Alnobani, Alla

AbstractBackgroundCorticobasal syndrome (CBS) is a progressive neurodegenerative syndrome that can result from several underlying neuropathologies, including Alzheimer’s disease (AD). Little is known about the utility of blood plasma measures to predict PET biomarker confirmed AD in CBS.MethodEighteen CBS patients (8 PET Aβ+; 10 PET Aβ‐) and 8 cognitively unimpaired Aβ‐ individuals (CU) were recruited by the Neurodegenerative Research group from the Department of Neurology, Mayo Clinic, Rochester, MN, underwent Aβ (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181, total tau, Aβ 42/40, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) using the Quanterix Simoa platform. Plasma concentrations were compared between Aβ‐, and Aβ+ CBS and controls using Kruskal‐Wallis corrected for multiple comparisons using Dunn’s test, with effect size measured with area under the receiver operating characteristic curve (AUROC) analysis. Spearman correlations were calculated to assess relationships between plasma concentrations and Aβ and tau PET uptake.ResultThe CBS Aβ+ group showed reduced Aβ42/40 ratio, with elevated p‐tau 181, GFAP and NfL plasma concentrations compared to CU, while the CBS Aβ‐ group only showed elevated NfL concentration compared to CU (Figure 1). Both p‐tau 181 (AUROC=0.95) and GFAP (AUROC=0.91) plasma concentrations were able to differentiate CBS Aβ‐ from CBS Aβ+. Plasma p‐tau 181 and GFAP concentrations showed a positive correlation to both Aβ and tau PET uptake, and the Aβ42/40 ratio showed a negative correlation to Aβ PET uptake (Figure 2). No correlations were observed between NfL and Aβ and tau PET.ConclusionThis study supports the use of plasma p‐tau 181 and GFAP to detect AD in CBS, while NfL shows potential as a nonspecific disease biomarker of CBS regardless of underlying pathology. Plasma concentrations of these biomarkers may potentially be incorporated into clinical trials targeting CBS patients with underlying AD pathology.

AbstractBackgroundCorticobasal syndrome (CBS) is a progressive neurodegenerative syndrome that can result from several underlying neuropathologies, including Alzheimer’s disease (AD). Little is known about the utility of blood plasma measures to predict PET biomarker confirmed AD in CBS.MethodEighteen CBS patients (8 PET Aß+; 10 PET Aß‐) and 8 cognitively unimpaired Aß‐ individuals (CU) were recruited by the Neurodegenerative Research group from the Department of Neurology, Mayo Clinic, Rochester, MN, underwent Aß (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181, total tau, Aß 42/40, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) using the Quanterix Simoa platform. Plasma concentrations were compared between Aß‐, and Aß+ CBS and controls using Kruskal‐Wallis corrected for multiple comparisons using Dunn’s test, with effect size measured with area under the receiver operating characteristic curve (AUROC) analysis. Spearman correlations were calculated to assess relationships between plasma concentrations and Aß and tau PET uptake.ResultThe CBS Aß+ group showed reduced Aß42/40 ratio, with elevated p‐tau 181, GFAP and NfL plasma concentrations compared to CU, while the CBS Aß‐ group only showed elevated NfL concentration compared to CU (Figure 1). Both p‐tau 181 (AUROC=0.95) and GFAP (AUROC=0.91) plasma concentrations were able to differentiate CBS Aß‐ from CBS Aß+. Plasma p‐tau 181 and GFAP concentrations showed a positive correlation to both Aß and tau PET uptake, and the Aß42/40 ratio showed a negative correlation to Aß PET uptake (Figure 2). No correlations were observed between NfL and Aß and tau PET.ConclusionThis study supports the use of plasma p‐tau 181 and GFAP to detect AD in CBS, while NfL shows potential as a nonspecific disease biomarker of CBS regardless of underlying pathology. Plasma concentrations of these biomarkers may potentially be incorporated into clinical trials targeting CBS patients with underlying AD pathology.

AbstractBackgroundHomozygosity for the rare APOE3‐Christchurch (APOE3Ch) variant, encoding for apoE3‐R136S (apoE3‐Ch), was linked to resistance against an aggressive form of familial Alzheimer’s disease (AD). Carrying two copies of APOE3Ch was sufficient to delay autosomal AD onset by 30 years. This remarkable protective effect makes it a strong candidate for uncovering new therapies against AD. Thus, we aim to explore the protective mechanisms of APOE3Ch against AD onset, to inform therapy.MethodsWe used both amyloid mouse models and human induced‐pluripotent stem cells (iPSC) models to address this aim. We examined whether astrocytic expression of apoE3‐Ch through an AAV‐mediated approach can mitigate AD‐related pathology and toxicity in early (3.5 months old) and late (8 months old) amyloid pathology in 5xFAD mice. We also used isogenic iPSC lines carrying the APOE3Ch variant that were generated from APOE3 parental lines using CRISPR/Cas9 technology. Biochemical and biophysical properties of both recombinant and native apoE3‐Ch lipoprotein particles secreted by iPSC‐derived astrocytes have been investigated using different techniques including heparin affinity chromatography and size‐exclusion chromatography.ResultsWe investigated the impact of astrocytic apoE3‐Ch on amyloid pathology and toxicity in 3.5‐month‐old and 8‐month‐old 5xFAD mice. We confirmed successful AAV‐mediated overexpression of apoE3 and apoE3‐Ch in astrocytes. We found apoE3‐Ch specific changes in protein levels and solubility. Astrocytic expression of apoE3‐Ch reduced soluble Aβ oligomer levels and ameliorated ER stress response compared to apoE3 in the 8‐month‐old 5xFAD mice. Furthermore, our findings showed altered biochemical properties of HEK cell‐derived apoE3‐Ch protein, including decreased heparin binding, altered receptor binding, and enhanced lipid accepting capacity. We also characterized APOE3Ch iPSC‐derived cell models, including iPSC‐derived astrocytes, neurons, and cerebral organoids, and found differences between APOE3 and APOE3Ch at the functional level in these iPSC models.ConclusionsThe proposed work and the developed methods to study apoE3‐Ch promises to provide new insights into the possible roles of this rare, mutated protein in protecting against AD, offering new therapeutic avenues for AD treatment.

AbstractINTRODUCTIONCorticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker‐confirmed AD in CBS.METHODSA cohort of eighteen CBS patients (8 amyloid beta [Aβ]+; 10 Aβ−) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal–Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake.RESULTSCBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ− group only showed elevated NfL concentration compared to CU. Both p‐tau181 and GFAP were able to differentiate CBS Aβ− from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake.DISCUSSIONThis study supports use of plasma p‐tau181 and GFAP to detect AD in CBS. NfL shows potential as a non‐specific disease biomarker of CBS regardless of underlying pathology.Highlights Plasma phosphorylated tau (p‐tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)− from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ− and Aβ+ compared to controls. Plasma p‐tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.