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  • Walker, Jamie M.  (12)
  • 2020-2024  (12)
  • 1
    Online Resource
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    Genome-wide association study and functional validation implicates JADE1 in tauopathy
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Vol. 143, No. 1 ( 2022-01), p. 33-53
    Details
    In: Acta Neuropathologica, Springer Science and Business Media LLC, Vol. 143, No. 1 ( 2022-01), p. 33-53
    Type of Medium: Online Resource
    ISSN: 0001-6322 , 1432-0533
    URL: Article
    DOI: 10.1007/s00401-021-02379-z
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1458410-4
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  • 2
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    Interpretable deep learning of myelin histopathology in age-related cognitive impairment
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Communications Vol. 10, No. 1 ( 2022-09-21)
    Details
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2022-09-21)
    Abstract: Age-related cognitive impairment is multifactorial, with numerous underlying and frequently co-morbid pathological correlates. Amyloid beta (Aβ) plays a major role in Alzheimer’s type age-related cognitive impairment, in addition to other etiopathologies such as Aβ-independent hyperphosphorylated tau, cerebrovascular disease, and myelin damage, which also warrant further investigation. Classical methods, even in the setting of the gold standard of postmortem brain assessment, involve semi-quantitative ordinal staging systems that often correlate poorly with clinical outcomes, due to imperfect cognitive measurements and preconceived notions regarding the neuropathologic features that should be chosen for study. Improved approaches are needed to identify histopathological changes correlated with cognition in an unbiased way. We used a weakly supervised multiple instance learning algorithm on whole slide images of human brain autopsy tissue sections from a group of elderly donors to predict the presence or absence of cognitive impairment ( n  = 367 with cognitive impairment, n  = 349 without). Attention analysis allowed us to pinpoint the underlying subregional architecture and cellular features that the models used for the prediction in both brain regions studied, the medial temporal lobe and frontal cortex. Despite noisy labels of cognition, our trained models were able to predict the presence of cognitive impairment with a modest accuracy that was significantly greater than chance. Attention-based interpretation studies of the features most associated with cognitive impairment in the top performing models suggest that they identified myelin pallor in the white matter. Our results demonstrate a scalable platform with interpretable deep learning to identify unexpected aspects of pathology in cognitive impairment that can be translated to the study of other neurobiological disorders.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    URL: Article
    DOI: 10.1186/s40478-022-01425-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2715589-4
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  • 3
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    Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study
    Springer Science and Business Media LLC ; 2021
    In:  Acta Neuropathologica Communications Vol. 9, No. 1 ( 2021-12)
    Details
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2021-12)
    Abstract: Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection ( n  = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age ( p  = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age ( p  = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor ( p   〈  0.0001), but other features including ARTAG ( p  = 0.03) and hippocampal atrophy ( p  = 0.04) were also associated. In contrast, sex, APOE , psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    URL: Article
    DOI: 10.1186/s40478-021-01233-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 4
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    Artificial intelligence-derived neurofibrillary tangle burden is associated with antemortem cognitive impairment
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Communications Vol. 10, No. 1 ( 2022-10-31)
    Details
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2022-10-31)
    Abstract: Tauopathies are a category of neurodegenerative diseases characterized by the presence of abnormal tau protein-containing neurofibrillary tangles (NFTs). NFTs are universally observed in aging, occurring with or without the concomitant accumulation of amyloid-beta peptide (Aβ) in plaques that typifies Alzheimer disease (AD), the most common tauopathy. Primary age-related tauopathy (PART) is an Aβ-independent process that affects the medial temporal lobe in both cognitively normal and impaired subjects. Determinants of symptomology in subjects with PART are poorly understood and require clinicopathologic correlation; however, classical approaches to staging tau pathology have limited quantitative reproducibility. As such, there is a critical need for unbiased methods to quantitatively analyze tau pathology on the histological level. Artificial intelligence (AI)-based convolutional neural networks (CNNs) generate highly accurate and precise computer vision assessments of digitized pathology slides, yielding novel histology metrics at scale. Here, we performed a retrospective autopsy study of a large cohort ( n  = 706) of human post-mortem brain tissues from normal and cognitively impaired elderly individuals with mild or no Aβ plaques (average age of death of 83.1 yr, range 55–110). We utilized a CNN trained to segment NFTs on hippocampus sections immunohistochemically stained with antisera recognizing abnormal hyperphosphorylated tau (p-tau), which yielded metrics of regional NFT counts, NFT positive pixel density, as well as a novel graph-theory based metric measuring the spatial distribution of NFTs. We found that several AI-derived NFT metrics significantly predicted the presence of cognitive impairment in both the hippocampus proper and entorhinal cortex ( p   〈  0.0001). When controlling for age, AI-derived NFT counts still significantly predicted the presence of cognitive impairment ( p  = 0.04 in the entorhinal cortex; p  = 0.04 overall). In contrast, Braak stage did not predict cognitive impairment in either age-adjusted or unadjusted models. These findings support the hypothesis that NFT burden correlates with cognitive impairment in PART. Furthermore, our analysis strongly suggests that AI-derived metrics of tau pathology provide a powerful tool that can deepen our understanding of the role of neurofibrillary degeneration in cognitive impairment.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    URL: Article
