Neuropathology—the study of diseases of the nervous system at tissue level—emerged gradually from anatomical curiosity into a mature, molecularly-anchored discipline. Its story spans four broad eras.
Descriptions of brain injury appear on Egyptian papyri and in Galenic treatises, yet neither culture regarded the brain as the seat of disease. Vesalius’ De humani corporis fabrica (1543) provided the first modern neuro-anatomical atlas, but pathology remained speculative until autopsy became an accepted scientific act in the eighteenth century. Giovanni Battista Morgagni’s De sedibus et causis morborum (1761) linked symptoms to discrete lesions, sowing the principle that disease might be localised within the central nervous system (CNS).
2. Clinicopathological Correlation and Cellular Pathology (1800-1900).
French clinicians—Bayle, Trousseau, Charcot—systematically compared neurological signs with post-mortem findings, establishing multiple sclerosis, lateral sclerosis and movement-disorder nosology. The microscope transformed those macroscopic correlations. With his cell theory (1858), Rudolf Virchow coined glioma and described cerebral emboli, framing the brain as a tissue governed by general pathological laws. In Spain, Santiago Ramón y Cajal used Golgi’s silver impregnation to reveal discrete neurons and their degeneration; his drawings still undergird diagnostic recognition of neuronal loss and axonal swellings. The period closed with Alois Alzheimer’s 1906 lecture describing “plaques and tangle threads” in the presenile cortex—an iconic clinico-pathological entity rooted in systematic microscopy.
Between the World Wars, myelin and Nissl stains (Weigert, Luxol Fast Blue, Cresyl Violet) standardised tumour grading and demyelinating disease diagnosis. ∙ Neuropathologia became a defined subspecialty with the founding of the Journal of Neuropathology and Experimental Neurology (1942).
Virology and immunology then reshaped the field: polio, rabies‐Negri bodies, and slow viral encephalitides (Creutzfeldt-Jakob, sub-acute sclerosing panencephalitis) demanded new histochemical techniques. Electron microscopy (1950s) identified viral particles, myelin lamellae and the ultrastructural hallmarks of lysosomal storage diseases. Meanwhile, D. H. P. Thomas and Pío del Río-Hortega characterised oligodendrocytes and microglia, completing the cellular cast.
4. Molecular and Digital Convergence (1980-present)
Monoclonal antibodies launched immunohistochemistry: GFAP clarified astrocytoses; neurofilament, synaptophysin and cytokeratins refined tumour classification; β-amyloid and hyper-phosphorylated tau allowed in vivo–post mortem continuities in Alzheimer research. The 2000 and 2016 WHO tumour classifications integrated cytogenetics (1p/19q codeletion, IDH1/2 mutation) and, by 2021, DNA-methylation arrays could re-assign morphologically ambiguous neoplasms. Molecular autopsy uncovered repeat-expansion disorders (C9orf72 ALS/FTD) and prion strains, while next-generation sequencing identified POLR3A leukodystrophy and other “gene-first” leukoecephalopathies.
Digitisation is now redefining workflow. Whole-slide imaging permits tele-consultation and quantitative morphometry; convolutional neural networks achieve near-expert accuracy in brain-tumour grading and micro-metastasis detection. Deep-segmentation of cerebral small-vessel disease on MRI–histology pairs, and spatial transcriptomics that overlay mRNA grids onto sections, are closing the gap between morphology and multi-omics. Artificial-intelligence decision support is beginning to triage biopsies, forecast molecular class, and suggest ancillary tests, echoing Ramón y Cajal’s exhortation that “the future will belong to the microscopist equipped with better instruments.”
From Morgagni’s autopsy tables to cloud-based slide servers, neuropathology has continuously mirrored the prevailing technological frontier. Yet its core method—correlating clinical presentation with visualised tissue change—remains intact. The coming decade promises algorithmic augmentation and single-cell spatial biology, but the discipline’s historical trajectory suggests that careful morphological insight will persist as the anchor of nervous-system disease understanding.
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