Digital Pathology and Image Analysis for Robust High-Throughput Quantitative Assessment of Alzheimer Disease Neuropathologic Changes

Neltner, Janna H.; Abner, Erin L.; Schmitt, Frederick A.; Denison, Stephanie; Anderson, Sonya; Patel, Ela; Nelson, Peter T.

doi:10.1097/nen.0b013e3182768de4

Cited by 60 publications

(66 citation statements)

References 46 publications

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“…Indeed, the dynamic range of IHC is small, prohibiting a true analytic measurement of protein concentration from tissue (Rimm 2006). Further, analysis of cortical tissue, as compared with specific brain nuclei, is challenging due to the variable volume and orientation of cortical tissue in a given section (Neltner et al 2012). The vertical transection sampling method presented here identifies "representative cortex" to evaluate disease burden through random sampling to minimize sampling bias (Armstrong 2003), similar to methods used in manual quantification studies of neocortical FTLD neuropathology (Armstrong et al 1999a;Armstrong and Cairns 2012); but this approach does not replicate stereology (i.e., estimating 3-dimensional volume and cell/inclusion density from 2-dimensional images) (West et al 1991).…”

Section: Discussionmentioning

confidence: 99%

“…We chose this size because it maximized the number of tiles for random sampling (i.e. majority of tissue samples had >50 tiles) and the upper limit of inclusion counts per tile to prevent manual count fatigue (Neltner et al 2012). To determine the optimum number of random tiles to sample in our random sampling scheme, we performed a permutation analysis (Supplemental Fig.…”

Section: Sampling Methods Validationmentioning

confidence: 99%

“…Since FTLD neuropathology can often preferentially involve specific cortical layers (Armstrong et al 1999a;Armstrong et al 1999b;Mackenzie et al 2011;Tan et al 2013), it was necessary to sample the parallel-oriented cortex, as curved or tangentially cut areas of tissue may overor under-represent cortical layers and influence "whole-slide" random plot sampling methods (Armstrong 2003;Neltner et al 2012). As such, we selected the longest area of intact grey matter parallel to the pia matter (i.e., vertical transect sampling (Armstrong 2003) of the entire width of grey matter) for the region of interest (ROI) for measurement.…”

Section: Sampling Methods Validationmentioning

confidence: 99%

“…Emerging methods for automated digital image analysis of histology may provide a high-throughput means of quantification. Indeed, digital image analysis methods for quantifying Alzheimer's disease (AD) neuropathology have been previously described (Byrne et al 2009;Neltner et al 2012;Samaroo et al 2012), but there are minimal data on the neuropathology of FTLD. Further, FTLD spectrum pathology has a range of intracellular inclusions such as Pick bodies (PBs) as well as large dystrophic neurites (axonal or proximal dendritic inclusions; i.e., DNs; Fig.…”

Section: Research-article2015mentioning

confidence: 99%

“…These ratings are based on an examiner's subjective impressions of the burden of neurodegenerative pathology based on visual inspection. However, there may be inter-individual variability even among experts (Armstrong 2003), and ordinal scales provide limited statistical power for empirical studies (Neltner et al 2012). This is of particular importance in the context of less common and neuropathologically heterogeneous conditions like frontotemporal lobar degeneration (FTLD).…”

Section: Introductionmentioning

confidence: 99%

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Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

Irwin

Byrne²,

McMillan³

et al. 2015

J Histochem Cytochem.

103

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SummaryDigital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau-and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes. (J Histochem Cytochem 64:54-66, 2016)

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Section: Discussionmentioning

confidence: 99%

Section: Sampling Methods Validationmentioning

confidence: 99%

Section: Sampling Methods Validationmentioning

confidence: 99%

Section: Research-article2015mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

Irwin

Byrne²,

McMillan³

et al. 2015

J Histochem Cytochem.

103

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Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

et al. 2020

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IMPORTANCE Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein, and transactive response DNA-binding protein 43 ) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood.OBJECTIVE To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and Aβ), α-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019. MAIN OUTCOMES AND MEASURESFrequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein ε4 (APOE ε4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (Յ13 points) ranges during the 12 years before death. RESULTSThe final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE ε4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16-5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range.CONCLUSIONS AND RELEVANCE Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically...

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Tau pathology associates with in vivo cortical thinning in Lewy body disorders

Spotorno

Coughlin

Olm

et al. 2020

Ann Clin Transl Neurol

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Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Ab 1-42 > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBDÀAD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBDÀAD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Ab, and alpha-synuclein using digital histopathology in five representative neocortical regions. Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBDÀAD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Ab or alpha-synuclein pathology. Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.

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Digital Pathology and Image Analysis for Robust High-Throughput Quantitative Assessment of Alzheimer Disease Neuropathologic Changes

Cited by 60 publications

References 46 publications

Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

Tau pathology associates with in vivo cortical thinning in Lewy body disorders

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