Fluid preservation in brain banking: a review.

Fluid preservation is nearly universally used in brain banking to store fixed tissue specimens for future research applications. However, the effects of long-term immersion on neural circuitry and biomolecules are not well characterized. As a result, there is a need to synthesize studies investigating fluid preservation of brain tissue. We searched PubMed and other databases to identify studies measuring the effects of fluid preservation in nervous system tissue. We categorized studies based on the fluid preservative used: formaldehyde solutions, buffer solutions, alcohol solutions, storage after tissue clearing, and cryoprotectant solutions. We identified 91 studies containing 197 independent observations of the effects of long-term storage on cellular morphology. Most studies did not report any significant alterations due to long-term storage. When present, the most frequent alteration was decreased antigenicity, commonly attributed to progressive crosslinking by aldehydes that renders biomolecules increasingly inaccessible over time. To build a mechanistic understanding, we discuss biochemical aspects of long-term fluid preservation. A subset of lipids appears to be chemical altered or extracted over time due to incomplete retention in the crosslinked gel. Alternative storage fluids mitigate the problem of antigen masking but have not been extensively characterized and may have other downsides. We also compare fluid preservation to cryopreservation, paraffin embedding, and resin embedding. Overall, existing evidence suggests that fluid preservation provides maintenance of neural architecture for decades, including precise structural details. However, to avoid the well-established problem of overfixation caused by storage in high concentration formaldehyde solutions, fluid preservation procedures can use an initial fixation step followed by an alternative long-term storage fluid. Further research is warranted on optimizing protocols and characterizing the generalizability of the storage artifacts that have been identified.

Does rural transformation affect rural income inequality? Insights from cross-district panel data analysis in Bangladesh.

Rural transformation plays a crucial role in enhancing the income and employment prospects of the rural labor force. We investigate the effects of rural transformation on rural income inequality at the district level in Bangladesh using data from five years of nationally representative Household Income and Expenditure Surveys. The Gini coefficient is used to measure rural income inequality. In contrast, the share of high-value agricultural outputs and the share of rural non-farm employment are used as indicators of rural transformation. We find that rural income inequality is positively associated with the share of high-value agricultural outputs and the share of rural non-farm employment. The non-linear regression result shows an inverted U-shaped relationship between rural transformation and income inequality, which indicates that income inequality initially increases with rural transformation but decreases in the long run. Additionally, we find that rural income inequality is positively correlated with the proportion of household education expenditures, agricultural rental activity, and the share of remittances. This study also reveals that income inequality in rural areas of Bangladesh has a significant negative correlation with the government's social safety net program.

"Right Into the Center": A Semantic Analysis of Direction in Operating Room Instruction.

OBJECTIVE: In our previous work, teaching surgeons used potentially ambiguous language in the OR 12.3 times per minute. Our objectives were to examine ambiguous examples featuring Directional Frame of Reference (DFoR), which involves instructions containing directional terms like "up" or "left," and to uncover what contributes to understanding or misunderstanding of such instruction. DESIGN: We videorecorded the critical moments of 6 surgeries, as chosen by the surgeons. With a semanticist, we applied constructs from formal semantics to choose potentially ambiguous DFoR terms commonly flagged in our previous work. We separately interviewed attending and resident surgeons, asking each to describe the meaning of those DFoR terms while they viewed case recordings alongside transcripts. We compared their responses, analyzing them for agreement in direction. We performed thematic analysis on case and interview transcripts for themes related to DFoR. SETTING: Midwestern academic university teaching hospital. PARTICIPANTS: Six attending and 6 resident surgeons. RESULTS: Attending and resident surgeons disagreed on direction in 9 of the 26 (34.6%) DFoR examples. Misunderstanding arose from using linear direction to describe three-dimensional space, e.g., "up" for anterior/cephalad/right. It also arose when combining degree modifiers with DfoR, e.g., "we're far enough back" combines the ambiguities of "back" (DfoR) and "far enough" (degree modifier). Use of axial parts (noun-like directional terms), e.g., "bottom," and confusing "left" for "right" also provoked misunderstanding. Misunderstanding was associated with lack of experience and mitigated by pointing with a finger or instrument, concurrent with speech. CONCLUSIONS: Use of ambiguous language with DFoR incurs a high potential for misunderstanding, especially with novice surgeons. We recommend avoiding linear directions and axial parts, and instead physically pointing to represent complex 3D directions. Degree modifiers can be replaced with exact distances e.g., replace "little more anterior" with "1 centimeter anterior," and semaphores can be used to clarify direction.

