Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

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.

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.

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.

The relationship between hippocampal amyloid beta burden and spatial distribution of neurofibrillary degeneration.

INTRODUCTION: Neurofibrillary degeneration in Alzheimer's disease (AD) typically involves the entorhinal cortex and CA1 subregion of the hippocampus early in the disease process, whereas in primary age-related tauopathy (PART), there is an early selective vulnerability of the CA2 subregion. METHODS: Image analysis-based quantitative pixel assessments were used to objectively evaluate amyloid beta (Aß) burden in the medial temporal lobe in relation to the distribution of hyperphosphorylated-tau (p-tau) in 142 cases of PART and AD. RESULTS: Entorhinal, CA1, CA3, and CA4 p-tau deposition levels are significantly correlated with Aß burden, while CA2 p-tau is not. Furthermore, the CA2/CA1 p-tau ratio is inversely correlated with Aß burden and distribution. In addition, cognitive impairment is correlated with overall p-tau burden. DISCUSSION: These data indicate that the presence and extent of medial temporal lobe Aß may determine the distribution and spread of neurofibrillary degeneration. The resulting p-tau distribution patterns may discriminate between PART and AD. HIGHLIGHTS: Subregional hyperphosphorylated-tau (p-tau) distribution is influenced by hippocampal amyloid beta burden. Higher CA2/CA1 p-tau ratio is predictive of primary age-related tauopathy-like neuropathology. Cognitive function is correlated with the overall hippocampal p-tau burden.

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-ß (Aß) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aß toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Head and Brain Postmortem Computed Tomography-Autopsy Correlation in Hospital Deaths.

The use of postmortem computed tomography (PMCT) to support autopsy pathology has increased in recent decades. To some extent, PMCT has also been contemplated as a potential alternative to conventional postmortem examination. The purpose of this study was to investigate the ability of PMCT to detect specific pathologic findings in the head and brain in natural hospital deaths.We examined postmortem CT images and autopsy data from 31 subjects who died at SUNY (State University of New York) Upstate University Hospital between 2013 and 2018. Each subject underwent a noncontrast PMCT and a traditional autopsy. A neuroradiologist analyzed PMCT images for head and brain abnormalities. The autopsies were performed by pathologists who were aware of the radiology results.In our series, PMCT was able to detect the majority of the significant space-occupying lesions, although it was not always reliable in ascertaining their nature. Postmortem computed tomography revealed findings usually challenging to detect at autopsy. Unfortunately, there were also situations in which PMCT was misleading, showing changes that were difficult to interpret, or that could be related to postmortem events. Therefore, we conclude PMCT should be used as an adjunct rather than a substitute to autopsy.

Artificial intelligence in neuropathology: deep learning-based assessment of tauopathy.

Accumulation of abnormal tau in neurofibrillary tangles (NFT) occurs in Alzheimer disease (AD) and a spectrum of tauopathies. These tauopathies have diverse and overlapping morphological phenotypes that obscure classification and quantitative assessments. Recently, powerful machine learning-based approaches have emerged, allowing the recognition and quantification of pathological changes from digital images. Here, we applied deep learning to the neuropathological assessment of NFT in postmortem human brain tissue to develop a classifier capable of recognizing and quantifying tau burden. The histopathological material was derived from 22 autopsy brains from patients with tauopathies. We used a custom web-based informatics platform integrated with an in-house information management system to manage whole slide images (WSI) and human expert annotations as ground truth. We utilized fully annotated regions to train a deep learning fully convolutional neural network (FCN) implemented in PyTorch against the human expert annotations. We found that the deep learning framework is capable of identifying and quantifying NFT with a range of staining intensities and diverse morphologies. With our FCN model, we achieved high precision and recall in naive WSI semantic segmentation, correctly identifying tangle objects using a SegNet model trained for 200 epochs. Our FCN is efficient and well suited for the practical application of WSIs with average processing times of 45 min per WSI per GPU, enabling reliable and reproducible large-scale detection of tangles. We measured performance on test data of 50 pre-annotated regions on eight naive WSI across various tauopathies, resulting in the recall, precision, and an F1 score of 0.92, 0.72, and 0.81, respectively. Machine learning is a useful tool for complex pathological assessment of AD and other tauopathies. Using deep learning classifiers, we have the potential to integrate cell- and region-specific annotations with clinical, genetic, and molecular data, providing unbiased data for clinicopathological correlations that will enhance our knowledge of the neurodegeneration.

BRAF mutation leading to central nervous system rosai-dorfman disease.

