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Variability of sclerosis along the longitudinal hippocampal axis in epilepsy: a post mortem study.

ABSTRACT: Detailed neuropathological studies of the extent of hippocampal sclerosis (HS) in epilepsy along the longitudinal axis of the hippocampus are lacking. Neuroimaging studies of patients with temporal lobe epilepsy support that sclerosis is not always localised. The extent of HS is of relevance to surgical planning and poor outcomes may relate to residual HS in the posterior remnant. In 10 post mortems from patients with long histories of drug refractory epilepsy and 3 controls we systematically sampled the left and right hippocampus at seven coronal anatomical levels along the body to the tail. We quantified neuronal densities in CA1 and CA4 subfields at each level using Cresyl Violet (CV), calretinin (CR), calbindin (CB) and Neuropeptide Y (NPY) immunohistochemistry. In the dentate gyrus we graded the extent of granule cell dispersion, patterns of CB expression, and synaptic reorganisation with CR and NPY at each level. We identified four patterns of HS based on patterns of pyramidal and interneuronal loss and dentate gyrus reorganisation between sides and levels as follows: (1) symmetrical HS with anterior-posterior (AP) gradient, (2) symmetrical HS without AP gradient, (3) asymmetrical HS with AP gradient and (4) asymmetrical cases without AP gradient. We confirmed in this series that HS can extend into the tail. The patterns of sclerosis (classical versus atypical or none) were consistent between all levels in less than a third of cases. In conclusion, this series highlights the variability of HS along the longitudinal axis. Further studies are required to identify factors that lead to focal versus diffuse HS.

SUBMITTER: Thom M

PROVIDER: S-EPMC3500681 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Variability of sclerosis along the longitudinal hippocampal axis in epilepsy: a post mortem study.

Thom Maria M Liagkouras Ioannis I Martinian Lillian L Liu Joan J Catarino Claudia B CB Sisodiya Sanjay M SM

Epilepsy research 20120516 1-2

Detailed neuropathological studies of the extent of hippocampal sclerosis (HS) in epilepsy along the longitudinal axis of the hippocampus are lacking. Neuroimaging studies of patients with temporal lobe epilepsy support that sclerosis is not always localised. The extent of HS is of relevance to surgical planning and poor outcomes may relate to residual HS in the posterior remnant. In 10 post mortems from patients with long histories of drug refractory epilepsy and 3 controls we systematically sa ...[more]

PMID: 22608064

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Project description:The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P < 0.001). Analysis of Braak stages within age groups showed a significant increase in mid-Braak stages (III/IV), in middle age (40-65 years) compared with data from an ageing non-epilepsy series (P < 0.01). There was no clear relationship between seizure type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P < 0.01). In 30% of patients, there was pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P < 0.001). Cerebrovascular disease present in 40.3% and cortical malformations in 11.3% were not significantly associated with Braak stage. Astrocytic-tau protein correlated with the presence of both traumatic brain injury (P < 0.01) and high Braak stage (P < 0.001). Hippocampal sclerosis, identified in 40% (bilateral in 48%), was not associated with higher Braak stages, but asymmetrical patterns of tau protein accumulation within the sclerotic hippocampus were noted. In over half of patients with cognitive decline, the Braak stage was low indicating causes other than Alzheimer's disease pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy.

Project description:BackgroundPost-mortem studies have not identified an association between β-amyloid or tau and rates of hippocampal atrophy in patients with Alzheimer's disease. TAR DNA binding protein 43 (TDP-43) is another protein linked to Alzheimer's disease. We aimed to investigate whether hippocampal TDP-43 is associated with increased rates of hippocampal atrophy.MethodsIn this longitudinal retrospective study, we analysed post-mortem brain tissue of all individuals with an Alzheimer's disease spectrum pathological diagnosis who had antemortem head MRI scans between Jan 1, 1999, and Dec 31, 2012, and who had been recruited into the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. We did TDP-43 immunohistochemistry and classified individuals as follows: no TDP-43 in the amygdala or hippocampus; TDP-43 restricted to the amygdala; and TDP-43 spreading into the hippocampus. Each individual was also assigned a neurofibrillary tangle stage (B1-B3), relating to the likelihood of having Alzheimer's disease. We used longitudinal FreeSurfer software and tensor-based morphometry with symmetric normalisation to calculate hippocampal volume on all serial MRI scans and used linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy and to assess the trajectory of TDP-43-associated atrophy.FindingsWe identified 298 individuals meeting the inclusion criteria, with 816 usable MRI scans (spanning 1·0-11·2 years of the disease) available for analysis. 141 individuals showed no TDP-43 in the amygdala or hippocampus, 33 had TDP-43 restricted to the amygdala, and 124 had TDP-43 in the hippocampus. Among individuals with a high likelihood of having Alzheimer's disease (neurofibrillary tangle stage B3; n=205), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=103, annual volume change -4·39%, 95% CI -4·82 to -3·95; p<0·0001) than did those with amygdala-only TDP-43 (n=20, -3·29%, -4·11 to -2·46; p<0·0001; difference -1·10%, 95% CI -2·02 to -0·19; p=0·02) and those without TDP-43 (n=82, -3·11%, -3·54 to -2·68; p<0·0001; difference -1·28%, -1·88 to -0·67; p<0·0001). Among individuals with an intermediate likelihood of having Alzheimer's disease (neurofibrillary tangle stage B2; n=56), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=17, annual volume change -4·05%, 95% CI -5·09 to -2·99; p<0·0001) than did those with amygdala-only TDP-43 (n=6, -1·78%, -3·04 to -0·55; p=0·004; difference -2·27%, 95% CI -3·79 to -0·67; p=0·006) and those without TDP-43 (n=33, -1·63%, -2·43 to -0·83; p=0·0002; difference -2·43%, -3·66 to -1·18; p=0·0002). Hippocampal TDP-43 was not associated with the rate of hippocampal atrophy in individuals with a low likelihood of having Alzheimer's disease (neurofibrillary tangle stage B1; n=37). The trajectory analysis suggested that increased rates of TDP-43-associated hippocampal atrophy might occur at least 10 years before death. Results were similar for FreeSurfer and tensor-based morphometry.InterpretationTDP-43 should be considered as a potential factor related to increased rates of hippocampal atrophy in patients with Alzheimer's disease. Given the importance of hippocampal atrophy in Alzheimer's disease, it is imperative that techniques are developed for detection of TDP-43 in vivo.FundingUS National Institute on Aging (National Institutes of Health).

Project description:The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia-neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1-CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

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Variability of sclerosis along the longitudinal hippocampal axis in epilepsy: a post mortem study.

Publications

Variability of sclerosis along the longitudinal hippocampal axis in epilepsy: a post mortem study.

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