Profiling of plasma biomarkers in the context of memory assessment in a tertiary memory clinic

Plasma biomarkers have shown promising performance in research cohorts in discriminating between different stages of Alzheimer's disease (AD). Studies in clinical populations are necessary to provide insights on the clinical utility of plasma biomarkers before their implementation in real-world settings. Here we investigated plasma biomarkers (glial fibrillary acidic protein (GFAP), tau phosphorylated at 181 and 231 (pTau181, pTau231), amyloid β (Aβ) 42/40 ratio, neurofilament light) in 126 patients (age = 65 ± 8) who were admitted to the Clinic for Cognitive Disorders, at Karolinska University Hospital. After extensive clinical assessment (including CSF analysis), patients were classified as: mild cognitive impairment (MCI) (n = 75), AD (n = 25), non-AD dementia (n = 16), no dementia (n = 9). To refine the diagnosis, patients were examined with [18F]flutemetamol PET (Aβ-PET). Aβ-PET images were visually rated for positivity/negativity and quantified in Centiloid. Accordingly, 68 Aβ+ and 54 Aβ- patients were identified. Plasma biomarkers were measured using single molecule arrays (SIMOA). Receiver-operated curve (ROC) analyses were performed to detect Aβ-PET+ using the different biomarkers. In the whole cohort, the Aβ-PET centiloid values correlated positively with plasma GFAP, pTau231, pTau181, and negatively with Aβ42/40 ratio. While in the whole MCI group, only GFAP was associated with Aβ PET centiloid. In ROC analyses, among the standalone biomarkers, GFAP showed the highest area under the curve discriminating Aβ+ and Aβ- compared to other plasma biomarkers. The combination of plasma biomarkers via regression was the most predictive of Aβ-PET, especially in the MCI group (prior to PET, n = 75) (sensitivity = 100%, specificity = 82%, negative predictive value = 100%). In our cohort of memory clinic patients (mainly MCI), the combination of plasma biomarkers was sensitive in ruling out Aβ-PET negative individuals, thus suggesting a potential role as rule-out tool in clinical practice

Blood β-synuclein is related to amyloid PET positivity in memory clinic patients

INTRODUCTION: β-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-β (Αβ) pathology is unclear. METHODS: We investigated the association of plasma β-synuclein levels with [18F] flutemetamol positron emission tomography (PET) in patients with AD dementia (n = 51), mild cognitive impairment (MCI-Aβ+ n = 18, MCI- Aβ- n = 30), non-AD dementias (n = 22), and non-demented controls (n = 5). RESULTS: Plasma β-synuclein levels were higher in Aβ+ (AD dementia, MCI-Aβ+) than in Aβ- subjects (non-AD dementias, MCI-Aβ-) with good discrimination of Aβ+ from Aβ- subjects and prediction of Aβ status in MCI individuals. A positive correlation between plasma β-synuclein and Aβ PET was observed in multiple cortical regions across all lobes. DISCUSSION: Plasma β-synuclein demonstrated discriminative properties for Aβ PET positive and negative subjects. Our data underline that β-synuclein is not a direct marker of Aβ pathology and suggest different longitudinal dynamics of synaptic degeneration versus amyloid deposition across the AD continuum. HIGHLIGHTS: Blood and CSF β-synuclein levels are higher in Aβ+ than in Aβ- subjects. Blood β-synuclein level correlates with amyloid PET positivity in multiple regions. Blood β-synuclein predicts Aβ status in MCI individuals

A comparative VBM study of longitudinal neuroanatomical changes in AD transgenic mouse models

Purpose/Introduction: Neurodegeneration and signs of atrophy in brain areas such as the hippocampus and entorhinal cortex are typical for Alzheimer’s disease (AD). To various extents, available transgenic (TG) mouse models of AD recapitulate such hallmarks of the disease as amyloid and tangle pathology, cognitive impairment, synaptic and neuronal loss. Less is known, however, about the brain volumetric changes over time in different genetic strains. Voxel-based morphometry (VBM) of structural MRIs is an in vivo method used to study subtle volumetric changes over time in the whole brain longitudinally. Although it has been seldom used in mice, recent developments in automated image analysis algorithms made it a bridgeable gap. Subjects and Methods: In this study, we compared the progression of neurodegeneration in double (TASTPM; amyloid? at 6 m; tangle-) and triple (TAUPS2APP amyloid? ; tangle? ; both at 4 m) TG strains of AD with a longitudinal design. Control (C67/BL6), TG (TASTPM and TAUPS2APP) male and female mice received MRI scan at 4 m, 13 m, and 24 m; (N & 10–20 mice per group). Datapreprocessing was performed with toolkits from the AFNI, FMRIB, and ANTs software libraries; the statistical analysis—in SPM12 and the read-out of anatomical labels—in ITK-snap. Results: The flexible factorial analysis in SPM12 revealed a strong interaction between time and genotype among the 3 groups in the hippocampal formation, entorhinal area, vermis, thalamus, and neostriatum. In paired comparison—‘controls against TASTPM’ a strong interaction between time and genotype was seen in the nucleus accumbens, striatum, thalamus, cerebellum, and olfactory areas. The analogous comparison with TAUPS2APP group showed in triple TG mice this interaction was isolated to the hippocampal formation. Discussion/Conclusion: The present results extend previous evidence obtained from the same database (Micotti et al. 2015; manual tracing) disclosing novel regions of progressive brain atrophy in TASTPM mice (i.e., thalamus, nucleus accumbens, and cerebellum). The effect in the nucleus accumbens corroborated literature about early alterations of mesolimbic dopaminergic systems in Tg2576 TG mice overexpressing the APP695 protein (Nobili et al. 2017), while the alteration in the cerebellum fits previous observation of local AD pathology in early-onset AD patients with PS1 mutation (Larner and Doran 2006). Overall, the present approach was successful to unveil different abnormalities in the brain over time in two common TG strains of AD

Phylogenetic Clustering among Asylum Seekers with New HIV-1 Diagnoses in Montreal, QC, Canada

Migrants are at an increased risk of HIV acquisition. We aimed to use phylogenetics to characterize transmission clusters among newly-diagnosed asylum seekers and to understand the role of networks in local HIV transmission. Retrospective chart reviews of asylum seekers linked to HIV care between 1 June 2017 and 31 December 2018 at the McGill University Health Centre and the Jewish General Hospital in Montreal were performed. HIV-1 partial pol sequences were analyzed among study participants and individuals in the provincial genotyping database. Trees were reconstructed using MEGA10 neighbor-joining analysis. Clustering of linked viral sequences was based on a strong bootstrap support (>97%) and a short genetic distance (<0.01). Overall, 10,645 provincial sequences and 105 asylum seekers were included. A total of 13/105 participant sequences (12%; n = 7 males) formed part of eight clusters. Four clusters (two to three people) included only study participants (n = 9) and four clusters (two to three people) included four study participants clustered with six individuals from the provincial genotyping database. Six (75%) clusters were HIV subtype B. We identified the presence of HIV-1 phylogenetic clusters among asylum seekers and at a population-level. Our findings highlight the complementary role of cohort data and population-level genotypic surveillance to better characterize transmission clusters in Quebec

Astrocyte signature in Alzheimer’s disease continuum through a multi-PET tracer imaging perspective

Reactive astrogliosis is an early event in the continuum of Alzheimer's disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity-more than one subtype of astrocyte involved-in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages