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BACKGROUND: Alzheimer's disease (AD) patients suffer from cognitive dysfunction. This study assessed the structural magnetic resonance imaging (MRI) scoring among Alzheimer's patients (age ≥18 years) to correlate with dementia severity according to mini-mental state exam (MMSE) scores. METHODS: This cross-sectional study evaluated Bangladeshi adult AD patients from January 2018 to December 2022 who attended with subjective memory complaints and fulfilled the diagnostic and statistical manual of mental disorders criteria (DSM 5) for diagnosing dementia. The medial temporal lobe atrophy (MTA) and Koedam's score of the atrophy were measured utilising the 1.5 and 3 Tesla Magnetom symphony MRI systems. RESULTS: Of the 62 patients enrolled, the majority (39 cases; 62.9%) were aged over 60 years. Males were more predominant than females, with a male-to-female ratio of 2.6:1, and the moderate MMSE group consisted of 35.6% males and 64.7% females (P = 0.01). Further, MTA score severity is paradoxically associated with the MMSE score (P = 0.005). Additionally, we found a statistically significant negative correlation between the severity of the MMSE and only MTA scores (r = -0.350; 95% CI -0.551 to -0.110; P = 0.005). CONCLUSION: Structural magnetic resonance imaging among Alzheimer's patients is significantly correlated with the severity of dementia as per mini-mental state exam scores.

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Dysbiosis within microbiomes has been increasingly implicated in many systemic illnesses, such as cardiovascular disease, metabolic syndrome, respiratory infections, and Alzheimer disease (Ad). The correlation between Ad and microbial dysbiosis has been repeatedly shown, yet the etiologic cause of microbial dysbiosis remains elusive. From a neuropathology perspective, abnormal (often age-related) changes in the brain, associated structures, and bodily lumens tend toward an accumulation of oxygen-depleted pathologic structures, which are anaerobically selective niches. These anaerobic environments may promote progressive change in the microbial community proximal to the brain and thus deserve further investigation. In this review, we identify and explore what is known about the anaerobic niche near or associated with the brain and the anaerobes that it is harbors. We identify the anaerobe stakeholders within microbiome communities and the impacts on the neurodegenerative processes associated with Ad. Chronic oral dysbiosis in anaerobic dental pockets and the composition of the gut microbiota from fecal stool are the 2 largest anaerobic niche sources of bacterial transference to the brain. At the blood-brain barrier, cerebral atherosclerotic plaques are predominated by anaerobic species intimately associated with the brain vasculature. Focal cerebritis/brain abscess and corpora amylacea may also establish chronic anaerobic niches in direct proximity to brain parenchyma. In exploring the anaerobic niche proximal to the brain, we identify research opportunities to explore potential sources of microbial dysbiosis associated with Ad.

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The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.

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The clinical and neuropathological characteristics of progressive supranuclear palsy (PSP) with preservation of levodopa (L-dopa) response are described in this report. We present the case of a 73-year-old Japanese man with a 13-year history of dopa-responsive Parkinsonism and abnormalities observed in metaiodobenzylguanidine (MIBG) myocardial scintigraphy, suggesting Parkinson's disease. However, autopsy results revealed PSP pathology, including tuft-shaped astrocytes and globose-type neurofibrillary tangles, without Lewy body pathology. The degeneration was moderately to severely distributed in the globus pallidus, subthalamic nucleus, and substantia nigra, whereas striatal degeneration was mild. These findings suggest an intact response to L-dopa therapy throughout the patient's lifetime. Pathological examination of cardiac sympathetic nerves revealed intact nerves, suggesting functional involvement in the MIBG abnormality. This study provides further evidence of the clinical and pathological heterogeneity of PSP. Homozygosity for both the rs564309-C allele at TRIM11 and the rs2242367-G allele at SLC2A13 might have played a protective role. This case indicates a protracted course-PSP, which may hold promise for future treatments.

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IgG4-related disease (IgG4-RD) is a recently described multisystemic disorder with a spectrum of manifestations that continue to be described. Nonetheless, there are recognised distinct patterns of disease. Neurological involvement is rare, particularly in isolation, but IgG4-RD may present with orbital disease, hypophysitis or pachymeningitis. Typically, it is highly responsive to treatment. This review highlights neurological manifestations of IgG4-RD and emphasises the importance of a high index of clinical suspicion to facilitate investigation and appropriate management, avoiding irreversible tissue damage and neurological dysfunction. We present a treatment algorithm for suggested management of IgG4-RD affecting the nervous system.

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BACKGROUND: Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer's disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. RESULTS: Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid ß (Aß) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aß load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. CONCLUSION: Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

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Alzheimer's disease (AD) is the most common form of age-related dementia worldwide. Although the neuropathology of AD is clear, its pathogenesis remains unclear. Recently, conceptualising AD as brain-centred has reoriented many scientists because the close functional relationship between the peripheral and central nerves is increasingly recognised. Recently, various studies have focused on the crosstalk between peripherals and centrals. A new hotspot of research and new therapeutic strategies have emerged from this great progress. This mini-review is an overview of the potential molecular mechanism in AD via the bidirectional lung-brain axis, providing a new perspective for the systemic understanding of AD onset.