    DOI: 10.1186/s40478-022-01457-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 5
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    Spatial proteomics of hippocampal subfield‐specific pathology in Alzheimer's disease and primary age‐related tauopathy
    Wiley ; 2024
    In:  Alzheimer's & Dementia Vol. 20, No. 2 ( 2024-02), p. 783-797
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 20, No. 2 ( 2024-02), p. 783-797
    Abstract: Alzheimer's disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R hyperphosphorylated‐tau (p‐tau)‐positive neurofibrillary tangles (NFTs) but differ in the spatial p‐tau development in the hippocampus. METHODS Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT‐bearing and non‐NFT‐bearing neurons in AD ( n  = 7) and PART ( n  = 7) subjects. RESULTS Proteomic measures of synaptic health were inversely correlated with the subregional p‐tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aβ) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION These results suggest subfield‐specific proteome differences that may explain some of the differences in Aβ and p‐tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aβ in the pathologic process. Highlights Synaptic health is inversely correlated with local p‐tau burden. The proteome of NFT‐ and non‐NFT‐bearing neurons is influenced by the presence of Aβ in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v20.2
    DOI: 10.1002/alz.13484
    Language: English
    Publisher: Wiley
    Publication Date: 2024
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  • 6
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    Hippocampal subregion‐specific proteomic differences between Alzheimer disease (AD) and primary age‐related tauopathy (PART)
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S12 ( 2023-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S12 ( 2023-12)
    Abstract: Although Alzheimer disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R‐tau immunopositive Alzheimer‐type neurofibrillary degeneration, they differ in the spatial development of neurofibrillary tangles (NFTs) in the hippocampus. PART displays an early predilection for neurofibrillary degeneration in the CA2 subregion of the hippocampus, whereas AD typically develops NFTs in the entorhinal cortex and CA1 subregion initially (Figures 1‐2). Method Using Nanostring’s GeoMx™ Digital Spatial Profiling (DSP), we compared hippocampal subregion protein expression differences between AD and PART. The DSP panel allows for spatial analysis of the level of expression of 73 different proteins in multiple regions of interest (ROIs) on formalin‐fixed paraffin embedded sections. Our ROIs were NFT‐bearing neurons and non‐NFT‐bearing neurons in the entorhinal cortex, CA1 and CA2 hippocampal subregions, as well as the neuronal microenvironments in these regions. Result Analyses identified several proteins displaying differential expression in tangle‐bearing neurons when comparing AD to PART. These included higher levels of synaptic and neuronal markers in PART, such as Synaptophysin, MAP2, Calbindin and NRGN, as well as higher levels of proteins involved in degradation pathways, such as CTSD, GPNMB, Park7 and FUS. PART also displayed higher levels of Neprilysin in CA2, and higher IDE in CA1, which are proteins that help degrade β‐amyloid (Figure 3). Many of these proteins were also differentially expressed in the non‐tangle bearing neurons. In addition, AD demonstrated higher levels of p‐tau T231, S214, S199, and S396 in non‐tangle bearing neurons of CA1, as well as higher expression of Aβ1‐40. In the microenvironment, NEFL, NRGN, CLEC7a, GPNMB, and CTSD were higher in PART, while p‐tau S396 and BACE1 were higher in AD. Conclusion In conclusion, PART cases displayed higher levels of neuronal and synaptic markers, suggesting better maintenance of neuronal and synaptic integrity than AD, as well as higher levels of proteins important for degradation of detrimental proteins. AD cases expressed higher levels of certain p‐tau epitopes, especially in and around CA1 non‐tangle bearing neurons. In addition, AD displayed higher levels of BACE1, whereas PART displayed higher levels of CTSD, Neprilysin and IDE, which could explain the differences in β‐amyloid deposition in these cases.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S12
    DOI: 10.1002/alz.073721
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 7
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    Histopathologic brain age estimation via multiple instance learning
    Springer Science and Business Media LLC ; 2023
    In:  Acta Neuropathologica Vol. 146, No. 6 ( 2023-12), p. 785-802
    Details
    In: Acta Neuropathologica, Springer Science and Business Media LLC, Vol. 146, No. 6 ( 2023-12), p. 785-802
    Abstract: Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as elucidate pathological determinants of age-related functional decline and identify early disease changes in the context of Alzheimer’s and other disorders. Histopathological whole slide images provide a wealth of pathologic data on the cellular level that can be leveraged to build deep learning models to assess age acceleration. Here, we used a collection of digitized human post-mortem hippocampal sections to develop a histological brain age estimation model. Our model predicted brain age within a mean absolute error of 5.45 ± 0.22 years, with attention weights corresponding to neuroanatomical regions vulnerable to age-related changes. We found that histopathologic brain age acceleration had significant associations with clinical and pathologic outcomes that were not found with epigenetic based measures. Our results indicate that histopathologic brain age is a powerful, independent metric for understanding factors that contribute to brain aging.
