A rare case of Sporadic Creutzfeldt-Jakob disease at a remote mountain hospital in the Indian Himalayan Region.

Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative spongiform encephalopathy that causes neuronal derangement secondary to prion protein. Its initial diagnosis is often complex and challenging due to non-specific clinical presentation, lack of awareness, and low clinical suspicion. This disease is invariably fatal, and most patients die within 12 months of presentation. Definite diagnosis of prion disease requires neuropathological analysis, usually done at autopsy. Here, we present the autopsy findings of a 57-year-old male patient, illustrating the complexity of diagnosing this disease early in the clinical course and the need for a broad differential diagnosis at the onset.

Amyloid-ß peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer's disease with APPdup and Down syndrome.

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-ß (Aß) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aß can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aß and tau pathologies in postmortem brain tissues across cases and Aß peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aß peptides with MS-brain imaging. While intraparenchymal Aß deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aß deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aß deposits in capillaries. Investigation of Aß peptide profiles showed a specific increase in Aßx-37, Aßx-38 and Aßx-40 but not Aßx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aß2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aß peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aß deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aß peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.

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.

Associations of cerebrovascular disease and Alzheimer's disease pathology with cognitive decline: Analysis of the National Alzheimer's Coordinating Center Uniform Data Set.

Cerebrovascular disease (CVD) and Alzheimer's disease (AD) often co-occur and may impact specific cognitive domains. This study's goal was to determine effects of CVD and AD burden on cross-sectional and longitudinal executive function (EF) and memory in older adults. Longitudinally followed participants from the National Alzheimer Coordinating Center database (n = 3342) were included. Cognitive outcomes were EF and memory composite scores. Baseline CVD presence was defined by moderate-to-severe white matter hyperintensities or lacunar infarct on MRI. Baseline AD pathology was defined by amyloid positivity via PET or CSF. Linear mixed models examined effects of CVD, AD, and time on cognitive outcomes, controlling for sex, education, baseline age, MoCA score, and total number of study visits. At baseline, CVD associated with lower EF (p < 0.001), while AD associated with lower EF and memory (ps < 0.001). Longitudinally only AD associated with faster declines in memory and EF (ps < 0.001). These results extend our understanding of CVD and AD pathology, highlighting that CVD does not necessarily indicate accelerated decline.

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.

New Step in Understanding the Pathogenetic Mechanism of Sudden Infant Death Syndrome: Involvement of the Pontine Reticular Gigantocellular Nucleus.

This study aimed to investigate, for the first time, the potential role of the gigantocellular nucleus, a component of the reticular formation, in the pathogenetic mechanism of Sudden Infant Death Syndrome (SIDS), an event frequently ascribed to failure to arouse from sleep. This research was motivated by previous experimental studies demonstrating the gigantocellular nucleus involvement in regulating the sleep-wake cycle. We analyzed the brains of 48 infants who died suddenly within the first 7 months of life, including 28 SIDS cases and 20 controls. All brains underwent a thorough histological and immunohistochemical examination, focusing specifically on the gigantocellular nucleus. This examination aimed to characterize its developmental cytoarchitecture and tyrosine hydroxylase expression, with particular attention to potential associations with SIDS risk factors. In 68% of SIDS cases, but never in controls, we observed hypoplasia of the pontine portion of the gigantocellular nucleus. Alterations in the catecholaminergic system were present in 61% of SIDS cases but only in 10% of controls. A strong correlation was observed between these findings and maternal smoking in SIDS cases when compared with controls. In conclusion we believe that this study sheds new light on the pathogenetic processes underlying SIDS, particularly in cases associated with maternal smoking during pregnancy.

Beyond Hypertension: Examining Variable Blood Pressure's Role in Cognition and Brain Structure.

OBJECTIVES: Hypertension or high blood pressure (BP) is one of the twelve modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although hypertension is associated with cognitive decline and structural brain changes, less is known about the long-term association between variable BP and cognitive/brain changes. This study examined the relationship between variable BP and longitudinal cognitive, white matter hyperintensity (WMH), gray matter (GM), and white matter (WM) volume change over time and post-mortem neuropathology. METHODS: A total of 4,606 participants (32,776 follow-ups) from RADC Research Resource Sharing Hub (RUSH) and 2,114 participants (9,827 follow-ups) from Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. Participants were divided into one of three groups: normal, high, or variable BP. Linear mixed models investigated the relationship between BP and cognition, brain structure, and neuropathology. RESULTS: Older adults with variable BP exhibited the highest rate of cognitive decline followed by high and then normal BP. Increased GM volume loss and WMH burden was also observed in variable compared to high and normal BP. In post-mortem neuropathology, both variable and high BP had increased rates compared to normal BP. All the results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings. DISCUSSION: Damages potentially associated with variable BP may reduce resilience to future dementia related pathology and increased risk of dementia more than that caused by high BP. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.

Associations of amyloid-ß oligomers and plaques with neuropathology in the App NL-G-F mouse.

Amyloid-ß pathology and neurofibrillary tangles lead to glial activation and neurodegeneration in Alzheimer's disease. In this study, we investigated the relationships between the levels of amyloid-ß oligomers, amyloid-ß plaques, glial activation and markers related to neurodegeneration in the App NL-G-F triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein (App hu mouse). The relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry. Markers assessing human amyloid-ß proteins, microglial and astrocytic activation and neuronal and synaptic densities were used in mice between 2.5 and 12 months of age. We found that amyloid-ß oligomers were abundant in the brains of App hu mice in the absence of classical amyloid-ß plaques. These brains showed morphological changes consistent with astrocyte activation but no evidence of microglial activation or synaptic or neuronal pathology. In contrast, both high levels of amyloid-ß oligomers and numerous plaques accumulated in App NL-G-F mice in association with substantial astrocytic and microglial activation. The increase in amyloid-ß oligomers over time was more strongly correlated with astrocytic than with microglia activation. Spatial analyses suggested that activated microglia were more closely associated with amyloid-ß oligomers than with amyloid-ß plaques in App NL-G-F mice, which also showed age-dependent decreases in neuronal and synaptic density markers. A comparative study of the two models highlighted the dependence of glial and neuronal pathology on the nature and aggregation state of the amyloid-ß peptide. Astrocyte activation and neuronal pathology appeared to be more strongly associated with amyloid-ß oligomers than with amyloid-ß plaques, although amyloid-ß plaques were associated with microglia activation.

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.

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.

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.

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.

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.

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.

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.

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.