‐tau isoforms—i.e., tau phosphorylated at threonine‐181 (P‐tau181),...

Tau‐PET has great potential in Alzheimer’s disease (AD) clinical trials as pre‐trial inclusion biomarker and as trial endpoint. However, it is unclear which Tau‐PET ROI is optimal for tracking treatment response in relevant trial populations, and how best to enrich trials if using Tau‐PET as an endpoint. We aimed to determine the sample required to...

The behavioral variant of frontotemporal dementia (bvFTD) is characterized by marked changes in personality and behaviour. Approximately 30% of cases are genetic in nature and most commonly due to autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN) genes resulting in TAR DNA‐binding protein 43 (TDP...

Biomarkers for the prediction of cognitive decline in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD dementia are needed for inclusion of suitable patients in clinical trials. We therefore assessed the ability of tau‐PET, blood and cerebrospinal fluid (CSF) phospho‐Tau217 (pTau217), CSF neurofilament light...

Background and Objectives Phosphorylated tau (P-tau) in cerebrospinal fluid (CSF) is considered an important biomarker in Alzheimer’s disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including P-tau at threonines 181 (P-tau181), 217 (P-tau217) and 231 (P-tau231). However, no studies have compared their d...

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([18 F]RO948 in BioF...

Purpose A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which dem...

Purpose In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer’s disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 a...

Purpose The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomark...

Background The 2017 Alzheimer’s disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1–2), clinical validity (Phases 3–4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps...

Purpose This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [ ¹⁸ F]flortaucipir, [ ¹⁸ F]RO948, and [ ¹⁸ F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer’s disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neur...

Importance Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective To examine the prognostic accuracy of baseline fluorine 18 (¹⁸F)–flortaucipir and [¹⁸F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clin...

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average...

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College Lon...

Introduction: We studied usefulness of combining blood amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aβ deposition in different stages of early Alzheimer's disease (AD). Methods: Plasma biomarkers were measured using mass spectrometry (Aβ42/Aβ40) and immunoassays (p-tau217 and NfL...

Purpose Off-target binding in the skull and meninges is observed in some subjects undergoing tau positron emission tomography (PET) and could potentially differ between men and women. In this study we elucidate sex differences in tau off-target binding using three different tau PET tracers. Methods 541 cognitively unimpaired amyloid-β negative par...

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD) related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n=400) and ADNI (n=371). All had tau-PET ([18F]RO948 in BioFINDER...

Objective The clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination. Met...

Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer’s disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is fu...

Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphor...

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly indviduals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average o...

Purpose of review: This review provides a concise overview of recent advances in cerebrospinal fluid (CSF) and blood-based biomarkers of Alzheimer's disease lesions. Recent findings: Important recent advances for CSF Alzheimer's disease biomarkers include the introduction of fully automated assays, the development and implementation of certified...

We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outc...

Background Alzheimer's disease co‐pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives. Objective...

As cortical tau pathology in Alzheimer’s disease (AD) has been shown to correlate closely to neurodegeneration and onset of cognitive impairment, there is a growing interest in the further refinement of tau‐PET methods for clinical use. Similar to amyloid‐PET, tau‐imaging will likely be approved for visual‐read supported by quantification (i.e. sta...

A distinct subset of patients with Alzheimer’s disease (AD) experience early and predominant behavioral and personality changes, while the neurobiological origins of these symptoms are largely unknown. In this study, we examined the distribution of tau pathology using PET imaging or post‐mortem evaluation in patients with the behavioral variant of...

While the last two decades have seen important advances in the in vivo detection of Alzheimer’s disease (AD) pathology (i.e. β‐amyloid [Aβ] and Tau) using biomarkers (PET‐ and CSF‐based), the global use of these measures is quite limited due to high costs, insufficient availability and their invasive nature. Interest in blood‐based biomarkers for A...

In recent years, blood biomarkers for Alzheimer’s disease (AD) have attracted much interest. Technological advances have allowed quantification of markers for neurodegeneration (NfL), neurofibrillary tangles (p‐tau181) and amyloid‐β pathology (Aβ42, Aβ42/Aβ40), which perform well in cohorts stratified by cerebrospinal fluid and positron emission to...

Tau pathology is a key hallmark of Alzheimer’s disease (AD), but factors modifying the rate of tau accumulation are still largely unknown. Tau‐PET allows tau pathology to be visualized in vivo in AD. Our aim was to study factors associated with the accumulation rate of tau pathology, using [18F]flortaucipir PET. 419 participants from four longitudi...

Alzheimer’s disease (AD) is defined by amyloid‐β (Aβ) and tau pathology. Specifically, Aβ and tau are thought to interact, with Aβ mediating the spread of tau. We here aimed to examine the association between cross‐sectional Aβ and tau‐PET with change in tau‐PET SUVR. 51 subjects from the ongoing BioFINDER‐2 longitudinal sub‐study were included: 23...

