Automated deep learning segmentation of high-resolution 7 T postmortem MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases

Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high resolution of 135 postmortem human brain tissue specimens imaged at 0.3 mm$^{3}$ isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We then segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter. We show generalizing capabilities across whole brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm^3 and 0.16 mm^3 isotropic T2*w FLASH sequence at 7T. We then compute localized cortical thickness and volumetric measurements across key regions, and link them with semi-quantitative neuropathological ratings. Our code, Jupyter notebooks, and the containerized executables are publicly available at: https://pulkit-khandelwal.github.io/exvivo-brain-upennComment: Preprint submitted to NeuroImage Project website: https://pulkit-khandelwal.github.io/exvivo-brain-upen

Plasma GFAP associates with secondary Alzheimer's pathology in Lewy body disease

Abstract Objective Within Lewy body spectrum disorders (LBSD) with α‐synuclein pathology (αSyn), concomitant Alzheimer's disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p‐tau181) is sensitive to AD neuropathologic change (ADNC) in clinical AD, and plasma glial fibrillary acidic protein (GFAP) is associated with the presence of β‐amyloid plaques. While these plasma biomarkers are well tested in clinical and pathological AD, their diagnostic and prognostic performance for concomitant AD in LBSD is unknown. Methods In autopsy‐confirmed αSyn‐positive LBSD, we tested how plasma p‐tau181 and GFAP differed across αSyn with concomitant ADNC (αSyn+AD; n = 19) and αSyn without AD (αSyn; n = 30). Severity of burden was scored on a semiquantitative scale for several pathologies (e.g., β‐amyloid and tau), and scores were averaged across sampled brainstem, limbic, and neocortical regions. Results Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β = 0.31, 95% CI = 0.065–0.56, and P = 0.015), after covarying for age at plasma, plasma‐to‐death interval, and sex; plasma p‐tau181 was not (P = 0.37). Next, linear models tested associations of AD pathological features with both plasma analytes, covarying for plasma‐to‐death, age at plasma, and sex. GFAP was significantly associated with brain β‐amyloid (β = 15, 95% CI = 6.1–25, and P = 0.0018) and tau burden (β = 12, 95% CI = 2.5–22, and P = 0.015); plasma p‐tau181 was not associated with either (both P > 0.34). Interpretation Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β‐amyloid plaques

Digital Histological Study of Neocortical Grey and White Matter Tau Burden Across Tauopathies.

3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability across centers is unclear. We calculated regional percentage areas occupied by tau pathological inclusions from the middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) from cases from the University of Pennsylvania and the University of California San Diego with AD, LBD+tau, PSP, or CBD (n = 150) using QuPath. In both cohorts, AD and LBD+tau had the highest grey and white matter tau burden in the STC (p ≤ 0.04). White matter tau burden was relatively higher in 4R-tauopathies than 3R/4R-tauopathies (p < 0.003). Grey and white matter tau were correlated in all diseases (R2=0.43-0.79, p < 0.04) with the greatest increase of white matter per unit grey matter tau observed in PSP (p < 0.02 both cohorts). Grey matter tau negatively correlated with MMSE in AD and LBD+tau (r = -4.4 to -5.4, p ≤ 0.02). These data demonstrate the feasibility of cross-institutional digital histology studies that generate finely grained measurements of pathology which can be used to support biomarker development and models of disease progression

CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology

BACKGROUND AND OBJECTIVES: Cerebrospinal fluid (CSF) biomarkers amyloid-β42 (Aβ42), phosphorylated tau (p-tau181), total tau (t-tau) and neurogranin (Ng) can diagnose Alzheimer's disease (AD) in life. However, it is unknown if CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test if biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aβ42, p-tau181, t-tau and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD+αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD+αSyn affected diagnostic accuracy of two CSF-based strategies: the ATN framework and the t-tau/Aβ42 ratio. METHODS: Inclusion criteria were neuropathologic diagnoses of AD, mixed AD+αSyn, and αSyn. A convenience sample of non-impaired controls were selected with available CSF and a mini mental state exam (MMSE)≥27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aβ42, p-tau181, t-tau, and Ng differences across AD and AD+αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic amyloid-β and tau. Receiver operating characteristic and area under the curve (AUC), including 95% confidence intervals (CI), evaluated diagnostic accuracy. RESULTS: Participants were 61 AD, 39 mixed AD+αSyn, 20 αSyn, and 61 Controls. AD had similar median age (73 [IQR=12]), MMSE (23 [IQR=9]), and sex distribution (Male=49%) compared to AD+αSyn age (70 [IQR=13]; p=0.3), MMSE (25 [IQR=9.5]; p=0.19), and sex distribution (Male=69%; p=0.077). ANCOVAs showed AD+αSyn had lower p-tau181 (F(1,94)=17, p=0), t-tau (F(1,93)=11, p=0.0004), and Ng levels (F(1,50)=12, p=0.0004) than AD; there was no difference in Aβ42 (p=0.44). Models showed increasing αSyn related to lower p-tau181 (β=-0.26, SE=0.092, p=0.0065), t-tau (β=-0.19, SE=0.092, p=0.041), and Ng levels (β=-0.2, SE=0.066, p=0.0046); αSyn was not a significant factor for Aβ42 (p=1). T-tau/Aβ42 had the highest accuracy when detecting AD, including mixed AD+αSyn cases (AUC=0.95; CI=0.92 to 0.98). DISCUSSION: Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau181, t-tau, and Ng levels, and can affect diagnositic accuracy in AD patients

Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration

Abstract Early pathological features of frontotemporal lobar degeneration (FTLD) due to MAPT pathogenic variants (FTLD-MAPT) are understudied, since early-stage tissue is rarely available. Here, we report unique pathological data from three presymptomatic/early-stage MAPT variant carriers (FTLD Clinical Dementia Rating [FTLD-CDR] = 0–1). We examined neuronal degeneration semi-quantitatively and digitally quantified tau burden in 18 grey matter (9 cortical, 9 subcortical) and 13 white matter (9 cortical, 4 subcortical) regions. We compared presymptomatic/early-stage pathology to an intermediate/end-stage cohort (FTLD-CDR = 2–3) with the same variants (2 L315R, 10 P301L, 6 G272V), and developed a clinicopathological staging model for P301L and G272V variants. The 68-year-old presymptomatic L315R carrier (FTLD-CDR = 0) had limited tau burden morphologically similar to L315R end-stage carriers in middle frontal, antero-inferior temporal, amygdala, (para-)hippocampus and striatum, along with age-related Alzheimer’s disease neuropathological change. The 59-year-old prodromal P301L carrier (FTLD-CDR = 0.5) had highest tau burden in anterior cingulate, anterior temporal, middle/superior frontal, and fronto-insular cortex, and amygdala. The 45-year-old early-stage G272V carrier (FTLD-CDR = 1) had highest tau burden in superior frontal and anterior cingulate cortex, subiculum and CA1. The severity and distribution of tau burden showed some regional variability between variants at presymptomatic/early-stage, while neuronal degeneration, mild-to-moderate, was similarly distributed in frontotemporal regions. Early-stage tau burden and neuronal degeneration were both less severe than in intermediate-/end-stage cases. In a subset of regions (10 GM, 8 WM) used for clinicopathological staging, clinical severity correlated strongly with neuronal degeneration (rho = 0.72, p < 0.001), less strongly with GM tau burden (rho = 0.57, p = 0.006), and did not with WM tau burden (p = 0.9). Clinicopathological staging showed variant-specific patterns of early tau pathology and progression across stages. These unique data demonstrate that tau pathology and neuronal degeneration are present already at the presymptomatic/early-stage of FTLD-MAPT, though less severely compared to intermediate/end-stage disease. Moreover, early pathological patterns, especially of tau burden, differ partly between specific MAPT variants

Digital Histological Study of Neocortical Grey and White Matter Tau Burden Across Tauopathies

3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability across centers is unclear. We calculated regional percentage areas occupied by tau pathological inclusions from the middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) from cases from the University of Pennsylvania and the University of California San Diego with AD, LBD+tau, PSP, or CBD (n = 150) using QuPath. In both cohorts, AD and LBD+tau had the highest grey and white matter tau burden in the STC (p ≤ 0.04). White matter tau burden was relatively higher in 4R-tauopathies than 3R/4R-tauopathies (p < 0.003). Grey and white matter tau were correlated in all diseases (R2=0.43-0.79, p < 0.04) with the greatest increase of white matter per unit grey matter tau observed in PSP (p < 0.02 both cohorts). Grey matter tau negatively correlated with MMSE in AD and LBD+tau (r = -4.4 to -5.4, p ≤ 0.02). These data demonstrate the feasibility of cross-institutional digital histology studies that generate finely grained measurements of pathology which can be used to support biomarker development and models of disease progression

CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer\u2032s disease

Abstract: Diagnosis of dementia with Lewy bodies (DLB) is challenging and specific biofluid biomarkers are highly needed. We employed proximity extension-based assays to measure 665 proteins in the cerebrospinal fluid (CSF) from patients with DLB (n=109), Alzheimers disease (AD, n=235) and cognitively unimpaired controls (n=190). We identified over 50 CSF proteins dysregulated in DLB, enriched in myelination processes among others. The dopamine biosynthesis enzyme DDC was the strongest dysregulated protein, and could efficiently discriminate DLB from controls and AD (AUC:0.91 and 0.81 respectively). Classification modeling unveiled a 7-CSF biomarker panel that better discriminate DLB from AD (AUC:0.93). A custom multiplex panel for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1) was developed and validated in independent cohorts, including an AD and DLB autopsy cohort. This DLB CSF proteome study identifies DLB-specific protein changes and translates these findings to a practicable biomarker panel that accurately identifies DLB patients, providing promising diagnostic and clinical trial testing opportunities

CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease

Abstract Diagnosis of dementia with Lewy bodies (DLB) is challenging and specific biofluid biomarkers are highly needed. We employed proximity extension-based assays to measure 665 proteins in the cerebrospinal fluid (CSF) from patients with DLB (n = 109), Alzheimer´s disease (AD, n = 235) and cognitively unimpaired controls (n = 190). We identified over 50 CSF proteins dysregulated in DLB, enriched in myelination processes among others. The dopamine biosynthesis enzyme DDC was the strongest dysregulated protein, and could efficiently discriminate DLB from controls and AD (AUC:0.91 and 0.81 respectively). Classification modeling unveiled a 7-CSF biomarker panel that better discriminate DLB from AD (AUC:0.93). A custom multiplex panel for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1) was developed and validated in independent cohorts, including an AD and DLB autopsy cohort. This DLB CSF proteome study identifies DLB-specific protein changes and translates these findings to a practicable biomarker panel that accurately identifies DLB patients, providing promising diagnostic and clinical trial testing opportunities