Background: Alzheimer's disease drug development has produced a 99.6 percent failure rate for disease-modifying compounds (244 compounds tested 2002-2012, one regulatory approval; Cummings et al., 2014; Cummings, 2018)-the most sustained and costly therapeutic failure in the history of modern medicine. The field's standard explanation is that the biology is intractable. The present analysis offers a different and more instructive diagnosis: the failure was not primarily scientific. It was institutional. Objective: To characterize the structural and institutional forces that sustained investment in repeatedly ineffective mechanisms of action across 567 Phase 2 and Phase 3 Alzheimer's trials from 2010 to 2026, and to determine whether peer-reviewed alternative pathogenic frameworks were available at the time each major Go/No Go decision was made. Methods: Trials were identified from ClinicalTrials.gov using the following criteria: primary diagnosis of Alzheimer's disease or mild cognitive impairment attributed to Alzheimer's disease; Phase 2 or Phase 3; status of terminated or completed; primary completion date between January 1, 2010 and May 4, 2026. After exclusion of 70 trials not classifiable by mechanism of action, a final analytic dataset of 497 trials was classified by primary mechanism using the Common Alzheimer's Disease Research Ontology (CADRO). A temporal alignment analysis was conducted for the 12 largest trials by enrollment (N ≥ 1,300), mapping each trial's initiation date against the publication dates of peer-reviewed alternative mechanistic frameworks available at the time of trial launch. Results: Amyloid-targeting approaches accounted for approximately 31 percent of the 497 classified trials, nearly all of which failed to demonstrate clinical efficacy. Among the 12 largest trials, 11 targeted amyloid pathology and 10 were terminated for futility or lack of efficacy. All 12 trials were initiated after the publication in high-impact journals of peer-reviewed alternative frameworks, including the TREM2 neuroinflammation pathway, the antimicrobial protection hypothesis, the periodontitis-associated bacterial pathogenesis hypothesis, and the GLP-1 metabolic pathways. The post-2022 period revealed that genuinely novel non-amyloid mechanisms-TREM2 agonism, GLP-1 receptor stimulation, filamin A modulation, and progranulin/sortilin restoration-also failed to produce clinical benefit at scale despite confirmed target engagement. Three establishment forces are identified as operative causes: regulatory path dependency, institutional entrenchment within grant and editorial review panels, and shareholder-driven sunk-cost pressures. Conclusion: The 567-trial record constitutes a structural verdict on a model of drug development that was never designed to solve a problem of this complexity. The uniformity of negative results across all mechanism categories-amyloid, tau, neuroinflammation, metabolic, and synaptic-points toward deeper problems of disease definition, intervention timing, and endpoint validity that institutional and financial pressures have prevented the field from confronting. The Dominantly Inherited Alzheimer Network (DIAN) biomarker data demonstrates that pathology precedes symptoms by 15-25 years; the 2025 DIAN Trials Unit (DIAN-TU) extension provides the first evidence that treatment before symptom onset may delay dementia. Prevention trials in asymptomatic at-risk populations represent the only strategy the accumulated trial record has not yet refuted.
Background: DNA methylation profiling is a tool that provides key support for central nervous system (CNS) tumor classification. However, diagnostically ambiguous pediatric cases may result in discordant outputs across classifiers. We developed MAGIBU, a cross-platform, projection-based framework that embeds individual methylomes into a fixed CNS reference landscape, ranking diagnostic entities by local epigenetic proximity to support clinician-led integrative diagnosis. Methods: As a proof-of-concept, we evaluated MAGIBU in eight morphologically challenging pediatric/juvenile CNS tumors with unresolved diagnoses after institutional and central pathology review. To establish a benchmark in the absence of a definitive histopathological ground truth, a consensus epigenetic reference was defined a priori for cases showing concordant results between the Heidelberg CNS Tumor Methylation Classifier and Methylscape Analysis. Comparisons were also performed with Epigenomic Digital Pathology (EpiDiP). To validate MAGIBU beyond this discovery cohort, performance was assessed at the family level across the CNS methylation spectrum (n = 678, 28 methylation families), on non-array platforms (whole-genome bisulfite sequencing and Oxford Nanopore), and in a focused analysis of the low-grade glioma and diffuse midline glioma compartment across four independent cohorts (n = 670). Results: In the discovery cohort, MAGIBU achieved high concordance with the consensus reference (Cohen's κ = 0.855), outperforming EpiDiP (κ = 0.278), which frequently placed low-grade tumors in proximity to higher-grade reference regions. Conclusions: MAGIBU provides a stable, quantitative differential diagnosis framework that mitigates the limitations of rigid categorical assignments. By leveraging a distance-based proximity metric, it offers a transparent decision-support tool that integrates effectively with clinical, radiological, and molecular data. While performance is inherently dependent on reference atlas composition, MAGIBU represents a robust complementary approach for the diagnostic workup of ambiguous CNS tumors.
