We recently reported genetic associations with dementia-related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP-43, Ab/Tau, and a-synuclein related neuropathology endophenotype scores. However, we have not evaluated multiallelic sites, which are genetic variants with mutations that are more complex than simple nucleotide variation where conventional genetic coding (e.g., 0, 1, and 2 alleles) cannot be used. Here, we perform genome-wide multiallelic variant analyses using whole genome sequencing (WGS) data generated by Alzheimer's Disease Sequencing Project (ADSP). Participant data were drawn from the National Alzheimer's Coordinating Center (NACC) neuropathology (NP) v10-11 data (from the September 2023 data freeze) linked to ADSP WGS data. After filtering out low quality calling variants, we evaluated 672,004 multiallelic variants in total (chromosomes 1 to 22). We applied score tests under the generalized linear model framework (assuming the normal distribution) adjusted for sex, age at death, and the top three principal components and computed global p-values. The total of 392 participants who were included in the multidimensional generalized partial credit modeling had both NACC NP and ADSP WGS data. The top hitters that had suggestively significant (defined as p-value of less than 1×10-5) associations with the TDP-43 pathology (i.e., limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes, LATE-NC) related latent scores were variants located in chr18:35995261 on RPRD1A (global score test p-value = 1.4×10-6), chr7:132612663 on PLXNA4 (global score test p-value = 6.0×10-6), chr6:54528730 in an intergenic region (global score test p-value = 8.2×10-6), and chr14:72531431 on RGS6 (global score test p-value = 9.5×10-6). Some multiallelic variants were suggestively associated with TDP-43 proteinopathy. PLXNA4 has been reported as an AD-associated gene in previous studies. Further analyses are required to confirm these associations using independent cohort data.

BackgroundBrain arteriolosclerosis (B‐ASC), a subtype of small vessel pathology, is present in more than 50% of individuals over the age of 80 years and is associated with cognitive impairment, motor dysfunction, and sleep disturbance. We previously conducted an autopsy‐based genome‐wide association study (GWAS) and identified the B‐ASC‐associated single nucleotide polymorphisms (SNPs). To characterize the genetic architecture of B‐ASC, however, we need to investigate beyond SNPs. Multiallelic variants are likely to be ignored in GWAS because standard statistical analysis methods are designed for biallelic variants. In this study, we applied score‐based testing within the generalized linear model framework and explored multiallelic variant associations with autopsy‐confirmed B‐ASC in autosomal chromosomes.MethodWe used whole‐genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP) and B‐ASC phenotype data from the National Alzheimer's Coordinating Center (NACC) neuropathology (NP) dataset (September 2023 data freeze). We dichotomized the B‐ASC data (NACCARTE) into 0 = no/mild (n = 1,192) and 1 = moderate/severe (n = 948) (Table 1). The model included sex, age at death, and the top three principal components as covariates. We then computed global scores and the corresponding p‐values.ResultAfter variant filtering and quality control, 1,388,681multiallelic variants were retained for study. The genomic regions and genes listed in Table 2 (with their p‐values of less than 1×10‐5) indicate potential involvement of these loci in BASC. Further investigation of the identified genes (HULC, CCDC3, DCUN1D2) and associated intergenic regions may provide insights into the genetic basis of B‐ASC.ConclusionWe investigated possible associations between human multiallelic variants and B‐ASC risk. These are underexplored areas — both the genetic phenomena of multiallelic variants, and B‐ASC as a dementia‐driving pathology. Identifying novel genetic variants putatively contributing to the pathogenesis of B‐ASC will move the field forward although validation with independent datasets is required.