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IMPORTANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly with the incidence rising exponentially after the age of 65 years. Unfortunately, effective treatments are extremely limited and definite diagnosis can only be made at autopsy. This is in part due to our limited understanding of the complex pathophysiology, including the various genetic, environmental, and metabolic contributing factors. In an effort to better understand this complex disease, researchers have employed nonhuman primates as translational models. CASE PRESENTATION: This report aims to describe the AD-like neuropathology in the brain of a 37-year-old female baboon (Papio hamadryas), which at the time of her death made her the oldest hamadryas baboon at any member institution of the Association of Zoos and Aquariums. A diagnostic necropsy was performed, and the brain was evaluated for neurodegenerative disease. Frequent amyloid-ß deposits were identified, consistent with what has been described in other geriatric nonhuman primates. Phospho-tau pathology, including neurofibrillary tangles, a feature not well-described in other primate models, was also abundant. CONCLUSIONS AND RELEVANCE: Our results suggest that more detailed, prospective, longitudinal studies are warranted utilizing this particular species to see if they represent a viable model for human brain aging.

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The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

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OBJECTIVE: The aim of this study is to assess the feasibility and implementation of a novel approach for intraoperative brain smears within the operating room, which is augmented with deep learning technology. Materials and methods: This study is designed as an observational to evaluate the feasibility and implementation of using an innovative approach to intraoperative brain smears within the operating room, augmented with deep learning technology. The study will be conducted at Aga Khan University Hospital in Karachi, Pakistan, from May 2024 to July 2026, with an estimated sample size of 258. A neurosurgical trainee, trained by the study neuropathologist, will prepare and examine the smears under a microscope in the operating room. The findings of the trainee will be documented and compared to routine intraoperative consultations (smear and/or frozen section) and final histopathology results obtained from the pathology department. Additionally, the study will incorporate artificial intelligence tools to assist with the interpretation of smear and a telepathology interface to enable consultation from an off-site neuropathologist. CONCLUSIONS: The results of this study will hold significant potential to revolutionise neurosurgery practices in lowand middle-income countries by introducing a cost-effective, efficient, and high-quality intraoperative consultation method to settings that currently lack the necessary infrastructure and expertise. The implementation of this innovative approach has the potential to improve patient outcomes and increase access to intraoperative diagnosis, thereby addressing a significant unmet need in LMICs.

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The management of medulloblastoma, a pediatric brain tumor, has evolved significantly with the advent of genomic subgrouping, yet morbidity and mortality remain high in LMICs like Pakistan due to inadequate multidisciplinary care infrastructure. This paper aims to establish evidence-based guidelines tailored to the constraints of such countries. An expert panel comprising neuro-oncologists, neurosurgeons, radiologists, radiation oncologists, neuropathologists, and pediatricians collaborated to develop these guidelines, considering the specific challenges of pediatric brain tumor care in Pakistan. The recommendations cover various aspects of medulloblastoma treatment, including pre-surgical workup, neurosurgery, neuropathology, chemotherapy, radiation therapy, and supportive care. They offer both minimum required and additional optional protocols for more advanced centers, ensuring comprehensive patient management with attention to complications and complexities encountered in Pakistan. The paper's consensus guidelines strive for uniformity in healthcare delivery and address significant gaps in diagnosis, treatment, and follow-up of pediatric medulloblastoma patients.

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Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other tissues through the bloodstream. The presence of BAs in the central nervous system (CNS) has been related to their capacity to cross the blood-brain barrier (BBB) from the systemic circulation. However, the expression of enzymes and receptors involved in their synthesis and signaling, respectively, support the hypothesis that there is an endogenous source of BAs with a specific function in the CNS. Over the last decades, BAs have been tested as treatments for many CNS pathologies, with beneficial effects. Although they were initially reported as neuroprotective substances, they are also known to reduce inflammatory processes. Most of these effects have been related to the activation of the Takeda G protein-coupled receptor 5 (TGR5). This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies.

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Low-grade gliomas are a cause of severe and often life-long disability in children. Pathology plays a key role in their management by establishing the diagnosis, excluding malignant alternatives, predicting outcomes and identifying targetable genetic alterations. Molecular diagnosis has reshaped the terrain of pathology, raising the question of what part traditional histology plays. In this review, we consider the classification and pathological diagnosis of low-grade gliomas and glioneuronal tumours in children by traditional histopathology enhanced by the opportunities afforded by access to comprehensive genetic and epigenetic characterisation.