We report a case of atypical central neurocytoma with anaplastic histological features in the lateral ventricle of a previously healthy 37-year-old man. Histologically, the tumor exhibited anaplastic cell morphology, necrosis, increased mitotic activity, and vascular proliferation. The tumor had copy number alterations, but methylation profiling did not provide a match to any known methylation class, and mutation analyses were negative for pathogenic alterations. Atypical central neurocytoma is a challenging and rare diagnosis, and the World Health Organization (WHO) Classification of Tumors has not yet clarified diagnostic criteria for this putative entity. In a literature review, however, atypical central neurocytoma showed increased aggressiveness compared to conventional central neurocytoma, WHO grade 2.
Multiple sclerosis (MS) is the inflammatory-demyelinating disease of the CNS with the highest prevalence. Despite significant progress in reducing relapse activity by immunomodulatory or immunosuppressive treatments, there are ongoing challenges in understanding its initiation and predicting disease evolution. Furthermore, since we only partially understand the mechanisms driving disease progression, its successful treatment represents a major challenge. Therefore, this review article summarizes key research findings from the last 18 months, covering advances in the understanding of pathophysiology including the effects of aging on glial and immune cells as well as the functional role of tissue-resident memory cells. Additionally, we discuss advances in imaging technologies and biomarkers as well as the use of AI to predict disease evolution. Finally, we report the most recent findings from clinical trials targeting immune cells within the CNS.
The present collection of studies highlights major conceptual and translational advances in contemporary neurooncology related to the field of neuropathology. Central themes include the increasing recognition of neuron-tumor interactions, immune microenvironment remodeling, vascular heterogeneity, and epigenetic plasticity as key drivers of brain tumor progression and therapeutic resistance. Glioblastoma emerges as a highly dynamic and synaptically integrated disease entity, while melanoma brain metastases demonstrate profound microglial reprogramming with direct implications for immunotherapy. Novel molecular and spatial profiling approaches further reveal distinct vascular and immune landscapes across gliomas and brain metastases as well as lineage-dependent developmental programs in medulloblastoma. In parallel, rapid advances in artificial intelligence, nanopore sequencing, and real-time molecular diagnostics are reshaping neuropathological workflows and intraoperative decision-making. Proteomic and multi-omics analyses additionally uncover clinically relevant immune-hot glioma subtypes associated with adverse prognosis and spatial immune remodeling. Together, these studies underscore the increasing convergence of molecular neurobiology, immunology, epigenetics, and computational pathology in modern neurooncology and highlight emerging opportunities for precision diagnostics and targeted therapeutic intervention.
