Prevalence of secondary brain injuries and association with trauma circumstances in neuropathologically examined medico-legal autopsy cases with primary head trauma.

Primary head injury is often followed by secondary brain damage. However, the association between injury circumstances and the prevalence of secondary injuries remains unclear. We report the prevalence and association of secondary brain injuries with the circumstances in which a head injury was sustained. The sample comprised 76 neuropathologically examined medico-legal autopsy cases with an acute primary head injury. Neuropathology reports were analysed to determine the prevalence of various secondary injuries, i.e., hypoxic-ischaemic neuronal injury, brain oedema, and vascular axonal injury (VAI). The prevalences were compared between cases from three distinct injury circumstances, i.e., fall, assault, and strangulation. The sample had a median age of 49 years (interquartile range 27-73) and 71.1% were identified as male. As for distinct injury circumstances, the sample comprised 14 fall cases, 21 assault victims, and 6 strangulation victims. The prevalence of hypoxic-ischaemic neuronal injury was highest in strangulations (100.0%), followed by assaults (81.0%) and falls (64.3%); of specific brain regions, statistically significant differences between the three case groups were found in frontal and parietal cortex (p ≤ 0.018) and the hippocampus (p = 0.005). Brain oedema was present in approximately half of assault (47.6%) and strangulation cases (50.0%), contrastingly to the lower prevalence in falls (7.1%; p = 0.024). The prevalence of VAI appeared higher among assault (23.8%) and strangulation cases (16.7%) compared to falls (7.1%), but the differences were not statistically significant. We conclude that hypoxic-ischaemic neuronal injury and brain oedema were more prevalent among assault and strangulation cases compared to falls.

Fast-track neuropathological screening for neurodegenerative diseases.

Background: The postmortem diagnostic of individuals having suffered presumptive neurodegenerative disease comprises exclusion of a prion disease, extensive brain sampling and histopathological evaluation, which are resource-intensive and time consuming. To exclude prion disease and to achieve prompt accurate preliminary diagnosis, we developed a fast-track procedure for the histopathological assessment of brains from patients with suspected neurodegenerative disease. Methods: Based on the screening of two brain regions (frontal cortex and cerebellum) with H&E and six immunohistochemical stainings in 133 brain donors, a main histopathological diagnosis was established and compared to the final diagnosis made after a full histopathological work-up according to our brain bank standard procedure. Results: In over 96 % of cases there was a concordance between the fast-track and the final main neuropathological diagnosis. A prion disease was identified in four cases without prior clinical suspicion of a prion infection. Conclusion: The fast-track screening approach relying on two defined, easily accessible brain regions is sufficient to obtain a reliable tentative main diagnosis in individuals with neurodegenerative disease and thus allows for a prompt feedback to the physicians. However, a more thorough histological work-up taking into account the clinical history and the working diagnosis from fast-track screening is necessary for accurate staging and for assessment of co-pathologies.

Machine learning quantification of Amyloid-ß deposits in the temporal lobe of 131 brain bank cases.

Accurate and scalable quantification of amyloid-ß (Aß) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aß deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aß deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aß deposit types in GM and WM, and (3) investigate correlates of Aß deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aß deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aß load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.

Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases.

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.

Neuropathology of deaths due to acute alcohol toxicity in Australia, 2011-2022.