Abstract BackgroundWe recently reported genetic associations with dementia‐related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP‐43, Aβ/Tau, and a‐synuclein related neuropathology endophenotype scores.MethodParticipant data were drawn from the National Alzheimer’s Coordinating Center (NACC) neuropathology (NP) data (from the September 2023 data freeze) linked to Alzheimer’s Disease Genetics Consortium (ADGC) genotype data. ADGC genotype data were imputed by TOPMed Imputation Server (https://imputation.biodatacatalyst.nhlbi.nih.gov/). The AD summary statistics were obtained from GWAS Catalog (https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90027001‐GCST90028000/GCST90027158/) created by Bellenguez et al. We calculated biological pathway‐based PRS by Gene Ontology (GO) terms listed for Homo sapiens from Ensembl (http://www.ensembl.org/biomart/martview/) with the subset of retained SNPs based on r2 = 0.1 with a physical distance threshold of 250 kb and p‐value < 0.0001 using PRSice‐2 (https://www.prsice.info/). We then estimated the associations between each of the PRS scores and each of the three latent proteinopathy scores adjusting for age at death, sex, the top three principal components, and the two non‐outcome latent scores than the outcome. We adjusted the p‐values using the Bonferroni correction.ResultThe total 19,596,813 single nucleotide variants (SNVs) or short indels were overlapped in ADGC imputed genotype and the GWAS summary statistics. We extracted 1,850 biological process, 542 molecular function, and 405 cellular component GO terms that were constructed of 5 or more SNVs. The AD PRSs in “membrane” cellular component and “protein binding” molecular function were strongly associated with the Ab/Tau pathology related latent score (Bonferroni corrected p‐value = 1.7 × 10‐6 and 0.00011, respectively). There was no biological pathway‐based AD PRS associated with TDP‐43 and α‐synuclein pathology‐related latent scores.ConclusionThe biological pathway‐based AD PRSs were associated with only Aβ/Tau pathway related latent proteinopathy score. We will explore PRSs for other diseases that are potentially related to AD etiology including Parkinson’s disease linked to α‐synuclein pathology, amyotrophic lateral sclerosis (ASL) with TDP‐43 aggregation, cardiovascular diseases, cardiovascular risk factors, and psychiatric diseases.

BackgroundPolygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans.MethodsIn this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.ResultsThe PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results.ConclusionsWe showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Abstract Background““Mixed” neuropathologies (NPs) are common in aged brains. Classic Alzheimer’s disease neuropathologic change (ADNC) proteinopathies are amyloid‐β plaques and tau neurofibrillary tangles (NFTs). In addition, α‐synuclein and TDP‐43 are also key proteinaceous disease markers, and cerebrovascular diseases (CVDs) often coexist. Although the scientific problems regarding mixed NPs are increasingly recognized, genetic associations with mixed NPs have not been well‐investigated. In this study, we applied item response theory (IRT) to optimize the clustering and combination of mixed NPs and examined the genetic associations.MethodNP data were drawn from the National Alzheimer’s Coordinating Center (NACC) NP v10‐11 forms through the March 2022 data freeze, including Thal phase ratings (A score); Braak NFT stage (B score); CERAD neuritic plaque scores (C score); Lewy bodies (LBs); TDP‐43; hippocampal sclerosis (HS); cerebral amyloid angiopathy (CAA); infarct and lacunes; microinfarcts; atherosclerosis of the circle of Willis; and brain arteriolosclerosis. We determined dominant pathology patterns in 1,228 participants who had no missing data using a multidimensional graded response model within the IRT framework. The NACC NP data were linked to the U.S. Alzheimer’s Disease Research Centers genetic data provided by the Alzheimer’s Disease genetic Consortium.ResultFrom the leave one out cross validation simulation, the model fitness tests showed that the 4‐factor model had fewer differences from the data than the other models. As shown in Figure, the predominant NPs were TDP‐43 and HS for factor 1 (F1), CVDs other than CAA for factor 2 (F2), A, B, and C scores and CAA for factor 3 (F3), and LBs for factor 4 (F4). The TMEM106B locus was genome‐wide significant with F1 (TDP‐43/HS) and the APOE locus was genome‐wide significant with F3 (ADNC/CAA) after adjusted for age at death, sex, and other factor scores. The SDK1 and FMNL2 loci were not genome‐wide significant, but had noteworthy associations with F2 (CVDs).ConclusionOur new approach to create mixed NP scores could detect the TMEM106B and APOE loci as TDP‐43/HS related and ADNC related regions, respectively. Although previous studies reported SDK1 as an ADNC related gene, we showed that the gene may be associated with CVDs.