Rosai-Dorfman disease (RDD) is an uncommon histiocytic proliferative disorder that can present in nodal, extranodal, or, extremely rarely, in central nervous system (CNS)-restricted form. RDD is characterized histologically as a non-Langerhans cell histiocytosis composed of atypical CD68+ /S-100+ /CD1a- macrophages demonstrating prominent emperipolesis and effacement of the surrounding tissue. Previously thought to represent a reactive process, recent studies have raised the possibility that RDD and other histiocytic lesions, including Erdheim-Chester and Langerhans cell histiocytosis, are clonal processes linked to somatic mutations in the mitogen-activated protein (MAP) kinase pathway. Herein, we present a fatal case of RDD isolated to the CNS and used a next-generation targeted gene panel and Sanger sequencing to uncover a pathogenic deletion in the ß3-αC loop of the kinase domain in exon 12 of BRAF. This mutation, previously described in melanoma and Langerhans cell histiocytosis, represents the first BRAF mutation of this kind identified in RDD. These findings support the idea that RDD is a neoplastic condition and raise the possibility that inhibitors of the MAP kinase pathway may be effective in RDD. Ann Neurol 2018;83:147-152.

Massive intracranial bleeding due to the rupture of a rare spontaneous pseudoaneurysm of the middle cerebral artery in a pediatric patient: case report with clinical, radiological, and pathologic findings.

Intracranial pseudoaneurysm (IPA) is a rare but likely underdiagnosed cause of intracranial hemorrhage, which accounts for just 1-6% of all intracranial aneurysms. Spontaneous IPAs are exceptionally rare, and their etiology and features are not well defined. Herein, we report a case of a pediatric patient who died from massive intracranial bleeding due to the rupture of a spontaneous IPA after undergoing multiple radiological studies and neurosurgical operations. At the postmortem examination of the brain, a giant size pseudoaneurysm of the right middle cerebral artery was observed. Microscopic examination demonstrated variable wall thickness and dense fibrosis focally in the vessel wall with disruption of the media structure together with a loss and fragmentation of the elastic laminae, loss of organization of smooth muscle cells in the media, and multifocal areas of hemorrhage throughout the vessel wall, as well as direct evidence of wall dissection. Since IPAs without any traumatic or infective history are extremely uncommon, further pathologic studies should be performed to clarify spontaneous pseudoaneurysm etiology.

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis.

According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

Unusual skull tumors with psammomatoid bodies: a diagnostic challenge.

AIM: We describe a series of three diagnostically challenging, histologically similar fibro-osseous skull masses. METHODS: The cases were identified in our archives among 50,000 neuropathology specimens. A comprehensive review of the histological, immunohistochemical, ultrastructural, and imaging features as well as the clinical outcome was performed. RESULTS: The routine histology was similar in all 3 cases and showed spindle cell proliferations with frequent calcospheres or psammomatoid bodies. There was no evidence of an underlying subdural component. Immunohistochemistry for the meningioma markers EMA and SSTR2A raised the possibility of intraosseous meningioma, as all 3 lesions were convincingly positive for epithelial membrane antigen (EMA) and 1 lesion was convincingly positive for the somatostatin receptor subtype 2A (SSTR2A); weak, questionable positivity for SSTR2 was present in the remaining 2 cases. In addition, electron microscopy was available in 1 case and showed features consistent with meningioma. CONCLUSIONS: Overall, the findings were most consistent with intraosseous meningioma. Primary intraosseous meningiomas are rare lesions that may present a diagnostic challenge. It is important to consider meningiomas in the differential diagnosis, as extradural meningiomas are associated with an increased risk of recurrence and may occasionally undergo malignant transformation.
.

Linking spermatid ribonucleic acid (RNA) binding protein and retrogene diversity to reproductive success.

Spermiogenesis is a postmeiotic process that drives development of round spermatids into fully elongated spermatozoa. Spermatid elongation is largely controlled post-transcriptionally after global silencing of mRNA synthesis from the haploid genome. Here, rats that differentially express EGFP from a lentiviral transgene during early and late steps of spermiogenesis were used to flow sort fractions of round and elongating spermatids. Mass-spectral analysis of 2D gel protein spots enriched >3-fold in each fraction revealed a heterogeneous RNA binding proteome (hnRNPA2/b1, hnRNPA3, hnRPDL, hnRNPK, hnRNPL, hnRNPM, PABPC1, PABPC4, PCBP1, PCBP3, PTBP2, PSIP1, RGSL1, RUVBL2, SARNP2, TDRD6, TDRD7) abundantly expressed in round spermatids prior to their elongation. Notably, each protein within this ontology cluster regulates alternative splicing, sub-cellular transport, degradation and/or translational repression of mRNAs. In contrast, elongating spermatid fractions were enriched with glycolytic enzymes, redox enzymes and protein synthesis factors. Retrogene-encoded proteins were over-represented among the most abundant elongating spermatid factors identified. Consistent with these biochemical activities, plus corresponding histological profiles, the identified RNA processing factors are predicted to collectively drive post-transcriptional expression of an alternative exome that fuels finishing steps of sperm maturation and fitness.

