The Neuropathology of Schizophrenia

Abstract

Insofar as schizophrenia is a neuropsychiatric syndrome involving the brain, neuropathology is a promising, if not essential investigative approach. Although traditional neuropathology has yet to yield a pathognomonic lesion in schizophrenia, there have been no shortages of findings. Unfortunately, many of these findings have not only failed to be pathognomonic, but they have not been consistently replicated. Fortunately, newer neuropathological techniques, such as post-mortem neurochemistry, have resulted in findings among the most reproducible in schizophrenia research. Although one of these, increased dopamine receptors in the basal ganglia of schizophrenic patients, has been replicated many times, it suffers from doubts as to its clinical relevance. Are these increases in dopamine receptors primary to the illness or a side effect of the treatment? This article discusses the relevance of this finding, reviews other highlights of postmortem neurochemistry and traditional neuropathology, and discusses new horizons such as autoradiography, immunocytochemistry, and neuronal morphometrics.

White Matter Microstructure Alterations in Early Psychosis and Schizophrenia

“…These patterns of preferentially altered extra-axonal environment are also consistent with reports of global increase in "free water" using the FWI technique in SZ cohorts 35 , although FWI conflates potential pathological mechanisms by defining a tissue compartment (intra-and extra-axonal) vs a free water (CSF) one. The pathological WM changes suggested by WMTI-W are indeed supported by neuroimaging findings beyond dMRI, such as a 14% reduction in WM volume 83 , and ultrastructural post-mortem studies reporting myelinated WM fiber pathology, such as decompacting and splitting of the myelin sheath, inclusions of vacuoles in-between myelin layers, small-axons atrophy, and the presence of swollen or dystrophic oligodendroglia [22][23][24] and microglia 25 . In parallel to these morphological changes, a 27-28% reduction in oligodendrocyte densities were reported in cortical layer III and subcortical areas 21 of SZ specimens.…”

“…Pathological WM changes identified using WMTI-W are further supported by neuroimaging findings beyond dMRI, such as a 14% reduction in WM volume 94 , and ultrastructural post-mortem studies reporting myelinated WM fiber pathology, mainly consequence of the decompacting and splitting of the myelin sheath, but also the inclusions of vacuoles in between myelin layers, small-axons atrophy, and the presence of swollen or dystrophic oligodendroglia 22–24 and microglia 25 . In parallel to these morphological changes, a 27-28% reduction in oligodendrocyte densities were reported in cortical layer III and subcortical areas 21 of SZ brains.…”

“…Such heterogeneity may arise not only from cross-cohort heterogeneity 20 but also from different pathological processes affecting the WM, with some tracts showing non-degenerating early maturational shifts, or displaying accelerated aging 4 . Postmortem studies further substantiate the WM involvement found in first-episode psychosis participants 3 and in SZ, reporting splitting and decompacting of myelin sheaths together with dystrophic oligodendroglia [21][22][23][24] and microglia 25 . The heterogeneity in the possible DTI interpretations highlights the importance of improving the dMRI-derived microstructure characterization.…”

“…Using WMTI-W, we aim to characterize for the first time WM pathology in EP and SZ with increased specificity, thus overcoming the inconsistencies previously found in EP and SZ literature and relate WM pathology to commonly used clinical measures and characteristics, such as age of psychosis onset, illness duration, medication, and symptomatology. In light of previous post-mortem ultrastructural findings of myelinated fiber pathology (myelin sheath splitting with inclusions of vacuoles, small-axons atrophy, dystrophic oligodendroglia [21][22][23][24] ), we hypothesize that our dMRI findings will be mainly reflected as increased diffusivity of the extra-axonal space and as reduced axonal density.…”

Microglial Reactivity in the Prefrontal Cortex in Schizophrenia

“…Микроглия регулирует процесс миелинизации и связанной с ним когнитивной функции для сохранения целостности миелина путем предотвращения его дегенерации [75]. Нейровоспаление и активация микроглии участвуют в повреждении белого вещества мозга при шизофрении, что может привести к структурным и функциональным нарушениям нейронных связей даже при первом эпизоде психоза [76]. Исследование методом диффузионно-тензорной визуализации показало, что нарушения целостности миелина при шизофрении связаны с активным воспалительным процессом в ЦНС во время обострения психоза [77].…”