The COVID-19 pandemic has had a significant impact on medical services. Many countries postponed nonemergent procedures to preserve hospital resources for the unprecedented situation. Surgical backlogs caused by the COVID-19 pandemic have been evaluated by different groups. However, the impact of this pandemic on pathology and specifically neuropathology (NP) services has received limited attention. In this study, we reviewed all NP reports of the London Health Sciences Centre from January 2018 (2 years before the pandemic declaration) until the end of the year 2021. Demographic information and pathology details were collected. For tumors, site, histopathology types, and WHO grading were analyzed. In nontumoral specimens, pathological diagnoses were compared in pre- and postpandemic time. The total number of NP samples reached its lowest in April 2020, corresponding to the first Ontario provincial lockdown, and fluctuated throughout the studied period. Among the different types of NP surgical specimens, muscle and epilepsy-related specimens showed a more significant reduction, compared to neoplastic specimens. In 2020, the proportion of tumor specimens from patients older than 40 years of age increased. Similarly, the proportion of high-grade glioma and brain metastasis diagnoses also increased. Lastly, we observed a marked increase in biopsies for temporal arteritis and other inflammatory lesions.

From neurology to neuropathology and back.

Additional file 1: Table S1. Meteorological and gaseous data measured by the EPA Guting air quality monitoring stations during the study period. Figure S1. Spectrums of MDA analysed by LC-MS/MS. Figure S2. Effects (3- and 6-months exposure) of PM2.5 on the inflammatory infiltration of lungs in SH rats. Subpleural alveolar infiltration of mononuclear cells was observed in the lungs after 3- and 6-months exposure of HEPA and/or PM2.5. Figure S3. Alteration in body weight of SH rats between HEPA (control) and PM2.5 (exposure) groups after 6-months exposure. Figure S4. IHC images of total Tau (t-Tau) in the cerebellum, hippocampus, and cortex of SH rats after 6 months of exposure to HEPA (control) and PM2.5 (exposure). Scar bar is 50 μm. Figure S5. Chronic effects (6-months exposure) of PM2.5 on the histological changes of cerebellum, hippocampus, and cortex in SH rats. Scale bar: 200 μm.