Identification of influential weather parameters and seasonal drought prediction in Bangladesh using machine learning algorithm.

Droughts pose a severe environmental risk in countries that rely heavily on agriculture, resulting in heightened levels of concern regarding food security and livelihood enhancement. Bangladesh is highly susceptible to environmental hazards, with droughts further exacerbating the precarious situation for its 170 million inhabitants. Therefore, we are endeavouring to highlight the identification of the relative importance of climatic attributes and the estimation of the seasonal intensity and frequency of droughts in Bangladesh. With a period of forty years (1981-2020) of weather data, sophisticated machine learning (ML) methods were employed to classify 35 agroclimatic regions into dry or wet conditions using nine weather parameters, as determined by the Standardized Precipitation Evapotranspiration Index (SPEI). Out of 24 ML algorithms, the four best ML methods, ranger, bagEarth, support vector machine, and random forest (RF) have been identified for the prediction of multi-scale drought indices. The RF classifier and the Boruta algorithms shows that water balance, precipitation, maximum and minimum temperature have a higher influence on drought intensity and occurrence across Bangladesh. The trend of spatio-temporal analysis indicates, drought intensity has decreased over time, but return time has increased. There was significant variation in changing the spatial nature of drought intensity. Spatially, the drought intensity shifted from the northern to central and southern zones of Bangladesh, which had an adverse impact on crop production and the livelihood of rural and urban households. So, this precise study has important implications for the understanding of drought prediction and how to best mitigate its impacts. Additionally, the study emphasizes the need for better collaboration between relevant stakeholders, such as policymakers, researchers, communities, and local actors, to develop effective adaptation strategies and increase monitoring of weather conditions for the meticulous management of droughts in Bangladesh.

Cooperation of ILC2s and TH2 cells in the expulsion of intestinal helminth parasites.

Type 2 immune responses form a critical defence against enteric worm infections. In recent years, mouse models have revealed shared and unique functions for group 2 innate lymphoid cells and T helper 2 cells in type 2 immune response to intestinal helminths. Both cell types use similar innate effector functions at the site of infection, whereas each population has distinct roles during different stages of infection. In this Perspective, we review the underlying mechanisms used by group 2 innate lymphoid cells and T helper 2 cells to cooperate with each other and suggest an overarching model of the interplay between these cell types over the course of a helminth infection.

Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy.

INTRODUCTION: 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 (Aß) 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 Aß 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 Aß 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 Aß 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.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

The alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration.

As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is essential to restore new T-cell production following tissue damage from environmental factors and therapeutic interventions. Here, we show the alarmin interleukin (IL) 33 is a product of Sca1+ thymic mesenchyme both necessary and sufficient for thymus regeneration via a type 2 innate immune network. IL33 stimulates expansion of IL5-producing type 2 innate lymphoid cells (ILC2), which triggers a cellular switch in the intrathymic availability of IL4. This enables eosinophil production of IL4 to re-establish thymic mesenchyme prior to recovery of thymopoiesis-inducing epithelial compartments. Collectively, we identify a positive feedback mechanism of type 2 innate immunity that regulates the recovery of thymus function following tissue injury.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Histopathologic brain age estimation via multiple instance learning.

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.

Postmortem changes in brain cell structure: a review.

Brain cell structure is a key determinant of neural function that is frequently altered in neurobiological disorders. Following the global loss of blood flow to the brain that initiates the postmortem interval (PMI), cells rapidly become depleted of energy and begin to decompose. To ensure that our methods for studying the brain using autopsy tissue are robust and reproducible, there is a critical need to delineate the expected changes in brain cell morphometry during the PMI. We searched multiple databases to identify studies measuring the effects of PMI on the morphometry (i.e. external dimensions) of brain cells. We screened 2119 abstracts, 361 full texts, and included 172 studies. Mechanistically, fluid shifts causing cell volume alterations and vacuolization are an early event in the PMI, while the loss of the ability to visualize cell membranes altogether is a later event. Decomposition rates are highly heterogenous and depend on the methods for visualization, the structural feature of interest, and modifying variables such as the storage temperature or the species. Geometrically, deformations of cell membranes are common early events that initiate within minutes. On the other hand, topological relationships between cellular features appear to remain intact for more extended periods. Taken together, there is an uncertain period of time, usually ranging from several hours to several days, over which cell membrane structure is progressively lost. This review may be helpful for investigators studying human postmortem brain tissue, wherein the PMI is an unavoidable aspect of the research.

