Expanding morphological dimensions in neuropathology,from sequence biology to pathological sequences and clinical consequences

One of the challenges in neuropathology is to clarify how molecules, functional carriers of uni‐dimensional sequence of amino acid or nucleic acid, behave to engender disease‐specific pathological processes in complex three‐dimensional (3D) structures such as the human brain in an ordered chronological sequence (four‐dimensional extension as a whole). Along with expanding molecular explanations for brain diseases, parallel and independent hypotheses based on morphological observations are particularly useful and necessary for reasonable understanding of the brain and its dysfunction. For example, with classical methods such as silver impregnations, it is possible to differentiate underlying molecular pathologies (three‐repeat tau/Campbell‐Switzer vs. four‐repeat tau/Gallyas silver impregnation) for improved histological diagnosis. Innovations with 3D reconstruction not only provide more realistic reproduction of the targets but also allow quantitative measurement on a 3D basis (3D volumetry). Contrary to the prevailing impression that pathological deposits are generally toxic to cells, quantification demonstrated possible countertoxic potentials of ubiquitin‐positive intranuclear inclusions in CAG‐repeat disorders on a two‐dimensional basis and of glial cytoplasmic inclusions of multiple system atrophy on 3D volumetry. Furthermore, 3D extension of neurites around target lesions is now traceable in relation to the relevant clinical consequences. This neurite neuropathology may pave the way for early specific diagnosis of neurodegenerative disorders, as established through ¹²³I‐metaiodobenzylguanidine cardiac scintigraphy for Parkinson disease, aiming at therapeutic intervention before depletion of mother neurons is feasible. For appropriate translation of sequence biology into the frame of human neuropathology, it is necessary to expand further the morphological dimensions so that comprehensive understanding of these disorders leads to specific diagnosis and treatment as early as possible.