The phenomenon of clasmatodendrosis

Abstract

Clasmatodendrosis derives from the Greek for fragment (klasma), tree (dendron), and condition (- osis). Cajal first used the term in 1913: he observed disintegration of the distal cell processes of astrocytes, along with a fragmentation or beading of proximal processes closer to the astrocyte cell body. In contemporary clinical and experimental reports, clasmatodendrosis has been observed in models of cerebral ischemia and seizures (including status epilepticus), in elderly brains, in white matter disease, in hippocampal models and cell cultures associated with amyloid plaques, in head trauma, toxic exposures, demyelinating diseases, encephalitides and infection-associated encephalopathies, and in the treatment of cancer using immune effector cells. We examine evidence to support a claim that clasmatodendrotic astrocyte cell processes overtly bead (truncate) as a morphological sign of ongoing damage premortem. In grey and white matter and often in relationship to vascular lumina, beading becomes apparent with immunohistochemical staining of glial fibrillary acidic protein when specimens are examined at reasonably high magnification, but demonstration of distal astrocytic loss of processes may require additional marker study and imaging. Proposed mechanisms for clasmatodendrotic change have examined hypoxic-ischemic, osmotic-demyelinating, and autophagic models. In these models as well as in neuropathological reports, parenchymal swelling, vessel-wall leakage, or disturbed clearance of toxins can occur in association with clasmatodendrosis. Clasmatodendrotic features may serve as a marker for gliovascular dysregulation either acutely or chronically. We review correlative evidence for blood-brain barrier (BBB) dysfunction associated with astrocytic structural change, with attention to interactions between endothelial cells, pericytes, and astrocytic endfeet.

Keywords: Astrocyte; Blood-brain barrier; Clasmatodendrosis; Endfoot; Endothelial cell; Pericyte.

Figure 1

Autolytic phenomena in the white matter of the brain of a female adult autopsied two hours after death (Ramón y Cajal 1913, fig. 18, public domain. [2]). A. Cell with preserved processes. B. Astrocyte with fragmentations. C, D, E. Astrocyte with disrupted cytoplasmic expansions, but with preservation of perikaryon. a. capillary. b. disaggregated end feet.

Figure 2

Postmortem neuropathologic evaluation showing prominent clasmatodendrosis in a patient with a history of acute lymphoblastic leukemia treated with anti-CD19 CAR T-cell therapy complicated by fulminant cerebral edema. Beading and fragmentation of astrocytic processes (highlighted by GFAP immunostains) were seen in sections of cortex (A, 200x; B, 400x) and were accentuated around blood vessels (C, 600x).

Figure 3

Schematic illustrating triggers leading to increased BBB permeability associated with astrocytic clasmatodendrosis. Blue row represents findings from a pericyte-deficient mouse model; stippled rows represent findings from co-culture study of astrocytes and endothelial cells; light yellow rows represent findings in ICANS. Abbreviations are those used elsewhere in this paper.