BACKGROUND: A major alcohol-related harm is structural pathology affecting the brain. The study aimed to: 1. Determine the frequency and nature of neuropathology amongst cases of death due to acute alcohol toxicity; 2. Compare diagnoses of brain atrophy with pathology in other organs; 3. Determine the demographic, clinical and organ pathology correlates of brain atrophy. METHODS: Retrospective study of 500 cases of death attributed to acute alcohol toxicity in Australia, 2011-2022. Data on clinical characteristics, toxicology, neuropathology and other organ pathology were retrieved from police reports, autopsies, toxicology and coronial findings. RESULTS: Mean age was 49.5 years, 69.4 % were male, with alcohol use problems documented in 70.2 %. Brain atrophy was diagnosed in 60 cases (12.0 %), most commonly in the cerebellum (32 cases, 6.4 %). Atrophy at other sites was present in 37 (7.4 %). The presence of brain atrophy was lower than other major pathologies: cardiomegaly (32.6 %, p<.001), nephro/arteriosclerosis (30.2 %, p<.001), and chronic obstructive pulmonary disease (21.8 %, p<.001) but not hepatic cirrhosis (11.9 % p=1.0). Those diagnosed with atrophy were older (53.4v 49.0 years, p<.001), more likely to have documented alcohol problems (85.0v 68.2 %, Odds ratio: OR 2.53) and seizure history (10.0v 3.0 %, OR 2.92), to have cardiomegaly (43.3v 31.0 %, OR 1.90, COPD (48.3v 18.2 %, 3.57) and nephro/arteriosclerosis (50.0 v 27.4 %, OR 2.27). CONCLUSIONS: Despite the majority of cases having a history of alcohol problems, the level of neuropathology amongst cases of death due to acute alcohol toxicity was comparatively low.

Rostral cranial fossa and sinonasal neoplasms with cribriform plate involvement in 32 dogs and 17 cats.

The rostral cranial fossa (RCF) consists of the sphenoid and ethmoid bones, which accommodate the olfactory bulbs and nerves along the recesses of the cribriform plate. Neoplasms located in the vicinities of the RCF can compress and/or invade the cribriform plate. Here we describe the clinical and pathologic findings of neoplasms involving the cribriform plate in 32 dogs and 17 cats autopsied over a 13-y period. The average ages of affected dogs and cats were 9.2 y and 9.7 y, respectively. No sex or breed predisposition was evident in dogs, but 13 of 18 cats were spayed females and 14 of 18 were domestic shorthair cats. The main clinical signs were seizures (10 cases) and epistaxis (5 cases) in dogs, and red-to-brown nasal discharge (5 cases) and seizures (4 cases) in cats. In dogs, the 22 sinonasal neoplasms included adenocarcinoma (14 cases), transitional carcinoma (4), squamous cell carcinoma (2), lymphoma (1), and histiocytic sarcoma (1); the 10 intracranial neoplasms consisted of high-grade gliomas (3 cases), psammomatous meningiomas (2), histiocytic sarcomas (2), olfactory neuroblastomas (2), and a meningeal granular cell tumor (1). In cats, the 14 sinonasal neoplasms included lymphoma (8 cases), adenocarcinoma (4), adenosquamous carcinoma (1), and squamous cell carcinoma (1); the 3 intracranial neoplasms consisted of oligodendroglioma (1), transitional meningioma (1), and olfactory neuroblastoma (1).

The artifact of cerebellar granule cell layer conglutination in veterinary medicine: a brief historical perspective and review.

Cerebellar granule cell layer conglutination is a tissue artifact associated with postmortem autolysis that causes cerebellar granule cell changes once thought to be caused by degeneration and necrosis. Granule cell layer conglutination has been reported mainly in humans and cattle and rarely in other animal species, but its frequency remains vastly unknown in veterinary medicine, mostly because this postmortem change is typically not recorded in autopsy reports. Pathology trainees should be aware of autolytic tissue changes that may mimic pathologic changes in the CNS, particularly when those changes are highly selective for a specific cell population within the cerebellar cortex. Here we provide a brief historical perspective on the evolution of cerebellar granule cell layer conglutination from "enzootic cerebellar necrosis," a presumed necrotic lesion affecting granule neurons in humans and cattle, to a tissue change associated with postmortem autolysis and increased tissue acidity in the cerebellum. We also provide an update on the animal species in which cerebellar granule cell layer conglutination has been observed during our diagnostic pathology routine.

Impaired olfactory system in metabolic imbalance-related neuropathology.