A-single spermatogonia heterogeneity and cell cycles synchronize with rat seminiferous epithelium stages VIII-IX.

In mammalian testes, "A-single" spermatogonia function as stem cells that sustain sperm production for fertilizing eggs. Yet, it is not understood how cellular niches regulate the developmental fate of A-single spermatogonia. Here, immunolabeling studies in rat testes define a novel population of ERBB3(+) germ cells as approximately 5% of total SNAP91(+) A-single spermatogonia along a spermatogenic wave. As a function of time, ERBB3(+) A-single spermatogonia are detected during a 1- to 2-day period each 12.9-day sperm cycle, representing 35%-40% of SNAP91(+) A-single spermatogonia in stages VIII-IX of the seminiferous epithelium. Local concentrations of ERBB3(+) A-single spermatogonia are maintained under the mean density measured for neighboring SNAP91(+) A-single spermatogonia, potentially indicative of niche saturation. ERBB3(+) spermatogonia also synchronize their cell cycles with epithelium stages VIII-IX, where they form physical associations with preleptotene spermatocytes transiting the blood-testis barrier and Sertoli cells undergoing sperm release. Thus, A-single spermatogonia heterogeneity within this short-lived and reoccurring microenvironment invokes novel theories on how cellular niches integrate with testicular physiology to orchestrate sperm development in mammals.

Neuroprotection with non-feminizing estrogen analogues: an overlooked possible therapeutic strategy.

Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds.

Cognitive resistance to and resilience against multiple comorbid neurodegenerative pathologies and the impact of APOE status.

Alzheimer disease (AD) is currently the leading cause of cognitive decline and dementia worldwide. Recently, studies have suggested that other neurodegenerative comorbidities such as limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Lewy body disease (LBD), and cerebrovascular disease frequently co-occur with Alzheimer disease neuropathologic change (ADNC) and may have significant cognitive effects both in isolation and synergistically with ADNC. Herein, we study the relative clinical impact of these multiple neurodegenerative pathologies in 704 subjects. Each of these pathologies is relatively common in the cognitively impaired population, while cerebrovascular pathology and ADNC are the most common in cognitively normal individuals. Moreover, while the number of concurrent neuropathologic entities rises with age and has a progressively deleterious effect on cognition, 44.3% of cognitively intact individuals are resistant to having any neurodegenerative proteinopathy (compared to 15.2% of cognitively impaired individuals) and 83.5% are resistant to having multiple concurrent proteinopathies (compared to 64.6% of cognitively impaired individuals). The presence of at least 1 APOE ε4 allele was associated with impaired cognition and the presence of multiple proteinopathies, while APOE ε2 was protective against cumulative proteinopathies. These results indicate that maintenance of normal cognition may depend on resistance to the development of multiple concurrent proteinopathies.

Cognitive symptoms progress with limbic-predominant age-related TDP-43 encephalopathy stage and co-occurrence with Alzheimer disease.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a neuropathologic entity characterized by transactive response DNA-binding protein of 43-kDa (TDP-43)-immunoreactive inclusions that originate in the amygdala and then progress to the hippocampi and middle frontal gyrus. LATE-NC may mimic Alzheimer disease clinically and often co-occurs with Alzheimer disease neuropathologic change (ADNC). This report focuses on the cognitive effects of isolated and concomitant LATE-NC and ADNC. Cognitive/neuropsychological, neuropathologic, genetic, and demographic variables were analyzed in 28 control, 31 isolated LATE-NC, 244 isolated ADNC, and 172 concurrent LATE-NC/ADNC subjects from the National Alzheimer's Coordinating Center. Cases with LATE-NC and ADNC were significantly older than controls; cases with ADNC had a significantly higher proportion of cases with at least one APOE ε4 allele. Both LATE-NC and ADNC exhibited deleterious effects on overall cognition proportional to their neuropathological stages; concurrent LATE-NC/ADNC exhibited the worst overall cognitive effect. Multivariate logistic regression analysis determined an independent risk of cognitive impairment for progressive LATE-NC stages (OR 1.66; p = 0.0256) and ADNC levels (OR 3.41; p < 0.0001). These data add to the existing knowledge on the clinical consequences of LATE-NC pathology and the growing literature on the effects of multiple concurrent neurodegenerative pathologies.

Cognitive and Neuropsychological Profiles in Alzheimer's Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies.

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-ß (Aß) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aß-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.

The Spectrum of Alzheimer-Type Pathology in Cognitively Normal Individuals.

BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology. RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels. CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-ß (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).