A Rare Hybrid Skin Cyst of the Scalp With Pilar and Apocrine Features.

Benign epithelial skin cysts containing multiple components of the folliculo-sebaceous apocrine unit are only rarely reported in the literature. Here, we describe a 12-year-old girl who presented with a cystic mass on the vertex of her scalp. Upon resection, it showed a hybrid benign skin cyst with interesting histological features of both pilar and apocrine differentiation. The clinicopathological and imaging findings of this unusual skin cyst, successfully managed by a plastic surgeon and neurosurgeon, are described. Pathologists and clinicians should be aware of this type of skin cyst rarely encountered in their clinical practice.

Towards Standardizing Nomenclature in Huntington's Disease Research.

The field of Huntington's disease research covers many different scientific disciplines, from molecular biology all the way through to clinical practice, and as our understanding of the disease has progressed over the decades, a great deal of different terminology has accrued. The field is also renowned for its collaborative spirit and use of standardized reagents, assays, datasets, models, and clinical measures, so the use of standardized terms is especially important. We have set out to determine, through a consensus exercise involving basic and clinical scientists working in the field, the most appropriate language to use across disciplines. Nominally, this article will serve as the style guide for the Journal of Huntington's Disease (JHD), the only journal devoted exclusively to HD, and we lay out the preferred and standardized terminology and nomenclature for use in JHD publications. However, we hope that this article will also serve as a useful resource to the HD research community at large and that these recommended naming conventions will be adopted widely.

Combined central and peripheral demyelination in two siblings, immune mediated or genetic?

We report unusual cases of combined central and peripheral demyelination in two siblings related to pregnancy, each presenting with progressive tetraparesis and cranial nerve palsies. The elder sister had a relapsing-remitting course with optic nerve dysfunction and died during a relapse from respiratory insufficiency. The younger sister presented with disorientation and acute-onset limb and facial weakness. She responded well to corticosteroid therapy. Their clinical presentation, response to immunomodulatory therapy, nerve conduction studies, cerebrospinal fluid and histology supported an acquired demyelinating cause. Whole-exome sequencing identified variants in two genes not previously linked to this clinical phenotype. Serological tests for antibody-mediated demyelination were negative. Despite the undefined pathogenesis, these cases provide a platform to explore the confluence of genetic, immune and environmental factors in the context of acquired demyelination. We discuss the differential diagnosis and a diagnostic approach to such cases from the perspectives of neuroimmunology and neurogenetics.

Research advances in huntingtin-associated protein 1 and its application prospects in diseases.

Huntingtin-associated protein 1 (HAP1) was the first protein discovered to interact with huntingtin. Besides brain, HAP1 is also expressed in the spinal cord, dorsal root ganglion, endocrine, and digestive systems. HAP1 has diverse functions involving in vesicular transport, receptor recycling, gene transcription, and signal transduction. HAP1 is strongly linked to several neurological diseases, including Huntington's disease, Alzheimer's disease, epilepsy, ischemic stroke, and depression. In addition, HAP1 has been proved to participate in cancers and diabetes mellitus. This article provides an overview of HAP1 regarding the tissue distribution, cell localization, functions, and offers fresh perspectives to investigate its role in diseases.

Multiparameter quantitative analyses of diagnostic cells in brain tissues from tuberous sclerosis complex.

The advent of high-dimensional imaging offers new opportunities to molecularly characterize diagnostic cells in disorders that have previously relied on histopathological definitions. One example case is found in tuberous sclerosis complex (TSC), a developmental disorder characterized by systemic growth of benign tumors. Within resected brain tissues from patients with TSC, detection of abnormally enlarged balloon cells (BCs) is pathognomonic for this disorder. Though BCs can be identified by an expert neuropathologist, little is known about the specificity and broad applicability of protein markers for these cells, complicating classification of proposed BCs identified in experimental models of this disorder. Here, we report the development of a customized machine learning pipeline (BAlloon IDENtifier; BAIDEN) that was trained to prospectively identify BCs in tissue sections using a histological stain compatible with high-dimensional cytometry. This approach was coupled to a custom 36-antibody panel and imaging mass cytometry (IMC) to explore the expression of multiple previously proposed BC marker proteins and develop a descriptor of BC features conserved across multiple tissue samples from patients with TSC. Here, we present a modular workflow encompassing BAIDEN, a custom antibody panel, a control sample microarray, and analysis pipelines-both open-source and in-house-and apply this workflow to understand the abundance, structure, and signaling activity of BCs as an example case of how high-dimensional imaging can be applied within human tissues.

Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.

Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.

Classifying Alzheimer's Disease Neuropathology Using Clinical and MRI Measurements.

Background: Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data. Objective: Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features. Methods: AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women). Results: Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status. Conclusions: Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.

Neurosurgical Intervention for Nerve and Muscle Biopsies.

(1) Background: Neurologic and musculoskeletal diseases represent a considerable portion of the underlying etiologies responsible for the widely prevalent symptoms of pain, weakness, numbness, and paresthesia. Because of the subjective and often nonspecific nature of these symptoms, different diagnostic modalities have been explored and utilized. (2) Methods: Literature review. (3) Results: Nerve and muscle biopsy remains the gold standard for diagnosing many of the responsible neurological and musculoskeletal conditions. However, the need for invasive tissue sampling is diminishing as more investigations explore alternative diagnostic modalities. Because of this, it is important to explore the current role of neurosurgical intervention for nerve and muscle biopsies and its current relevance in the diagnostic landscape of neurological and musculoskeletal disorders. With consideration of the role of nerve and muscle biopsy, it is also important to explore innovations and emerging techniques for conducting these procedures. This review explores the indications and emerging techniques for neurological intervention for nerve and muscle biopsies. (4) Conclusions: The role of neurosurgical intervention for nerve and muscle biopsy remains relevant in diagnosing many neurological and musculoskeletal disorders. Biopsy is especially relevant as a supportive point of evidence for diagnosis in atypical cases. Additionally, emerging techniques have been explored to guide diagnostics and biopsy, conduct less invasive biopsies, and reduce risks of worsening neurologic function and other symptoms secondary to biopsy.

Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice.

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies.

Practical Application of Deep Learning in Diagnostic Neuropathology-Reimagining a Histological Asset in the Era of Precision Medicine.

In the past few decades, neuropathology has experienced several paradigm shifts with the introduction of new technologies. Deep learning, a rapidly progressing subfield of machine learning, seems to be the next innovation to alter the diagnostic workflow. In this review, we will explore the recent changes in the field of neuropathology and how this has led to an increased focus on molecular features in diagnosis and prognosis. Then, we will examine the work carried out to train deep learning models for various diagnostic tasks in neuropathology, as well as the machine learning frameworks they used. Focus will be given to both the challenges and successes highlighted therein, as well as what these trends may tell us about future roadblocks in the widespread adoption of this new technology. Finally, we will touch on recent trends in deep learning, as applied to digital pathology more generally, and what this may tell us about the future of deep learning applications in neuropathology.

Age-dependent increase of perineuronal nets in the human hippocampus and precocious aging in epilepsy.

OBJECTIVE: Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. METHODS: Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. RESULTS: PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). SIGNIFICANCE: Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. PLAIN LANGUAGE SUMMARY: "Perineuronal nets" (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.

Pick's Disease Presenting as Tremulous Parkinsonism with Limited Levodopa Response-A Rare Cause of Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. OBJECTIVES: We would like to highlight a rare but important differential of corticobasal syndrome. METHODS: A 78-year-old female had a 4-year history of predominantly right-hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right-sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post-mortem. RESULTS: The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau-related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. CONCLUSIONS: Pick's disease can rarely present with clinical features of corticobasal syndrome.

Incidental Gliosis in the Central Nervous System of Control Nonhuman Primates and Rats.

Gliosis, including microgliosis and astrocytosis, can be challenging to interpret in nonclinical studies. Incidences of glial foci in brains and spinal cords of control rats and nonhuman primates (NHPs) were reviewed in the historical control databases from two contract research organizations, including one specializing in neuropathology. In the brain, minimal to mild (grades 1-2) microgliosis was the most common diagnosis, especially in NHPs, although occasional moderate or marked microgliosis (grades 3 and 4) was encountered in both species. Microgliosis was more common in the cerebral cortex, cerebellum, and medulla oblongata in both species and was frequent in the white matter (brain), thalamus, and basal nuclei of NHPs. Gliosis ("not otherwise specified") of minimal severity was diagnosed in similar brain sub-sites for both species and was more common in NHPs compared with rats. Astrocytosis was most prominent in the cerebellum (molecular layer) of NHPs but was otherwise uncommon. In the spinal cord, microgliosis was most common in the lateral white matter tracts in rats and NHPs, and in the dorsal white matter tracts in NHPs. These data indicate that low-grade spontaneous glial responses occur with some frequency in control animals of two common nonclinical species.