    Type of Medium: Online Resource
    ISSN: 0001-6322 , 1432-0533
    URL: Article
    DOI: 10.1007/s00401-023-02636-3
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 8
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    Cognitive and Neuropsychological Profiles in Alzheimer’s Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies
    IOS Press ; 2023
    In:  Journal of Alzheimer's Disease Vol. 92, No. 3 ( 2023-04-04), p. 1037-1049
    Details
    In: Journal of Alzheimer's Disease, IOS Press, Vol. 92, No. 3 ( 2023-04-04), p. 1037-1049
    Abstract: Background: Alzheimer’s disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. Objective: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). Methods: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I–IV, Thal phase 0, CERAD NP score “absent”) and 178 NT subjects from the National Alzheimer’s Coordinating Center dataset. Results: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Conclusion: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.
    Type of Medium: Online Resource
    ISSN: 1387-2877 , 1875-8908
    URL: Article
    DOI: 10.3233/JAD-230022
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2023
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  • 9
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    Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies
    Springer Science and Business Media LLC ; 2024
    In:  Acta Neuropathologica Vol. 147, No. 1 ( 2024-06)
    Details
    In: Acta Neuropathologica, Springer Science and Business Media LLC, Vol. 147, No. 1 ( 2024-06)
    Abstract: Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer’s Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.
    Type of Medium: Online Resource
    ISSN: 0001-6322 , 1432-0533
    URL: Article
    DOI: 10.1007/s00401-024-02716-y
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
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  • 10
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    Predictors of Successful Brain Aging: An Autopsy Study
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S24 ( 2023-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S24 ( 2023-12)
    Abstract: The neuropathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques and neurofibrillary tangles, also accumulate in the brains of aging individuals. However, some individuals are able to age successfully without significant degenerative neuropathology or cognitive impairment, a phenomenon referred to as “successful aging”. The predictors of successful “neuropathologic” and “cognitive” aging are not fully understood, creating a critical knowledge gap. Factors such as resistance, resilience, and reserve are believed to play important roles. Furthermore, the relationship between neuropathological changes, such as tau pathology and amyloid pathology, and cognitive impairment in the oldest old population remains unclear, and the concept of amyloid plaques causing tau pathology may not be universally valid. The association between amyloid plaques and dementia also continues to be debated. Methods In this study, we utilized a collection of 414 post‐mortem brain tissues (171 female, 241 male) from aged individuals (average age 90, range 80‐108) with neuropathological and clinical data (215 without cognitive impairment and 161 with cognitive impairment) to perform a cross‐sectional analysis. Our cohort included subjects who had cognitive assessments available and included those with no amyloid plaque pathology or mild burden based on neuropathological criteria. Variables (including new traits derived from A.I. based feature extraction) associated with the cognitive measures were determined using multivariable logistic regression. Results Our results revealed that age of death and Braak neurofibrillary tangle stage were significant predictors of cognitive impairment (p 〈 0.05), while amyloid positivity was not. These findings suggest that tau pathology may have a stronger association with cognitive impairment in the oldest old population compared to amyloid plaques. Conclusion Understanding the neuropathological factors associated with successful brain and cognitive aging will contribute to our knowledge of the underlying mechanisms and may pave the way for the development of interventions to promote successful aging and prevent cognitive decline in old age. Further research in this area is warranted to elucidate the complex relationship between neuropathology, cognitive function, and aging in the oldest old population.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S24
    DOI: 10.1002/alz.083154
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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