Selective neuronal vulnerability of human hippocampal CA1 neurons: lesion evolution, temporal course, and pattern of hippocampal damage in diffusion-weighted MR imaging

Abstract

The CA1 (cornu ammonis) region of hippocampus is selectively vulnerable to a variety of metabolic and cytotoxic insults, which is mirrored in a delayed neuronal death of CA1 neurons. The basis and mechanisms of this regional susceptibility of CA1 neurons are poorly understood, and the correlates in human diseases affecting the hippocampus are not clear. Adopting a translational approach, the lesion evolution, temporal course, pattern of diffusion changes, and damage in hippocampal CA1 in acute neurologic disorders were studied using high-resolution magnetic resonance imaging. In patients with hippocampal ischemia (n=50), limbic encephalitis (n=30), after status epilepticus (n=17), and transient global amnesia (n=53), the CA1 region was selectively affected compared with other CA regions of the hippocampus. CA1 neurons exhibited a maximum decrease of apparent diffusion coefficient (ADC) 48 to 72 hours after the insult, irrespective of the nature of the insult. Hypoxic-ischemic insults led to a significant lower ADC suggesting that the ischemic insult results in a stronger impairment of cellular metabolism. The evolution of diffusion changes show that CA1 diffusion lesions mirror the delayed time course of the pathophysiologic cascade typically observed in animal models. Studying the imaging correlates of hippocampal damage in humans provides valuable insight into the pathophysiology and neurobiology of the hippocampus.

Figure 1

Analysis of diffusion changes and apparent diffusion coefficient (ADC) in the hippocampus. The mean ADC was calculated by manually defining regions of interest (ROIs) that were positioned in the area of the hyperintense DWI lesion in CA1. Magnetic resonance images (3 T) showing a DWI lesion in the head of the right cornu ammonis in the coronal and transversal plane (upper and lower left) with a corresponding lesion in the T2-weighted image (inset, lower left). Inset (upper left) shows the magnified DWI lesion and the ADC signal changes in the coronal (upper right) and transversal plane (lower right) indicating the ROIs for quantifying the ADC values (insets upper and lower right).

Figure 2

(A) Anatomic classification of hippocampal lesions after Szabo et al. Four distinct patterns of hippocampal diffusion lesions can be identified depending on the extent of the lesion, including the complete hippocampus (a), the lateral (b) and partial sections of the hippocampus (c; posterior or anterior, the latter corresponding to the anterior choroidal artery), and small, focal dot-like lesions in the lateral hippocampus (d) that correspond to the CA1 area. The lesion pattern of types b and d corresponds to a selective affection of the CA1 region. The distribution of each lesion is presented as a schematic drawing (top row) and as a DWI hyperintense acute lesions (bottom row) on axial orientation. Bottom row indicates the neurologic diseases in which these different spatial lesion patterns can be observed. Only diffusion changes in CA1 were studied. (B) Bar graph illustrating the distribution of the different lesion pattern affecting the hippocampus.

Figure 3

The time course of ischemia-induced diffusion changes indicated by changes in the ratio of apparent diffusion coefficient (rADC) shows a typical minimal reduction around days 2 to 3 with a slow recovery to day 10. Insets show representative DWI images showing a selective affection of the CA1 region including swelling of this region (Pat 1 to 3). Insets show corresponding ADC maps. Pat 4 shows a small dot-like lesion in CA1 after a multiembolic stroke. Notably, Pat 2 shows the affection of the complete bilateral hippocampi with a reduced rADC but with a preferential affection of the CA1 region. Data expressed as mean±s.d. as well shown as individual values (black dots). Post hoc comparisons (t-test) of ADC between time periods show that during the acute phase at day 3, ADC was at its minimum and significantly reduced compared with day 1 as well as to the normalization phase after day 7. *P<0.05, **P<0.01. Pat, patient.

Figure 4

Postictal diffusion changes in the CA1 hippocampal area in patients with a status epilepticus showing a preferential to selective affection of CA1 neurons. Temporal course of the ratio of apparent diffusion coefficient (rADC) changes shows a minimal reduction around days 2 to 3 followed by a normalization to day 10. Post hoc comparisons (t-test) of ADC between time periods show that during all three time points in the acute phase (days 1 to 3) ADC was significantly reduced compared with the normalization phase around day 10. *P<0.05, **P<0.01.

Figure 5

Distribution of DWI lesions in patients with acute limbic encephalitis showing a preferential affection of the lateral hippocampus corresponding to the CA1 region. The time course of the ratio of apparent diffusion coefficient (rADC) in CA1 of the affected hippocampal cornu ammonis shows a reduction from days 1 to 3 and an increase to values >1 after a few weeks. Pairwise comparison shows a significantly different rADC in each of the initial four time points (1 to 14 days) with an increase in the later stages of the disease. Pat 5 shows highly selective involvement of both hippocampi in autoimmune limbic encephalitis (coronal FLAIR) with bilateral swelling and edema. Follow-up imaging 6 months after the encephalitis showed a prominent degeneration and atrophy of both hippocampi, which corresponded to profound memory deficits in this patient as a functional sequel of the hippocampal damage. Post hoc comparisons (t-test) of ADC between time periods show that during all time points in the acute and subacute phase (days 1 to 14) ADC was significantly reduced compared with the time points in the normalization phase starting around day 28. *P<0.05. Pat, patient.

Figure 6

Diffusion lesions detectable in patients with a transient global amnesia (TGA). (A) An anatomic template showing the various subfields of the hippocampal cornu ammonis according to Lorente de No. (B) The distribution of the DWI/T2 lesions within the cornu ammonis show that the lesions are confined to the CA1 subfield. (C) A model of the hippocampus in axial orientation showing the anterior–posterior distribution of the magnetic resonance imaging (MRI) lesions in TGA. (D) A representative 3 T MRI in a patient with TGA, showing the typical lesion in the diffusion-weighted imaging and apparent diffusion coefficient (ADC) map and the corresponding lesions in the T2-weighted images. Post hoc comparisons (t-test) of ADC between time periods indicate a significant increase in ADC from day 2 to days 4 to 5. *P<0.05.