Molecular differences in brain regional vulnerability to aging between males and females.

Background: Aging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive. Results: Using the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer's disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases. Conclusions: This integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD.

Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation.

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.

Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils.

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/fl Il7rCre/+ mice or induced ILC2 depletion in Icosfl-DTR-fl/+ Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5-/- mice induces EOS differentiation in bone-marrow cells from Rorafl/fl Il7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5-/- and Il13-/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5-/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/fl Il7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

An αvß3 integrin checkpoint is critical for efficient TH2 cell cytokine polarization and potentiation of antigen-specific immunity.

Naive CD4+ T lymphocytes initially undergo antigen-specific activation to promote a broad-spectrum response before adopting bespoke cytokine expression profiles shaped by intercellular microenvironmental cues, resulting in pathogen-focused modular cytokine responses. Interleukin (IL)-4-induced Gata3 upregulation is important for the helper type 2 T cell (TH2 cell) polarization associated with anti-helminth immunity and misdirected allergic inflammation. Whether additional microenvironmental factors participate is unclear. Using whole mouse-genome CRISPR-Cas9 screens, we discovered a previously unappreciated role for αvß3 integrin in TH2 cell differentiation. Low-level αvß3 expression by naive CD4+ T cells contributed to pan-T cell activation by promoting T-T cell clustering and IL-2/CD25/STAT5 signaling. Subsequently, IL-4/Gata3-induced selective upregulation of αvß3 licensed intercellular αvß3-Thy1 interactions among TH2 cells, enhanced mammalian target of rapamycin (mTOR) signaling, supported differentiation and promoted IL-5/IL-13 production. In mice, αvß3 was required for efficient, allergen-driven, antigen-specific lung TH2 cell responses. Thus, αvß3-expressing TH2 cells form multicellular factories to propagate and amplify TH2 cell responses.

Group 2 innate lymphoid cells protect mouse heart from myocardial infarction injury via interleukin 5, eosinophils, and dendritic cells.

AIMS: Group 2 innate lymphoid cells (ILC2s) regulate adaptive and innate immunities. In mouse heart, production of myocardial infarction (MI) increased ILC2 accumulation, suggesting a role for ILC2 in cardiac dysfunction post-MI. METHODS AND RESULTS: We produced MI in ILC2-deficeint Rorafl/flIl7rCre/+ mice and in Icosfl-DTR-fl/+Cd4Cre/+ mice that allowed diphtheria toxin-induced ILC2 depletion. Genetic or induced deficiency of ILC2 in mice exacerbated cardiac dysfunction post-MI injury along with increased myocardial accumulation of neutrophils, CD11b+Ly6Chi monocytes, and CD4+ T cells but deficiency of eosinophils (EOS) and dendritic cells (DC). Post-MI hearts from genetic and induced ILC2-deficient mice contained many more apoptotic cells than those of control mice, and Rorafl/flIl7rCre/+ mice showed thinner and larger infarcts and more collagen-I depositions than the Il7rCre/+ mice only at early time points post-MI. Mechanistic studies revealed elevated blood IL5 in Il7rCre/+ mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rorafl/flIl7rCre/+ mice. Administration of recombinant IL5 reversed EOS losses in Rorafl/flIl7rCre/+ mice, but IL5 did not correct the DC loss in these mice. Adoptive transfer of ILC2, EOS, or DC from wild-type mice, but not ILC2 from Il5-/- mice improved post-MI cardiac functions in Rorafl/flIl7rCre/+ recipient mice. EOS are known to protect cardiomyocytes from apoptosis. Here we showed that DC acted like EOS in blocking cardiomyocyte apoptosis. Yet, ILC2 or IL5 alone did not directly affect cardiomyocyte apoptosis or TGF-ß (transforming growth factor-ß)-induced cardiac fibroblast Smad signalling. CONCLUSION: This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism.

Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum.

The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC hematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution, we have characterized bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK cell progenitors (ILC1/NKP), which we call "aceNKPs", are defined as lineage-Id2+IL-7Rα+CD25-α4ß7-NKG2A/C/E+Bcl11b-. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-γ and perforin upon IL-15 stimulation. Following reconstitution of Rag2-/-Il2rg-/- hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumor burden in a model of lung metastasis, where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.

Artificial intelligence-derived neurofibrillary tangle burden is associated with antemortem cognitive impairment.

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 (Aß) in plaques that typifies Alzheimer disease (AD), the most common tauopathy. Primary age-related tauopathy (PART) is an Aß-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 Aß 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.