Analyses from the Swedish BioFINDER‐2 study have shown that tau burden change seen via 18F‐RO‐948 tau PET tracer replicates the post‐mortem spreading pattern of tau. The greatest longitudinal changes have thus far been seen in Braak regions I/II for amyloid positive (Aβ+) cognitively unimpaired (CU) subjects, and Braak regions III/IV and V/VI for A...

In the last decade, the research community focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers to AD, with the aim to accelerate their dev...

The hippocampus is an important region to study in Alzheimer’s disease (AD) since it is an early site of tau accumulation. Accurate quantification of hippocampal tau signal using the most common tau‐PET tracer 18F‐flortaucipir is complicated, however, by off‐target binding in the adjacent choroid plexus. We here present a novel method for compensat...

In the last decade, the research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers (Pepe et al., 2001) to AD, with the aim...

Cerebrospinal fluid (CSF) p‐tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the brain. We have recently shown that also plasma p‐tau181 is a promising biomarker for AD (Janelidze et al, Nature Medicine, 2020). We now evaluate whether CSF p‐tau217 or plasma p‐...

Selective positron emission tomography (PET) tracers to target neurofibrillary tangles of the second generation have indicated to overcome some of the methodological issues observed with the tau‐tracers of the first generation. How these second‐generation tau tracers may be better suitable for clinical practice was assessed in the context of the Ge...

Though cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase diagnostic accuracy for early Alzheimer’s disease (i.e. AD at the MCI stage), several challenges remain with respect to their routine clinical use. In order to address these and related issues, a multidisciplinary task force was formed (Geneva Biomarker Roadmap In...

The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer’s disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer’s di...

Objective To evaluate a novel β-amyloid (Aβ)-PET–based quantitative measure (Aβ accumulation index [Aβ index]), including the assessment of its ability to discriminate between participants based on Aβ status using visual read, CSF Aβ 42 /Aβ 40 , and post-mortem neuritic plaque burden as standards of truth. Methods One thousand one hundred twenty-o...

Objective: The clinical phenotype of the rare behavioral variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using PET and postmortem examination. Methods: For the tau PET study, sev...

Increased cerebrospinal uid neuro lament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in fteen neurodegenerative diseases from two multicenter cohorts: King's College London (n = 847) and the Swedish BioFINDER study (n = 1464). Plasma...

Quantification may help in the context of amyloid-β positron emission tomography (PET). Quantification typically requires that PET images be spatially normalized, a process that can be subject to bias. We herein aimed to test whether a principal component approach (PCA) previously applied to [18F]flutemetamol PET extends to [18F]florbetaben. PCA wa...

Importance There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 particip...

We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI), using plasma biomarkers of beta-amyloid (Ab), tau, and neurodegeneration. We included MCI patients from the Swedish BioFINDER study (n=148) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=86 for model selection; n=425 for pro...

Medical imaging techniques, such as structural and functional magnetic resonance imaging and positron emission tomography, have been used to gain a better understanding of the alterations of the metabolic processes in the brain relating to type 2 diabetes melltius, insulin resistance and Alzheimer's disease. These studies have shown that there are...

Purpose: The hippocampus is affected by tau pathology early in Alzheimer's disease (AD) development. Accurate quantification of hippocampal tau signal using the tau-PET tracer ¹⁸F-flortaucipir is complicated, however, by off-target binding in the adjacent choroid plexus. We here present a new method for compensating for this off-target choroid plex...

Cerebrospinal fluid (CSF) neurofilament light (NfL) concentration has reproducibly been shown to reflect neurodegeneration in brain disorders, including Alzheimer’s disease (AD). NfL concentration in blood correlates with the corresponding CSF levels, but few studies have directly compared the reliability of these two markers in sporadic AD. Herein...

Importance The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known. Objective To examine the novel tau PET tracer RO948 F 18 ([¹⁸F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders. Design, Setting, and Participants In this diagnostic study,...

Objective To compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies. Methods A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disea...

Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screeni...

Purpose [¹⁸F]flortaucipir binds to paired helical filament tau and accurately identifies tau in Alzheimer’s disease (AD). However, “off-target” binding interferes with the quantification of [¹⁸F]flortaucipir in several brain regions. Recently, other tau PET tracers have been developed. Here, we compare [¹⁸F]flortaucipir with the novel tau tracer [¹...

The aggregation and accumulation of pathologic forms of the microtubule-associated tau protein into fibrils, eventually forming characteristic tangle pathology, hallmarks the majority of all dementia disorders which constitute the most prevalent family of neurodegenerative disorders. These so-called tauopathies are difficult to identify and diagnos...

Cellular accumulation of aggregated forms of the protein tau is a defining feature of so-called tauopathies such as Alzheimer's disease, progressive supranuclear palsy, and chronic traumatic encephalopathy. A growing body of literature suggests that conformational characteristics of tau filaments, along with regional vulnerability to tau pathology,...

Introduction: Neurofilament light chain (NfL) is a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) and other brain disorders. However, there are limited reports of how longitudinal NfL relates to imaging biomarkers. We herein investigated the relationship between blood NfL and brain metabolism in AD. Methods: Vo...