Olfactory dysfunction, influenced by factors such as aging and environmental stress, is linked to various neurological disorders. The olfactory bulb's connections to brain areas like the hypothalamus, piriform cortex, entorhinal cortex, and limbic system make olfactory dysfunction a contributor to a range of neuropathological conditions. Recent research has underscored that olfactory deficits are prevalent in individuals with both metabolic syndrome and dementia. These systemic metabolic alterations correlate with olfactory impairments, potentially affecting brain regions associated with the olfactory bulb. In cases of metabolic syndrome, phenomena such as insulin resistance and disrupted glucose metabolism may result in compromised olfactory function, leading to multiple neurological issues. This review synthesizes key findings on the interplay between metabolic-induced olfactory dysfunction and neuropathology. It emphasizes the critical role of olfactory assessment in diagnosing and managing neurological diseases related to metabolic syndrome.

Rosettes and pseudorosettes in veterinary neuropathology.

Rosettes and pseudorosettes are morphologic cell arrangements found in many neuroepithelial neoplasms in human medicine, including embryonal nervous system tumors (neuroblastoma, medulloblastoma, pineoblastoma, and retinoblastoma), non-embryonal nervous system tumors (ependymoma, astrocytoma, oligodendroglioma, and choroid plexus tumors), and other extraneural neuroepithelial neoplasms. Although these structures are also described in neuroepithelial neoplasms of domestic animals, their frequency is still poorly characterized or inconsistently documented in veterinary medicine. Furthermore, rosettes and pseudorosettes need to be interpreted with caution and within a clinical and pathologic context and should not be solely relied upon for diagnostic confirmation of a particular neoplasm. Here, we review the morphologic features and frequency of the most common types of rosettes and pseudorosettes described in neuroepithelial neoplasms of domestic animals, focusing primarily on those occurring in the nervous system and closely associated tissues.

Beriberi following sleeve gastrectomy.

Bariatric surgery is being undertaken more frequently in response to rising levels of obesity but is increasingly also requested as a cosmetic choice. Nutritional deficiencies are a recognised consequence of gastrectomy, with potentially severe and permanent neurological sequelae. We present two cases of acute, severe polyneuropathy following sleeve gastrectomy. Severe thiamine deficiency was considered in both cases but with delayed proof and a significant initial differential diagnosis. Neurologists must have a high index of suspicion for the peripheral as well as central presentations of thiamine deficiency to avoid permanent disability. We also call for explicit information resources warning of the risk and signs of thiamine deficiency to be provided routinely to patients after gastrectomy.

Is Simpler Always Better? The Case for Going Beyond the Amyloid Hypothesis in Alzheimer's Disease.

Alzheimer's disease (AD) research has been dominated by the single-factor amyloid hypothesis in the last decades. Several other hypotheses have been proposed and increasingly attract attention considering the limited success of amyloid-based therapeutic strategies. Surprisingly, most published alternative etiological hypotheses for AD are similarly single-factor hypotheses, such as vascular, metabolic, mitochondrial, infectious, and inflammatory hypotheses, but the existence of so many different hypotheses suggests that AD is most likely a complex, multifactorial disorder. This inventory of different etiological hypotheses will hopefully help the field to move forward with explanatory models that consider the multifaceted aspects of this devastating disorder.

Comorbid neuropathology and atypical presentation of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated. METHODS: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD. RESULTS: We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini-Mental Status Examination (MMSE) decline over time (p = 0.033). DISCUSSION: Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort. Highlights: Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-ß42 over Amyloid Positron Emission Tomography.

BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-ß42 (Aß42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aß42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aß42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aß42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

Evaluating the efficacy of few-shot learning for GPT-4Vision in neurodegenerative disease histopathology: A comparative analysis with convolutional neural network model.

