Serial ultrastructural study of experimental Creutzfeldt-Jacob disease in guinea pigs.

Guinea pigs inoculated with brain homogenate from serially passaged Creutzfeldt-Jakob disease (CJD) were killed biweekly starting at week 2 until terminal illness (about 200 days following inoculation). A mild swelling of postsynaptic dendrites and an increase in the number of glial filaments in astrocytic processes was seen at week 4, followed by increased swelling and lucency of axons and dendrites by week 6 post inoculation (p.i.). Severe undulation and focal interruptions of synaptic membranes were also observed both at weeks 4 and 6. By week 8, one could see cystically dilated cellular processes. These sometimes showed continuity with adjacent swollen processes through focally disrupted plasma membranes, and most likely represent a progressive enlargement of vacuoles through fusion and subsequent addition of adjoining processes. The spongiform changes increased mildly between week 8 and week 10 and remained essentially the same in subsequent weeks. After week 24 there was a sharp increase in both the number and size of vacuoles. At week 24 severe structural alterations were present both in the neurons and astrocytes, and numerous intranuclear inclusions were demonstrated in many neuronal nuclei. This study shows that morphological changes in the brain occur considerably earlier than the clinical manifestations of the disease. In the early phase of the disease, there were significant alterations on the dendrites and synapses.