Cognitive integrity in Non-Demented Individuals with Alzheimer's Neuropathology is associated with preservation and remodeling of dendritic spines.

INTRODUCTION: Individuals referred to as Non-Demented with Alzheimer's Neuropathology (NDAN) exhibit cognitive resilience despite presenting Alzheimer's disease (AD) histopathological signs. Investigating the mechanisms behind this resilience may unveil crucial insights into AD resistance. METHODS: DiI labeling technique was used to analyze dendritic spine morphology in control (CTRL), AD, and NDAN post mortem frontal cortex, particularly focusing on spine types near and far from amyloid beta (Aß) plaques. RESULTS: NDAN subjects displayed a higher spine density in regions distant from Aß plaques versus AD patients. In distal areas from the plaques, NDAN individuals exhibited more immature spines, while AD patients had a prevalence of mature spines. Additionally, our examination of levels of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), a protein associated with synaptic plasticity and AD, showed significantly lower expression in AD versus NDAN and CTRL. DISCUSSION: These results suggest that NDAN individuals undergo synaptic remodeling, potentially facilitated by Pin1, serving as a compensatory mechanism to preserve cognitive function despite AD pathology. HIGHLIGHTS: Spine density is reduced near Aß plaques compared to the distal area in CTRL, AD, and NDAN dendrites. NDAN shows higher spine density than AD in areas far from Aß plaques. Far from Aß plaques, NDAN has a higher density of immature spines, AD a higher density of mature spines. AD individuals show significantly lower levels of Pin1 compared to NDAN and CTRL.

Nipah virus-associated neuropathology in African green monkeys during acute disease and convalescence.

BACKGROUND: Nipah virus is an emerging zoonotic virus that causes severe respiratory disease and meningoencephalitis. The pathophysiology of Nipah virus meningoencephalitis is poorly understood. METHODS: We have collected the brains of African green monkeys during multiple Nipah virus, Bangladesh studies, resulting in 14 brains with Nipah virus-associated lesions. RESULTS: The lesions seen in the brain of African green monkeys infected with Nipah virus, Bangladesh were very similar to those observed in humans with Nipah virus, Malaysia infection. We observed viral RNA and antigen within neurons and endothelial cells, within encephalitis foci and in uninflamed portions of the CNS. CD8+ T cells had a consistently high prevalence in CNS lesions. We developed a UNet model for quantifying and visualizing inflammation in the brain in a high-throughput and unbiased manner. While CD8+ T cells had a consistently high prevalence in CNS lesions, the model revealed that CD68+ cells were numerically the immune cell with the highest prevalence in the CNS of NiV-infected animals. CONCLUSION: Our study provides an in-depth analysis on Nipah virus infection in the brains of primates, and similarities between lesions in patients and the animals in our study validate this model.

Quantitative cellular pathology of the amygdala in temporal lobe epilepsy and correlation with magnetic resonance imaging volumetry, tissue microstructure, and sudden unexpected death in epilepsy risk factors.

