As expected, the CA1 region was the area most commonly involved by HS in HS-FTLD, HS-TLE, and H–I. Our study uncovered differences in the extent of involvement of the CA1-prox and the CA1-dist as well as the likelihood of involvement of hippocampal subregions other than the CA1 (). Although some of these findings, such as the involvement of the CA4-CA3 regions in a subset of TLE cases, have been established in previous literature (1
), to our knowledge, this is the first study where the anatomic extent of HS was directly compared among FTLD, TLE, and H–I cases in rigorously defined hippocampal subfields.
The novel findings included the observations that the CA1-dist and the prosubiculum were the areas that are most commonly involved in FTLD, whereas the CA1-prox and the CA1-mid were more likely to be involved in TLE and H–I (). The area most commonly involved in ischemic injury is the CA1-prox (). Interestingly, the prosubiculum was occasionally involved even in the absence of CA1 involvement in FTLD; this finding underlines the specific vulnerability of the prosubiculum for HS in FTLD. A similar finding was previously reported in FTLD with motor neuron disease (FTLD-MND) by Nakano, who described depletion of neurons in the CA1-subiculum border zone in the rostral hippocampus (level of the pes hippocampi) (19
). This lesion usually disappeared at more caudal levels of the hippocampus. In our series, 2 of the 3 FTLD-TDP cases with HS limited to the prosubiculum at the level of the lateral geniculate nucleus had no history of motor neuron disease (a detailed clinical history was unavailable in the third case), which suggests that the prosubiculum is highly vulnerable to HS in FTLD in general and not only in FTLD-MND. In a post hoc analysis, we examined the prevalence of HS in the anterior hippocampus of our FTLD cases and found that HS was present in 50% (21 out of 42) of FTLD cases in the anterior hippocampus compared with 31% (14 out of 45) in the posterior hippocampus (p = 0.08, not significant). Hippocampal sclerosis limited to the prosubiculum occurred in 24% of the FTLD cases with HS in the anterior hippocampus and in 21% of the FTLD cases with HS in the posterior hippocampus (not significant). Because we only had 2 FTLD-MND cases, we could not determine the distribution and prevalence of HS in cases with MND versus cases without MND.
The differential vulnerability of the CA1-prox compared with the CA1-dist found in this study is surprising because CA1 is traditionally considered a single homogeneous subregion of the hippocampus. Further studies are needed to characterize the differences in neurochemistry and gene expression that might potentially underlie the differential vulnerability of the CA1-prox and the CA1-dist. The differences that have been uncovered to date include the finding that certain glial cell line–derived neurotrophic factor family ligands and receptors are preferentially expressed in the CA1-prox compared with the CA1-dist (20
We found that labeling of the hippocampal mossy fibers by immunohistochemistry for ZNT3 was helpful in defining the border between CA3 and CA2 in routinely processed formalin-fixed human autopsy tissue (). Immunohistochemistry for ZNT3 has been previously used to stain the hippocampal mossy fibers in the mouse brain (22
). The traditional method for staining the hippocampal mossy fibers is Timm stain for zinc, which requires treating the tissue with sulfide before fixation and is, therefore, unsuitable for routinely processed formalin-fixed human tissue (23
We found that different hippocampal subfields and CA1 subsegments are preferentially involved in FTLD, TLE, and ischemic injury, suggesting that the pathogenesis of HS is at least to some extent different in these conditions. There is little doubt that release of glutamate in the extracellular space (excitotoxicity) plays an important role in hippocampal neuronal death in epilepsy. Although the distributions of glutamate receptor subtypes in the normal human hippocampus (24
) do not appear to explain the selective vulnerability of the CA1-prox and the CA1-mid reported in the current study, this leaves open the possibility that the distributions of glutamate receptors could be altered in disease states compared with normal. Only limited studies addressing this possibility have been performed. In a receptor autoradiography study of the human hippocampus, highest binding for glutamate, NMDA, and AMPA receptors was seen in the molecular layer of the dentate gyrus and throughout CA1 in specimens of hippocampi from subjects without epilepsy, subjects with epilepsy caused by an extrahippocampal tumor, and subjects with TLE (26
). Binding for kainate receptors was highest in CA3 (26
As in TLE, there is strong evidence that excitotoxicity contributes to hippocampal neuronal death after a hypoxic insult. For example, a recent study showed a highly significant protection from hypoxic injury in all hippocampal subfields (CA1–CA4 and dentate gyrus) in GluK4 receptor–knockout mice (27
). However, the precise mechanism mediating this widespread hippocampal neuroprotection is not clear because the expression of the GluK4 is concentrated in CA3 (27
). In another animal experiment, a neonatal hypoxic insult resulted in an early (i.e. 6 hours after hypoxic insult) and nearly total loss of glial glutamate transporters throughout CA1, CA2, and CA3 but not in the dentate gyrus granule neurons, which corresponded to the areas of subsequent neuronal injury (28
). The connection of these results to the more restricted areas of selective vulnerability in the adult human hippocampus, as observed in our study, is unclear.
To our knowledge, the distribution of glutamate receptor subtypes has not been studied in FTLD, which leaves open the possibility that altered distribution of these receptors could potentially explain the selective vulnerability of the CA1-dist and prosubiculum to HS in FTLD. In addition to excitotoxicity, alternative promising hypotheses on hippocampal selective vulnerability in ischemic injury and neurodegenerative diseases include impairment of protein degradation secondary to proteasomal stress (29
Interestingly, the prosubiculum, a region that we found to be selectively vulnerable to HS in FTLD, is characterized by a unique neurochemical and gene expression profile as well as dense amygdalo-hippocampal terminal projections (17
). These projections to the prosubiculum originate in the basal nucleus of the amygdala, express acetylcholinesterase, and do not significantly extend to the adjacent subiculum proper or CA1 (17
). Future studies should look for a possible correlation between neuropathologic alterations such as TDP-43 inclusions in the basal nucleus of the amygdala and HS involving the prosubiculum in FTLD.