Background and objectives: Posterior Cortical Atrophy (PCA) is a focal variant of Alzheimer's Disease (AD) characterized by disproportionate and early visuospatial deficits with relative sparing of other cognitive abilities. PCA commonly arises before age 65, consistent with early onset AD (EOAD). Because studies of PCA pathology in patients with detailed cognitive assessment are rare, relationships between severity and distribution of neurofibrillary tangle (NFT) density and visuospatial deficits in PCA are not fully known. Our objectives were to: (1) determine if ratio of NFT density in occipital cortex (OC) versus hippocampus (HC) is higher in PCA than typical EOAD and (2) determine if this ratio correlates with severity of visuospatial deficits in EOAD generally. Methods: We determined density of tau NFT pathology in primary visual cortex (OC), midfrontal cortex (MF), and HC and calculated ratios of these densities for EOAD patients with PCA (n = 12) or non-PCA (n = 33) clinical phenotypes. Groups were compared using linear regression that adjusted for age at death and sex. Correlation between NFT density and visuospatial and other cognitive domain scores were examined using linear regression that adjusted for age at cognitive testing, education, sex and test-death interval. Analyses were repeated with the non-PCA EOAD patients grouped into those with mild (EOAD-Typical, n = 21) or severe (EOAD-Visual, n = 12) visuospatial impairment. Results: PCA patients had lower HC (β = -11.7 ± 5.7, p = 0.045) and a trend toward higher OC (β = 6.9 ± 3.7, p = 0.07) NFT density, and higher OC/HC (β = 0.30 ± 0.14, p = 0.04) and OC/MF (β = 0.56 ± 0.16, p = 0.001) ratios, than typical non-PCA EOAD patients. The EOAD-Visual had higher OC/HC NFT ratios (β = 0.38 ± 0.13, p = 0.008) than the EOAD-Typical non-PCA patients even though they did not meet clinical criteria for PCA. Correlations between OC/HC NFT ratios and visuospatial domain scores were strong (β = -1.29 ± 0.45, p = 0.008) and remained significant when limited to the non-PCA EOAD group (β = -1.22 ± 0.43, p = 0.008). Discussion: PCA is associated with a distribution of NFT pathology (i.e., high OC/HC NFT ratio) that coincides with early predominant visuospatial impairment. Non-PCA EOAD with a memory-predominant presentation and concomitant visuospatial impairment has an NFT distribution profile similar to PCA. NFT pathology in occipital cortex may moderate degree of visuospatial impairment in EOAD regardless of clinical syndrome.
Expansion microscopy (ExM) physically enlarges biological specimens to enable ultrastructural imaging with conventional fluorescence microscopes. However, its performance in postmortem human brain tissue is unclear. Here, we evaluated how a previously established ExM protocol performs on cortical tissue from eight banked brains with postmortem intervals ranging from 40 minutes to 91 hours, and compared these data with electron microscopy (EM) on a subset of matched samples. Both techniques revealed similar patterns of ultrastructural features, including irregular, rounded, unstained spaces as postmortem artifacts that increased with longer postmortem intervals. While EM provided superior resolution for synaptic details, ExM enabled more high-throughput volumetric imaging of neural circuits. ExM also enabled molecular annotation of ultrastructure through immunofluorescence, as demonstrated by SMI-312 neurofilament and γ-protocadherin labeling. Our findings show that ExM can visualize aspects of ultrastructure in routinely banked brain tissue. While EM provides better resolution for fine synaptic detail, ExM offers a complementary approach that combines nanoscale imaging with molecular specificity and more accessible high-throughput volumetric capabilities.
Background: The defining neuropathological hallmarks of Alzheimer's disease (AD)—amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs)—are now understood to exist along a continuum with brain aging, yet their fundamental trigger in sporadic disease remains enigmatic. The clinical failure of therapies targeting these proteins, despite their successful removal, underscores a critical dissociation between hallmark pathology and core pathogenesis. Objective: This clinicopathological update synthesizes emerging evidence on pervasive environmental nanoplastics (NPs) with the persistent paradoxes of AD to propose the dual sequestration hypothesis (DSH). Methods and Results: We suggest that Aβ plaques and tau NFTs could be reinterpreted as evolutionarily conserved, compartment-specific innate immune sequestration mechanisms—an extracellular "sarcophagus" and an intracellular "lockbox"—based on their roles in microbial defense and stress response. We posit that in the modern "Plasticene" era, indestructible NPs detected in human cerebrospinal fluid (CSF) and brain tissue act as permanent, inorganic nucleation seeds that hijack these responses, forming indigestible synthetic protein complexes. NPs directly nucleate Aβ fibrillation and tau hyperphosphorylation, initiating the sequestration response. Chronic microglial engagement with these complexes triggers a state of "immune frustration," leading to a maladaptive phase transition. This pivot could be explained by glutamate excitotoxicity, which drives microglial NLRP3 inflammasome activation and pyroptotic cell death. Lytic pyroptosis liberates intact synthetic seeds into the paravascular space, where they are distributed via glymphatic flow, physically obstructing clearance and providing a mechanistic model for the stereotypical progression of Braak stages. Conclusion: The DSH offers a unified explanation for the therapeutic failure of anti-Aβ/anti-tau antibodies (which remove the biological response but not the synthetic trigger) and amyloid-related imaging abnormalities (ARIA) as an inflammatory rebound. It necessitates a paradigm shift in neuropathological practice, calling for novel detection techniques to visualize the synthetic core within classical lesions, thereby unifying environmental etiology with canonical pathology. The presence of synthetic NPs at the physical center of Aβ plaques and tau tangles in human AD brain tissue is currently a prediction of the DSH awaiting empirical validation, not an established finding.