The history of neuropathology is inseparable from neurosurgery. Harvey Cushing credited his understanding of pathology in part to his experience as a house officer being required to perform all bacterial and pathological studies under his charge. As Dr Cushing attempted to advance the understanding of neurosurgical disease, he recognized the critical importance of specimens to establish patterns. This led him to establish the Cushing Tumor registry with Percival Bailey. The role of pathology in the field of neurosurgery remains as integral to our understanding now as it did over a hundred years ago with Dr Cushing. This review series has been organized in order to re-familiarize neurosurgeons with the molecular and histochemical features of the diseases we encounter in our patients daily. We are often focused initially on the surgical approach, reviewing relevant anatomical structures and considering other technical issues that will help provide exemplary care in the immediate surgical setting. But if we overlook the pathology and its association with the patient's disease, we run the risk of providing suboptimal long term care and adversely impacting long term outcomes. In recent years there have been dramatic technical advances in neuropathology, leading to the role of molecular characterization in determining the diagnosis rather than using patterns on cells as at the advent of the subspecialty. The development of immunocytochemistry with specific antibodies and in situ hybridization with messenger RNA probes for cellular and pathogen gene expression have changed the classification of many lesions. The World Health Organization (WHO) updated its brain tumor classification system in 2016 several notable changes in classification. Several brain tumor diagnoses, including oligoastrocytoma and gliomatosis cerebri, were redefined or excluded. Simultaneously, the WHO recognized some new entities, such as multinodular vacuolating tumor of the cerebrum. Recognizing the importance of genetic factors that directly impact tumorigenesis and help to direct patient care through targeted treatment, the categorization of gliomas was significantly reorganized to define several infiltrating subtypes in both children and adults based solely on their genetic features. The next frontier is still in its infancy but techniques including tissue, gene, and protein arrays; laser capture of single cells; and fluorescent in situ hybridization will soon make their way from the research laboratory to clinical settings. This series will describe general pathological principles as well as review advances in molecular characterization of meningiomas, glial tumors, neuronal and glioneuronal tumors, tumors of peripheral nerves, tumors of familial syndromes, skull base tumors, pediatric tumors, ependymoma and chordoma, pituitary and sellar lesions, and lesions associated with epilepsy. A stronger understanding of these principles will help to achieve the best outcomes for patients by integrating modern advances with time-honed skills. Disclosures The author has no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Purpose: Determine whether density of nerve fibers in the cornea and corneal function are valid markers for early detection and treatment of peripheral neuropathy in rat models of prediabetes and type 2 diabetes. Methods: Rat models for prediabetes and type 2 diabetes were created and longitudinally studied for loss of structure and function of sensory nerves in the cornea and skin as well as nerve conduction velocity and vascular reactivity of epineurial arterioles. Reversibility of neuro and vascular pathology was also examined in these models following chronic obesity or type 2 diabetes after dietary intervention with menhaden oil a natural source of long chain omega-3 polyunsaturated fatty acids. Results and Conclusions: Our longitudinal study demonstrated that vascular and neural dysfunction associated with obesity or type 2 diabetes occur early and are progressive. Decrease in cornea nerve fiber length and function were valid markers of disease in both the prediabetic and diabetic rat models and were more sensitive than decrease in intraepidermal nerve fiber density of the skin and thermal nociception of the hindpaw. Late intervention with menhaden oil reversed both vascular and peripheral damage induced by chronic obesity or type 2 diabetes. These studies provide support for examination of corneal structure and function as an early marker of peripheral neuropathy in prediabetes and diabetes. Furthermore, we demonstrate that omega-3 polyunsaturated fatty acids derived from fish oil as an effective treatment for peripheral neuropathy that occurs with chronic obesity or type 2 diabetes. Disclosure M.A. Yorek: Consultant; Self; Novo Nordisk Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK107339); U.S. Department of Veterans Affairs (RX000889)

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Expert Commentary on "The Broad Field of Neuropathology" 1000 Brain "Tumours'', B. The Encephalitides, C. Wilson's Disease in India by Darab K. Dastur.

Neuropathology, my friend - on the paths of being and non-being.

Neuropathology through the ages - My life between neurology and neuropathology.

2019 Japanese <i>Neuropathology</i> Prizes

Magnetic Resonance (MR) is a non-invasive modality of choice for the evaluation of brain morphology, with superior performance as compared to other techniques. However, MR images are typically assessed qualitatively, thus relying on the experience of the involved radiologist. This may lead to errors of interpretation in the presence of subtle alterations and does not exploit the full potential of this technique as a quantitative diagnostic tool. To this end Magnetic Resonance Relaxometry (MRR), which is able to quantitively characterize the tissues under investigation through their relaxation rates, seems extremely promising. Many studies assessed the feasibility of relaxometry as a diagnostic tool in human brain disorders, with the most promising results obtained in the evaluation of neurodegenerative diseases and in the oncologic field. However, despite such extensive literature in human medicine, due to the lack of standardized protocols and the need of high-field MRI scanners, to date few studies have been performed on companion animals. In this work, first we describe relaxometry applications in human neuropathology and their possible extension to companion animals both in the experimental and clinical fields. Then, we present two experiments performed on a typical standard clinical scanner operating at 0.25 T to show that, despite the low field intensity, this technique may be promising even in the clinical setup. We tested the relaxometry protocol in a phantom study and then applied it to a real clinical case study. The results showed that this protocol used on a phantom led to a higher contrast, as compared to the standard approach. Furthermore, when applied to a real case study, this protocol revealed brain lesions undetected by the standard technique which were confirmed by a histopathological examination. These preliminary results are encouraging and support the development of this approach as an advanced diagnostic tool even in a clinical setting where low field MRI scanners are typically employed.