AIMS: Recent advances in artificial intelligence, particularly with large language models like GPT-4Vision (GPT-4V)-a derivative feature of ChatGPT-have expanded the potential for medical image interpretation. This study evaluates the accuracy of GPT-4V in image classification tasks of histopathological images and compares its performance with a traditional convolutional neural network (CNN). METHODS: We utilised 1520 images, including haematoxylin and eosin staining and tau immunohistochemistry, from patients with various neurodegenerative diseases, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We assessed GPT-4V's performance using multi-step prompts to determine how textual context influences image interpretation. We also employed few-shot learning to enhance improvements in GPT-4V's diagnostic performance in classifying three specific tau lesions-astrocytic plaques, neuritic plaques and tufted astrocytes-and compared the outcomes with the CNN model YOLOv8. RESULTS: GPT-4V accurately recognised staining techniques and tissue origin but struggled with specific lesion identification. The interpretation of images was notably influenced by the provided textual context, which sometimes led to diagnostic inaccuracies. For instance, when presented with images of the motor cortex, the diagnosis shifted inappropriately from AD to CBD or PSP. However, few-shot learning markedly improved GPT-4V's diagnostic capabilities, enhancing accuracy from 40% in zero-shot learning to 90% with 20-shot learning, matching the performance of YOLOv8, which required 100-shot learning to achieve the same accuracy. CONCLUSIONS: Although GPT-4V faces challenges in independently interpreting histopathological images, few-shot learning significantly improves its performance. This approach is especially promising for neuropathology, where acquiring extensive labelled datasets is often challenging.

Assessment of Ki-67 and mitoses in pituitary neuroendocrine tumours-Consistency counts.

Pituitary neuroendocrine tumour Ki-67 proliferation index varies according to the number of tumour cells assessed. Consistent Ki-67 scoring approaches and re-evaluation of the recommended Ki-67 3% cut-off are required to clarify controversies in pituitary neuroendocrine tumour Ki-67 proliferation index assessment.

Molecular genetics and diversity of choroid plexus tumors.

Choroid plexus tumors are rare intraventricular brain tumors predominantly arising in children but also affecting adults. Chromosome-wide copy-number alterations and TP53 mutations do occur, but in most choroid plexus tumors, driver mutations have not been identified. Here we give a brief overview of the histopathological and clinical diversity of choroid plexus tumors and their genetic and epigenetic heterogeneity. Preliminary data indicate that choroid plexus carcinomas comprise at least 2 epigenetic subgroups, one of which is associated with TP53 mutation status. These findings strongly encourage us to further investigate the genetic and epigenetic heterogeneity in a larger cohort and to align molecular subgroup status with clinical annotations, in order to identify prognostic markers that may also aid stratification within future international trials.

Primary lateral sclerosis associated with PSEN1 Pro284Leu variant in a Colombian family: Clinical and neuropathological features.

INTRODUCTION: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). METHODS: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. RESULTS: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. DISCUSSION: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials. HIGHLIGHTS: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aß pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.

What traditional neuropsychological assessment got wrong about mild traumatic brain injury. II: limitations in test development, research design, statistical and psychometric issues.

PRIMARY OBJECTIVE: This is Part II of a four-part opinion review on traditional neuropsychological assessment methods and findings associated with mild traumatic brain injury (mTBI). This Part II review focuses on historical, psychometric and statistical issues involving traditional neuropsychological methods that have been used in neuropsychological outcome studies of mTBI, but demonstrates the critical limitations of traditional methods. RESEARCH DESIGN: This is an opinion review. METHODS AND PROCEDURES: Traditional neuropsychological tests are dated and lack specificity in evaluating such a heterogenous and complex injury as occurs with mTBI. MAIN OUTCOME AND RESULTS: In this review, we demonstrate traditional neuropsychological methods were never developed as standalone measures for detecting subtle changes in neurocognitive or neurobehavioral functioning and likewise, never designed to address the multifaceted issues related to underlying mTBI neuropathology symptom burden from having sustained a concussive brain injury. CONCLUSIONS: For neuropsychological assessment to continue to contribute to clinical practice and outcome literature involving mTBI, major innovative changes are needed that will likely require technological advances of novel assessment techniques more specifically directed to evaluating the mTBI patient. These will be discussed in Part IV.