Multiscale and multimodal analysis of post-mortem human brain tissue is essential for improving the characterisation of neurodegenerative diseases (NDDs). Brain bank repositories provide extensive collections of formalin-fixed paraffin-embedded (FFPE) tissue enabling investigation of cellular and subcellular alterations across NDDs. Although conventional and multiplex chromogenic immunohistochemistry (cIHC) support large-scale neuropathological assessment, they do not fully capture the spatial and cellular complexity. Immunofluorescence (IF) combined with confocal microscopy increases spatial resolution, but standard section thickness limits three-dimensional (3D) analysis. Here, we present a sequential, multimodal and semi-automated workflow within a unified pipeline that enhances the multiscale definition of the neuropathological signature. Using neuronal and pathological markers as technical references, we demonstrate stepwise additive spatial information across modalities: from anatomical distribution using single cIHC, to two-dimensional combinatorial detection using multiplex cIHC, and to volumetric intracellular localisation using multiplex IF on thick sections. When applied to human FFPE brain tissue, this workflow enables reproducible and scalable multiscale protein mapping. It supports consistent detection and spatial separation of multiple markers and links chromogenic pathology with high-resolution 3D fluorescence imaging, providing a practical framework for the integrated spatial analysis of neurodegenerative pathology and beyond.
Background: Individuals with Down syndrome (DS) face markedly increased risk of premature aging and age-related pathological changes, particularly Alzheimer's disease (AD)-like neuropathology. By the fourth decade of life, virtually all individuals with DS develop the hallmark AD features such as senile plaques (SPs) and neurofibrillary tangles (NFTs). The aim of this study was to characterize the topographical distribution of cerebral amyloid angiopathy, the morphology of senile plaques, and the spectrum of co-existing aging-related proteinopathies in autopsied DS patients, with reference to age-matched and elderly controls. Methods: Nine autopsied DS patients (aged 0.5-68.0 years at death) were examined alongside age-matched controls. Immunohistochemical staining was performed for amyloid-β (Aβ), phosphorylated tau, α-synuclein, and phosphorylated TDP-43. In addition, silver impregnation using the Gallyas method and Congo red staining were performed. Aging-related pathologies were assessed using established criteria for NFTs, Aβ deposits, cerebral amyloid angiopathy (CAA), and other neurodegenerative changes. Results: All four DS patients aged ≥ 28 years (D6-D9) showed moderate-to-severe AD neuropathological changes, whereas none of five age-matched controls (23.1-68.4 years old) did. In DS patients with AD, unclassifiable SPs were predominant, and NFTs with both 3-repeat and 4-repeat tau were observed. The distribution and progression of the latter were similar to those of sporadic AD patients. CAA was observed in three DS patients and, owing to systematic sampling, could be documented in the spinal arteries and subdural/subarachnoid bridging vessels-sites not routinely evaluated in autopsy series of sporadic CAA. All three DS cases with CAA reached Thal stage 3 CAA, contrasting with a maximum of stage 2 in CAA-positive sporadic AD and elderly control cases. Notably, two of three DS patients with CAA had a documented clinical history of subdural hemorrhage (SDH); both showed marked cerebral atrophy at autopsy, precluding definitive attribution of SDH to CAA. The high frequency of SDH suggests increased hemorrhagic risk in DS patients due to extensive vascular amyloid deposition. Conclusions: This study demonstrates accelerated ADNC development in DS, with characteristic unclassifiable SPs and extensive CAA representing unique features that distinguish DS from common aging patterns. The clinical history of SDH in DS patients with CAA, together with the histological extension of CAA to subdural bridging vessels, may warrant attention when considering the vascular safety of emerging anti-amyloid therapies in this population. However, causality between CAA and SDH could not be established from the present autopsy data. These findings provide crucial insights into AD pathogenesis and highlight the importance of developing targeted therapeutic strategies while considering safety implications.