Objective To investigate the clinical pathologic features of a distinct variant of focal cortical dysplasia (FCD) characterized by neuronal loss of layer four. Methods Between 2005 and 2017, approximately 3 000 surgeries were performed for the treatment of intractable epilepsy at Xuanwu Hospital, Capital Medical University and Yuquan Hospital, Tsinghua University. Retrospective analysis of clinic-pathological data of patients with epilepsy surgery was made and histological manifestations of neuronal loss of cortical layer four were included in this study. Results In this cohort, 25 patients (22 males and three females) were identified with early onset pharmaco-resistant epilepsy and regionally circumscribed neuronal loss of cortical layer four in surgical specimens from the occipital lobe. Histologically, except for neuronal loss in cortical layer four in all cases, glial scar lesions were found in some patients. Thus the histology of those cases can be subdivided into two groups: group A (13 cases) : neuronal loss of cortical layer four without glial scar lesions; and group B (12 cases) : neuronal loss of cortical layer four with glial scar lesions. Due to the prominent horizontal disorganization of cortical layering and lack of any other microscopically visible principle lesion, group A should be classified hitherto as FCD International League Against Epilepsy (ILAE) type Ⅰ b, however, group B with scar lesions and cortical dysplasia around the main leision, should be classified as FCD ILAE type Ⅲd. This retrospective analysis of clinical histories revealed a perinatal distress in 20 patients (80%), suggesting an acquired pathomechanism. Magnetic resonance imaging revealed abnormal signals in the occipital lobe in all patients, and signal changes suggestive of encephalomalacia were found in 18 patients. Surgical treatment achieved favorable seizure control (Engel class Ⅰ and Ⅱ) in 18 patients (75% among 24 available follow up). Comparion of the two groups with age at epilepsy onset (group A: 5.00±2.76, group B: 5.01±3.78) , the proportion of perinatal distress (group A: 11/13, group B: 9/12) and the follow-up results (favorable seizure control of the two groups was 9/13, 9/11 respectively) showed that there was no statistically significant difference between the two groups. Conculsion Neuronal loss of cortical layer four in the occipital lobe should be classified as a distinct variant of FCD ILAE type Ⅲd. Key words: Epilepsy; Focal cortical dysplasia; Occipital lobe; Neuropathology; Development; Retrospective studies

Impairment of memory retrieval is not the major presenting symptoms of vascular cognitive impairment (VCI), which can result from silent strokes occurring in uncommon vascular territories, and can be detected only on neuroimaging or neuropathology. The neuroanatomical substrate for VCI remains unclear. This report presents an uncommon location of silent strategic infarction resulting in an insidious onset and gradual progression of the cognitive decline without overt sensorimotor deficits. J Med Cases. 2019;10(7):203-205 doi: https://doi.org/10.14740/jmc3328

LEVERAGING NEUROPATHOLOGY TO INTEGRATE WITH RNA AND OTHER OMICS

Introduction: Frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders with heterogeneous clinical presentation, pathology and genetic abnormalities, which result in atrophy of the frontal and temporal lobes. Among hereditary forms of FTLD mutation in microtubule-associated protein tau gene (MAPT) has been identified as major genetic factor in the pathogenesis. Although, Tau pathology is considered to be main cause of neurodegeneration in FTLD with MAPT mutation, some reports indicate that TDP-43 may play a role in the pathogenesis.