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It has been established, using polymerase chain reaction (PCR), that herpes simplex virus type 1 (HSV1) is present in a high proportion of brains of elderly normal subjects and Alzheimer's disease (AD) patients. It was subsequently discovered that the virus confers a strong risk of AD when in brain of carriers of the type 4 allele of the apolipoprotein E gene (apoE-epsilon4). This study has now sought, using PCR, the presence of three other herpesviruses in brain: human herpesvirus 6 (HHV6)-types A and B, herpes simplex virus type 2 (HSV2) and cytomegalovirus (CMV). HHV6 is present in a much higher proportion of the AD than of age-matched normal brains (70% vs. 40%, p=0.003) and there is extensive overlap with the presence of HSV1 in AD brains, but HHV6, unlike HSV1, is not directly associated in AD with apoE-epsilon4. In 59% of the AD patients' brains harbouring HHV6, type B is present while 38% harbour both type A and type B, and 3% type A. HSV2 is present at relatively low frequency in brains of both AD patients and normals (13% and 20%), and CMV at rather higher frequencies in the two groups (36% and 35%); in neither case is the difference between the groups statistically significant. It is suggested that the striking difference in the proportion of elderly brains harbouring HSV1 and HSV2 might reflect the lower proportion of people infected with the latter, or the difference in susceptibility of the frontotemporal regions to the two viruses. In the case of HHV6, it is not possible to exclude its presence as an opportunist, but alternatively, it might enhance the damage caused by HSV1 and apoE-epsilon4 in AD; in some viral diseases it is associated with characteristic brain lesions and it also augments the damage caused by certain viruses in cell culture and in animals.

Hippocampal sclerosis (HS) is the most common pathological substrate for temporal lobe epilepsy with a characteristic pattern of loss of principle neurons primarily in CA1 and hilar subfields. Other cytoarchitectural abnormalities have been identified in human HS specimens, including dispersion of dentate granule cells and cytoskeletal abnormalities in residual hilar cells. The incidence of these features, their relationship to the severity of HS and potential indication of underlying hippocampal maldevelopment is unverified. In a series of 183 hippocampectomies we identified classical HS (grades 3 and 4) in 90% of specimens, granule cell disorganization or severe dispersion in 40% of cases with a bilaminar pattern in 10%, and cytoskeletal abnormalities in hilar cells in 55% of cases. The severity of granule cell disorganization correlated closely with the degree of hippocampal neuronal loss but not with the age at first seizure or a history of a precipitating event for epilepsy such as prolonged febrile seizures. These findings suggest that granule cell disorganization is closely linked with the progression of HS rather than a hallmark of impaired hippocampal maturation. Furthermore, stereological quantitation of granule cells showed evidence of cell loss but greater numbers in regions of maximal dispersion, which may indicate enhanced neurogenesis of these cells. Quantitation of reelin-and calretinin-positive Cajal-Retzius cells in the dentate gyrus molecular layer in 26 cases showed no correlation between the number of these cells and the severity of granule cell dispersion, but increased numbers of these cells were present in HS with respect to control groups. Although a role for Cajal-Retzius cells is therefore not implicated in the mechanism of granule cell disorganization, their excess number may be indicative of underlying hippocampal maldevelopment in HS.

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