Brain banking enables the study of human neural tissue and is essential for research on disease, physiology, and neuroanatomy. An essential step for whole brain studies is the extraction of the brain from the skull. Yet detailed technical descriptions of brain removal are rare, perhaps contributing to the artifactual tissue disruption sometimes observed as a result of the procedure. Here, we describe a method for whole brain extraction that could be implemented in the context of a whole-body donation, focused on the use case of fixed tissue banking. The method involves a sequential craniectomy that uses both circumferential and midline sagittal cuts, followed by a posterior approach to cutting the dura. We report the application of this protocol across n = 105 human whole-body donors. We document the time required for each procedural step and the frequency of craniectomy artifacts and skull edge artifacts at the brain surface. When the brain tissue is particularly soft, we also describe the potential use of in situ immersion fixation to increase tissue stiffness before removal, finding however that this also slows the diffusion of chemicals into the interior of the brain. Our experience suggests that the effectiveness of brain extraction can be improved via procedural optimizations. Technicians can become comfortable with the method after approximately 5-10 cases. We anticipate that improving brain extraction quality may support downstream work in the development of diagnostics and treatments for neurological and psychiatric disease.
This review discusses key publications in forensic neuropathology from the 2025 literature. In abusive head trauma (AHT), biomechanical models help clarify injury mechanisms, particularly the role of sagittal angular acceleration in younger infants. However, challenges remain, such as detecting subtle brainstem pathology with neuroimaging, stressing the need for prospective clinicopathological correlation. Meanwhile, understanding of chronic traumatic encephalopathy (CTE) is expanding beyond contact sports to include victims of intimate partner violence. Research on sudden unexpected death in epilepsy (SUDEP) indicates overlaps with sudden infant death syndrome (SIDS) and identifies key risk factors. At the same time, forensic neuropathology's primary role remains the exclusion of other causes of death. Artificial intelligence shows promise for analyzing radiological and histopathological data in traumatic brain injury (TBI) and epilepsy, though its adoption for routine purposes remains a distant goal. Further developments include a better understanding of the cerebellum's vulnerability to TBI, standardized postmortem MRI protocols, and the use of cerebrospinal fluid biomarkers, such as GFAP and S100B, to estimate time of death. Finally, research continues to probe the complex links between brain morphology and behavior, and recent studies of the neuropathology of alcohol use disorder have revealed microglial changes rather than overt neuronal loss.
The terms "Alzheimer's disease" and "Alzheimer disease" are often used interchangeably in the biomedical literature. Yet this seemingly minor grammatical difference carries implications that extend beyond style: the possessive form, marked by the 's eponym, may imply ownership of a disease by an individual, a notion discouraged by several authoritative medical style guides and international health organizations [1]. In this article, we examine the historical emergence of the term "Alzheimer's disease", analyze the trajectories of the possessive and non-possessive eponyms in PubMed-indexed article titles from 1950 to 2025, and assess how the choice of terminology influences literature retrieval. Our analysis indicates that the possessive form has overwhelmingly dominated the literature for decades. However, searches using "Alzheimer's disease" or "Alzheimer disease" retrieve non-identical, only partially overlapping sets of records in PubMed. We argue that adopting the non-possessive form "Alzheimer disease" would improve conceptual clarity, terminological consistency, and the completeness of literature retrieval, particularly in systematic reviews and meta-analyses.
