The hippocampus, amygdala complex, and entorhinal region represent anatomically linked limbic structures of the mesiotemporal lobe. Chronic seizures and mnestic deficits in patients with pharmacoresistant mesial temporal lobe epilepsy (TLE) appear to correlate with distinct patterns of histopathological alterations in these areas. The complex anatomical organization of the amygdala and entorhinal region, however, render a detailed neuropathological evaluation of surgical specimens difficult. In this study, we present a combined cytoarchitectonical, pigmentarchitectonical, myelinarchitectonical, and immunohistochemical reconstruction of the amygdala, entorhinal region, and hippocampus from surgical TLE specimens (n = 20) in order to analyze their regional and cellular patterns of pathology. Anterior mesiotemporal lobes dissected in different spatial planes were obtained from 4 autopsy control patients and used for the characterization of neuroanatomical landmarks. Lateral, basal, and granular subnuclei of the amygdala were consistently identified in the surgical specimens. Major histopathological alterations included neuronal cell loss as revealed by extracellular lipofuscin accumulation, glial satellitosis, as well as cellular and fibrillary gliosis. The regional distribution of neuropathological changes varied considerably between different subnuclei but the lateral nucleus was more often involved than basal and granular nuclei. These amygdala nuclei appeared to be more severely affected compared to the adjacent entorhinal region. In addition, patients presenting with secondary generalized tonic-clonic seizures showed significantly more damage in mesiotemporal structures. Pathological alterations in the amygdala and entorhinal region were found to be associated with Ammon's horn sclerosis in most but not all cases. Our findings reveal the amygdala as a major target for epilepsy-associated neuronal cell damage. Significant variations in the lesional pattern among patients with chronic TLE would also be compatible with different spreading pathways of epileptogenic activity within the mesial temporal lobe.

Objectives Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1). Methods Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression. Results In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68). Conclusions CHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development. The amygdala is a brain region involved in the regulation of emotions, and amygdalar maldevelopment due to infection-induced MIA may lead to amygdala-related disorders. MIA priming of glial cells during development has been linked to abnormalities seen in later life; however, little is known about its effects on amygdalar biochemical and cytoarchitecture integrity. Time-mated C57BL6J mice were administered a single intraperitoneal injection of 50 μg/kg lipopolysaccharide (LPS) on embryonic day 12 (E12), and the effects of MIA were examined at prenatal, neonatal, and postnatal developmental stages using immunohistochemistry, real-time quantitative PCR, and stereological quantification of cytoarchitecture changes. Fetal brain expression of pro-inflammatory cytokines (IL-1β, TNFα, and IL-6) was significantly upregulated at 4 h postinjection (E12) and remained elevated until the day of birth (P0). In offspring from LPS-treated dams, amygdalar expression of pro-inflammatory cytokines was also increased on day 7 (P7) and expression was sustained on day 40 (P40). Toll-like receptor (TLR-2, TLR-4) expression was also upregulated in fetal brains and in the postnatal amygdala in LPS-injected animals. Morphological examination of cells expressing ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) suggested long-term microglial activation and astrogliosis in postnatal amygdalar regions. Our results showed that LPS-induced MIA at E12 induces a pro-inflammatory cytokine profile in the developing fetal brain that continues up to early adulthood in the amygdala. Inflammation elicited by MIA may activate cells in the fetal brain and lead to alterations in glial (microglia and astrocyte) cells observed in the postnatal amygdala. Moreover, increased pro-inflammatory cytokines and their effects on glial subpopulations may in turn have deleterious consequences for neuronal viability. These MIA-induced changes may predispose offspring to amygdala-related disorders such as heightened anxiety and depression and also neurodevelopmental disorders, such as autism spectrum disorders.

Data on the internal organization, and neuronal connections of the human hippocampal formation and related structures of the limbic system are briefly reviewed. In the healthy brain, somatosensory, visual, and auditory input proceeds through neocortical core and belt fields to a variety of association areas, and from here the data is transported via long cortico-cortical pathways to the extended prefrontal association cortex. Tracts generated from this highest organizational level of the brain guide the data via the frontal belt (premotor cortex) to the frontal core (primary motor area). The striatal and cerebellar loops provide the major routes for this data transfer. The main components of the limbic system (the hippocampal formation, the entorhinal region, and the amygdala) maintain a strategic position between the sensory and the motor association areas. Part of the stream of data from the sensory association areas to the prefrontal cortex branches off and eventually converges on the entorhinal region and the amygdala. These connections establish the afferent leg of the limbic loop. In addition, the limbic centers receive substantial input from nuclei processing viscerosensory information. The entorhinal region, the hippocampal formation, and the amygdala are densely interconnected. Important among these connections is the perforant path, which originates in the entorhinal cortex and projects to the hippocampal formation (fascia dentata, Ammon's horn, and subiculum). The subiculum projects to the amygdala, entorhinal region, mamillary nuclei, and anterior and midline thalamic nuclei. The hippocampal formation, the entorhinal region, and the amygdala generate the efferent leg of the limbic loop, which is directed toward the prefrontal cortex. Additional projections reach the key nuclei that control endocrine and autonomic functions. Furthermore, the amygdala exerts influence on all nonthalamic nuclei projecting in a nonspecific manner to the cerebral cortex (ie, the cholinergic magnocellular forebrain nuclei, the histaminergic tuberomamillary nucleus, the dopaminergic nuclei of the ventral tegmentum, the serotonergic anterior raphe nuclei, and the noradrenergic locus ceruleus). The limbic loop centers thus are in the unique strategic position to perform integration of exteroceptive sensory data of various sources with interoceptive stimuli from autonomic centers. Their efferent projections exert influence on both the prefrontal association cortex and the key centers controlling endocrine and autonomic functions. (J Child Neurol 1996;11:265-275).