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Little is known about whether clinical, radiological or neuropathological features are associated with cognitive impairment before intracerebral haemorrhage. We conducted a community-based cohort study of 125 adults with intracerebral haemorrhage (lobar n = 71, non-lobar n = 54) with consent to brain autopsy. We compared small vessel disease biomarkers on diagnostic CT head and neuropathological findings including neurofibrillary tangles and amyloid plaques in adults without cognitive impairment versus cognitive impairment without dementia versus dementia before intracerebral haemorrhage, stratified by lobar and non-lobar intracerebral haemorrhage. In non-lobar intracerebral haemorrhage, severe cortical atrophy was less common in those without cognitive impairment (8/36, 22%) and cognitive impairment without dementia (0/9, 0%) versus dementia (5/9, 56%); P = 0.008. Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder neurofibrillary tangle pathology measured by median Braak stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [interquartile range, 2-3] versus cognitive impairment without dementia 4 [2-6] versus dementia 5.5 [4-6]; P = 0.004; non-lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [1-2] versus dementia 5 [3-6]; P < 0.001). Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder amyloid plaque pathology measured by median Thal stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [2-3] versus dementia 2.5 [2-3.5]; P = 0.033; non-lobar intracerebral haemorrhage: no cognitive impairment 1 [0-1] versus cognitive impairment without dementia 0 [0-2] versus dementia 3 [2-3]; P = 0.002). Our findings suggest that irrespective of intracerebral haemorrhage location, adults with cognitive impairment before an intracerebral haemorrhage have more Alzheimer's disease neuropathologic change.

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A 51-year-old woman developed subacute progressive gait and cognitive difficulties, with depression and anxiety. She had psychomotor slowing, axial rigidity, fixed dystonic posturing of right hand and symmetrical generalised bradykinesia. MR brain scan identified bilateral multifocal non-enhancing high signal intensity in the frontal subcortical and periventricular areas, with corpus callosal thinning and areas of paraventricular diffusion restriction, suggesting an adult-onset leukodystrophy. Genetic analysis identified a heterogenous pathogenic variant in the colony-stimulating factor 1 receptor (CSF1R) causing this autosomal dominant leukoencephalopathy (OMIM 221820). The patient was unusual in having a CSF1R-related leukoencephalopathy without a relevant family history.

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Dear colleagues, It is my pleasure and honor to host the 68th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) in Regensburg. Since the Magdeburg meeting in 2019 this is the first pure national meeting of our society that will be held in presence after five long years. While the meeting in 2020 was cancelled due to the Corona pandemic, the 2021 meeting (organized by the colleagues in Gießen) took place as a mere online meeting. In 2022 and 2023 our national society meetings were embedded in the "Neurowoche" and the International Congress of Neuropathology in Berlin. We are enthusiastic about this years' reunion of our society in Regensburg. In our Regensburg meeting, we aim to provide a comprehensive update on the major and hot topics in neuropathology. Neuropathologists address some of the currently most relevant and discussed health care issues, such as for example cancer, neuroimmunological diseases like Multiple Sclerosis, neurodegenerative diseases including Alzheimer's and Parkinson's, and muscle/nerve diseases. As tissue specialists, neuropathologists directly study diseases in human materials. Neuropathologists use state of-the-art methods to uncover disease processes on the molecular level. During our congress, we will hear a lot on the methodical progress made in this regard. Neuropathology is also becoming increasingly clinical as many of our scientific and diagnostic findings influence and directly guide treatment decisions. We were able to attract renowned national and international speakers and our meeting will allow for an intensive interchange both within our society and with our neighboring disciplines. Program highlights include a Pre-Congress hands-on Workshop on Next Generation Sequencing, a session on Molecular Tumorboards and a Mini-Symposium on Quality Assurance in Neuropathology. We are delighted about the submission of 31 abstracts covering the research fields Neurooncology, Neuroimmunology, Muscle/Nerve, Neurodegeneration, and Methods/Free Topics. The abstracts are published below in this edition of Free Neuropathology. I want to thank the scientific committee of our congress for helping in evaluating the submissions and selecting the poster talks and poster spotlight presentations. Many of the abstracts were submitted by our young researchers. They deserve our special attention! Posters will be exhibited throughout the entire congress and we will have plenty of time for poster viewing and discussions on Thursday evening at the Welcome Reception and at the main poster session on Friday at noon. So let me again welcome you all to our beautiful city of Regensburg. I am looking forward to inspiring talks, vivid discussions and enriching encounters with like-minded people. Yours, Prof. Dr. Markus J. Riemenschneider Regensburg University Hospital, Department of Neuropathology Congress President DGNN Annual Meeting 2024.

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The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer's disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer's disease (n = 17), primary tauopathies (n = 8), synucleinopathies (n = 27), frontotemporal lobar degeneration (n = 8), mixed pathology (n = 11), other neurodegenerative diseases (n = 6), and cognitively normal controls (n = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer's disease, primary tauopathies and controls with Alzheimer's disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (n = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (n = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (n = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.

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