Hippocampal sclerosis in dementia, epilepsy, and ischemic injury: differential vulnerability of hippocampal subfields

Abstract

Severe neuronal loss in the hippocampus, that is, hippocampal sclerosis (HS), can be seen in 3 main clinical contexts: dementia (particularly frontotemporal lobar degeneration [FTLD]), temporal lobe epilepsy (TLE), and hippocampal ischemic injury (H-I). It has been suggested that shared pathogenetic mechanisms may underlie selective vulnerability of the hippocampal subfields such as the CA1 in these conditions. We determined the extent of neuronal loss in cases of HS-FTLD (n=14), HS-TLE (n=35), and H-I (n=20). Immunohistochemistry for zinc transporter 3 was used to help define the CA3/CA2 border in the routinely processed human autopsy tissue samples. The subiculum was involved in 57% of HS-FTLD, 10% of H-I, and 0% of HS-TLE cases (p<0.0001). The CA regions other than CA1 were involved in 57% of HS-TLE, 30% of H-I, and 0% of HS-FTLD cases (p=0.0003). The distal third of CA1 was involved in 79% of HS-FTLD, 35% of H-I, and 37% of HS-TLE cases (p=0.02). The distal third of CA1 was the only area involved in 29% of HS-FTLD, 3% of HS-TLE, and 0% of H-I cases (p=0.019). The proximal-middle CA1 was the only area affected in 50% of H-I, 29% of HS-TLE, and 0% of HS-FTLD cases (p=0.004). These findings support heterogeneity in the pathogenesis of HS.

FIGURE 1

An example of a case classified as hippocampal ischemic injury. A remote microinfarct (arrows) in the proximal CA1 of a subject with a clinical history of multiple strokes. Hematoxylin and eosin; original magnification: 40×. Scale bar = 200 µm.

FIGURE 2

Immunohistochemical and special stains can be helpful in delineating the hippocampal subfields in some cases. (A–C) Sections of the hippocampus without hippocampal sclerosis in a 90-year-old man. The border between CA2 and CA1 can be recognized based on the widening of the pyramidal cell layer when moving from CA2 to CA1 (A). Immunohistochemistry for ZNT3 highlights the mossy fibers extending from the dentate gyrus to CA3 but not CA2 (B), thus delineating the border between CA3 and CA2 (arrow). Immunohistochemistry for choline acetyltransferase (ChAT) shows a decrease in staining from CA2 to CA1 (C), which confirms the location of the border between CA2 and CA1 (arrow). (D–F) Sections of the hippocampus with hippocampal sclerosis (mesial temporal sclerosis) in a 44-year-old man with a history of temporal lobe epilepsy. Severe loss of neurons is limited to CA1, whereas CA2 is spared ([D] H&E). An arrow points to the border between CA2 and CA1 (D). Immunohistochemistry for ZNT3 highlights the border between CA3 and CA2 ([E] arrow). The subiculum is spared from severe neuronal loss ([F] H&E), which makes the oblique border between CA1 and the subiculum (dashed line) stand out. In this case, the CA1/subiculum border coincides with the termination of a strip of white matter in the overlying stratum lacunosum-moleculare (arrow); this strip may contain the Schaffer collaterals that extend from CA3 to CA1 but not subiculum. (G–I) Hippocampus of a 79-year-old woman with frontotemporal lobar degeneration with TDP-43–positive inclusions (FTLD-TDP); the prosubiculum is severely affected by neuronal loss and gliosis, whereas CA1 and the subiculum proper are relatively spared ([G] H&E). The border between CA1 and the prosubiculum is indicated by a dashed line (G). A Hirano silver stain highlights a bundle of axons in the overlying stratum lacunosum-moleculare (H); the bundle of axons terminates at the CA1/prosubiculum border (arrow), suggesting that some of the axons represent Schaffer collaterals. A higher magnification view of the CA1/prosubiculum border ([I] dashed line) shows relative sparing of neurons in CA1, which contrasts with the severe neuronal loss and gliosis in the prosubiculum. Original magnification: (A–F) 20×; (G–H) 40×; (I) 100×. Scale bars = (F) 200 µm in (A–F); (H) 100 µm in (G, H); (I) 40 µm.

FIGURE 3

Heat map showing the likelihood of involvement of hippocampal subfields by hippocampal sclerosis (HS), defined as severe neuronal loss, in frontotemporal lobar degeneration with HS (HS-FTLD), temporal lobe epilepsy with HS (HS-TLE), and hippocampal ischemic injury (H–I). HS-FTLD is distinguished from the other two groups by a higher likelihood of involvement of the CA1-dist and the subiculum. In both HS-TLE and H–I, the region extending from the CA1-prox to the CA1-mid was the area most commonly affected. Involvement of CA3 and CA4 was also common in HS-TLE but relatively infrequent in H–I. See Results for p values. dist, distal; presubic, presubiculum; prosubic, prosubiculum; prox, proximal.