Objective: Brain branks preserve extensive material relevant to neurodegenerative disease research. As these collections age, tissue becomes archival, raising the question of whether long-term fixed and stored human brain tissue remains suitable for contemporary immunohistochemical analyses. Materials and Methods: Forty-one autopsy brains collected between 1946 to 1980 were examined. For each case, midbrain and hippocampus were available both as original paraffin-embedded blocks and as tissue stored long term in fixative. New paraffin blocks were prepared from the long-term fixated tissue. Sections from original and newly prepared blocks were immunohistochemically stained for α-synuclein, hyperphosphorylated tau and amyloid-β. Immunoreactivity was assessed using semi-quantitative scoring. Results: Original blocks consistently showed good staining intensity and morphological preservation for each protein pathology. Newly prepared blocks showed slightly lower semi-quantitative scores for Lewy-related pathology, without statistically significant differences, except for astrocytic α-synuclein in the substantia nigra in cases from the 1960s. Tau pathology displayed modestly reduced labelling, particularly of the neuropil threads and neurofibrillary tangles, most evident in cases from the 1950s. Amyloid-β-positive senile plaques showed similar or slightly higher scores in newly prepared blocks, with no significant differences across regions. Conclusion: Human brain tissue preserved as paraffin-embedded blocks or stored in fixative for up to 78 years remains suitable for immunohistochemical analyses. Adequate-to-good detection of aggregated α-synuclein, hyperphosphorylated tau and amyloid-β is achievable, indicating preserved pathological hallmarks of Lewy Body Disease and Alzheimer’s Disease in archival tissue.
Across neurodegenerative diseases, the shape and spatial organization of pathology carry rich mechanistic information. Vacuoles, spongiosis, oligodendroglial coiled bodies, dendritic dystrophic neurites, amyloid plaque compactness, and phase-separated droplets each reflect distinct cellular identities, subcellular compartments, trafficking pathways, and biophysical material states. Here, I synthesize morphological signatures across neurodegenerative diseases to propose a framework that links morphology to mechanism. Morphology is neither incidental nor merely descriptive. Rather, it is a readout of the basic mechanisms that govern self-assembly of proteins into aggregates, the cell’s attempts at proteostasis (clearance, sequestration, and transport), and the failure that ensues.
This meditation with apologies by a psychiatrist who is not a neuropathologist but attends CPCs of movement disorder patients speculates about how microscopic mechanical processes produce the variety of cellular neuropathological forms, which differ with diagnoses, and wonders what may be revealed by the shapes of these traces by future neuropathologists. New discoveries about tiny machines, nanotubules and the like only increase the intrigue and possibilities of revelations, likened to a crime scene investigation.
Introduction: Neuropathology is important in the diagnosis of neurologic and neuro-oncologic diseases. But despite its immense importance, it remains underrepresented in medical training across different parts of Sub-Saharan Africa. Training in this region is limited by a low number of specialists (e.g., a ratio of 1.7 million inhabitants per an unspecialized pathologist), fragmented data, poor infrastructure, and minimal exposure. Most times, neuropathology is embedded in general pathology curricula with limited mentorship, specialized facilities, and tailored subspecialty pathways (e.g., Nigeria, Tanzania). But despite these prevailing challenges, digital tools like telepathology and virtual microscopy may help bridge those gaps. Aim: This scoping review aims to understand the structure of existing neuropathology training and identify important gaps in structure and resources across Sub-Saharan Africa. It also seeks to explore how regional and global collaborations and digital innovations can be integrated to bridge these gaps. Methodology: Using PRISMA-ScR guidelines, we searched literature published between 2000 and 2025 across major databases such as PubMed, Scopus, Web of Science, AJOL, and grey sources. We included and thematically analyzed studies that focused on training in neuropathology, workforce, and digital tools in Sub-Saharan Africa. We mapped out data to capture country, program type, curriculum content, resource availability, and digital tool integration. Quantitative synthesis summarized the frequency and geographic distribution of programs, while qualitative thematic analysis identified recurring patterns in training gaps, infrastructural limitations, and the application of virtual microscopy and telepathology. Result: We reviewed eleven studies that indicate limited neuropathology programs, an extremely low number of neuropathologists (e.g., 0.4-0.6 per million in many Sub-Saharan Africa nations), inadequate mentorship, and limited training resources. However, telepathology and virtual microscopy show improved accuracy in diagnosis and quality training (e.g., Tanzania recorded a 35 % increment in accuracy by specialized pathologists using telepathology over general pathologists). Strengthening international collaborations also demonstrates feasibility and enhanced quality training. Conclusion: Neuropathology in Sub-Saharan Africa is underdeveloped and fragmented; however, the increasing access to newer digital solutions presents low-cost options as practical alternatives for overcoming diagnostic and training obstacles. To narrow these gaps, the track toward becoming a subspecialist in neuropathology should be formed, accessible digital libraries of learning materials must be developed, and regional and international telepathology networks should be strengthened.