OBJECTIVE: Amygdala enlargement can occur in temporal lobe epilepsy, and increased amygdala volume is also reported in sudden unexpected death in epilepsy (SUDEP). Apnea can be induced by amygdala stimulation, and postconvulsive central apnea (PCCA) and generalized seizures are both known SUDEP risk factors. Neurite orientation dispersion and density imaging (NODDI) has recently provided additional information on altered amygdala microstructure in SUDEP. In a series of 24 surgical temporal lobe epilepsy cases, our aim was to quantify amygdala cellular pathology parameters that could predict enlargement, NODDI changes, and ictal respiratory dysfunction. METHODS: Using whole slide scanning automated quantitative image analysis methods, parallel evaluation of myelin, axons, dendrites, oligodendroglia, microglia, astroglia, neurons, serotonergic networks, mTOR-pathway activation (pS6) and phosphorylated tau (pTau; AT8, AT100, PHF) in amygdala, periamygdala cortex, and white matter regions of interest were compared with preoperative magnetic resonance imaging data on amygdala size, and in 13 cases with NODDI and evidence of ictal-associated apnea. RESULTS: We observed significantly higher glial labeling (Iba1, glial fibrillary acidic protein, Olig2) in amygdala regions compared to cortex and a strong positive correlation between Olig2 and Iba1 in the amygdala. Larger amygdala volumes correlated with lower microtubule-associated protein (MAP2), whereas higher NODDI orientation dispersion index correlated with lower Olig2 cell densities. In the three cases with recorded PCCA, higher MAP2 and pS6-235 expression was noted than in those without. pTau did not correlate with SUDEP risk factors, including seizure frequency. SIGNIFICANCE: Histological quantitation of amygdala microstructure can shed light on enlargement and diffusion imaging alterations in epilepsy to explore possible mechanisms of amygdala dysfunction, including mTOR pathway activation, that in turn may increase the risk for SUDEP.

Glaucoma: what the neurologist needs to know.

Glaucoma is a progressive optic neuropathy resulting from pathological changes at the optic disc due to elevated intraocular pressure. Its diagnosis, treatment and follow-up are almost entirely conducted in ophthalmology clinics, with screening conducted by community optometrists. Despite this, neurologists may encounter glaucoma in both its acute presentation (as angle closure, presenting as acute headache) and its chronic forms (often as optic neuropathy of unknown cause). An awareness of the underlying pathological process, and the key distinguishing signs and symptoms, will allow neurologists to identify the glaucomatous process rapidly. Timely referral is essential as glaucoma invariably results in progressive visual loss without treatment. This review therefore condenses the wide field of glaucoma into a practical summary, aimed at practitioners with limited clinical experience of this ophthalmic condition.

Vestibular dysfunction in Parkinson's disease: a neglected topic.

Dizziness and postural instability are frequently observed symptoms in patient with Parkinson's disease (PD), potentially linked to vestibular dysfunction. Despite their significant impact on quality of life, these symptoms are often overlooked and undertreated in clinical practice. This review aims to summarize symptoms associated with vestibular dysfunction in patients with PD and discusses vestibular-targeted therapies for managing non-specific dizziness and related symptoms. We conducted searches in PubMed and Web of Science using keywords related to vestibular dysfunction, Parkinson's disease, dizziness, and postural instability, alongside the reference lists of relevant articles. The available evidence suggests the prevalence of vestibular dysfunction-related symptoms in patients with PD and supports the idea that vestibular-targeted therapies may be effective in improving PD symptoms.

Progress and trends in neurological disorders research based on deep learning.

In recent years, deep learning (DL) has emerged as a powerful tool in clinical imaging, offering unprecedented opportunities for the diagnosis and treatment of neurological disorders (NDs). This comprehensive review explores the multifaceted role of DL techniques in leveraging vast datasets to advance our understanding of NDs and improve clinical outcomes. Beginning with a systematic literature review, we delve into the utilization of DL, particularly focusing on multimodal neuroimaging data analysis-a domain that has witnessed rapid progress and garnered significant scientific interest. Our study categorizes and critically analyses numerous DL models, including Convolutional Neural Networks (CNNs), LSTM-CNN, GAN, and VGG, to understand their performance across different types of Neurology Diseases. Through particular analysis, we identify key benchmarks and datasets utilized in training and testing DL models, shedding light on the challenges and opportunities in clinical neuroimaging research. Moreover, we discuss the effectiveness of DL in real-world clinical scenarios, emphasizing its potential to revolutionize ND diagnosis and therapy. By synthesizing existing literature and describing future directions, this review not only provides insights into the current state of DL applications in ND analysis but also covers the way for the development of more efficient and accessible DL techniques. Finally, our findings underscore the transformative impact of DL in reshaping the landscape of clinical neuroimaging, offering hope for enhanced patient care and groundbreaking discoveries in the field of neurology. This review paper is beneficial for neuropathologists and new researchers in this field.