Effects of corticosterone treatment and rehabilitation on the hippocampal formation of neonatal and adult rats. An unbiased stereological study

Elevations in the plasma levels of glucocorticoids are associated with cognitive impairments that have been ascribed to loss of neurons in the hippocampal formation. However, recent studies have strongly challenged this view. In order to clarify this issue, we have employed for the first time the optical fractionator and the Cavalieri principle, two unbiased stereological tools, to estimate respectively the total number of neurons and the volumes of the main subdivisions of the hippocampal formation of rats submitted to corticosterone treatment for different periods, either neonatally or in adulthood. A significant reduction in the number of neurons and in the volumes of the layers of the dentate gyrus and CA3 hippocampal field was found in rats exposed to glucocorticoids in the neonatal period; furthermore, animals treated with corticosterone from birth until 180 days of age had also a reduction in the volume of the stratum radiatum of the CA1 hippocampal field. Conversely, when the exposure occurred only during adulthood, no significant neuronal loss was observed, but there were significant reductions in the volume of layers in the dentate gyrus and CA3 hippocampal field. To search for signs of structural recovery, we incorporated a group of rats submitted to corticosterone treatment during the neonatal period in which the hormonal conditions were restored thenceforth. In this group we found a significant increase in the volume of the molecular layer of the dentate gyrus when compared with rats that were kept under corticosteroid treatment. In conclusion, these data provide a sound structural basis for the cognitive deficits observed during, and following, exposure to increased levels of glucocorticoids.     

Cell loss in the hippocampus of schizophrenics

Summary To investigate whether volume reduction of the hippocampal formation of schizophrenics, as described previously, is paralleled by loss of neurons and fibre systems, tissue volumes and cell numbers of all parts of the hippocampal formation in post mortem brains of 13 schizophrencis and 11 agematched controls belonging to the Vogt collection were determined.Volumes of the whole hippocampal formation (P < 0.01), the whole pyramidal band (P < 0.001) and the hippocampal segments CA1/CA2 (P < 0.01), CA3 (P < 0.05), CA4 (P < 0.01) were decreased, whereas no significant volume reduction of the alveus and fimbria hippocampi and presubiculum/subiculum could be found. The perforant path showed a trend towards volume reduction (P < 0.1).The absolute number of pyramidal cells (tissue volume × cell density) was diminished in CA1/CA2 (P < 0.05), CA3 (P < 0.05) and CA4 (P < 0.05), but was not significantly changed in the prosubiculum/subiculum, the presubiculum/parasubiculum and the granular cell layer of the dentate fascia.Pyramidal cell loss in CA1/CA2, CA3, CA4 was more distinct in the paranoid patients than in catatonics. The findings are discussed with respect to current hypotheses of limbic dysfunction in schizophrenia.Rheinische Landesklinik, Psychiatrische Klinik der Universität Düsseldorf, Bergische Landstrasse 2, D-4000 Düsseldorf 12 Federal Republic of Germany     

Mitochondrial dysfunction and altered ribostasis in hippocampal neurons with cytoplasmic inclusions of multiple system atrophy

Multiple system atrophy (MSA) is a sporadic adult‐onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA.     

Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps

BACKGROUND: While most patients with mild cognitive impairment (MCI) transition to Alzheimer disease (AD), others develop non-AD dementia, remain in the MCI state, or improve. OBJECTIVE: To test the following hypotheses: smaller hippocampal volumes predict conversion of MCI to AD, whereas larger hippocampal volumes predict cognitive stability and/or improvement; and patients with MCI who convert to AD have greater atrophy in the CA1 hippocampal subfield and subiculum. DESIGN: Prospective longitudinal cohort study. SETTING: University of California-Los Angeles Alzheimer's Disease Research Center. PATIENTS: We followed up 20 MCI subjects clinically and neuropsychologically for 3 years. MAIN OUTCOME MEASURE: Baseline regional hippocampal atrophy was analyzed with region-of-interest and 3-dimensional hippocampal mapping techniques. RESULTS: During the 3-year study, 6 patients developed AD (MCI-c), 7 remained stable (MCI-nc), and 7 improved (MCI-i). Patients with MCI-c had 9% smaller left and 13% smaller right mean hippocampal volumes compared with MCI-nc patients. Radial atrophy maps showed greater atrophy of the CA1 subregion in MCI-c. Patients with MCI-c had significantly smaller hippocampi than MCI-i patients (left, 24%; right, 27%). Volumetric analyses showed a trend for greater hippocampal atrophy in MCI-nc relative to MCI-i patients (eg, 16% volume loss). After permutation tests corrected for multiple comparison, the atrophy maps showed a significant difference on the right. Subicular differences were seen between MCI-c and MCI-i patients, and MCI-nc and MCI-i patients. Multiple linear regression analysis confirmed the group effect to be highly significant and independent of age, hemisphere, and Mini-Mental State Examination scores at baseline. CONCLUSIONS: Smaller hippocampi and specifically CA1 and subicular involvement are associated with increased risk for conversion from MCI to AD. Patients with MCI-i tend to have larger hippocampal volumes and relative preservation of both the subiculum and CA1.     

Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat

Abuse of stimulant drugs such as methamphetamine (METH) and cocaine has been associated with long-lasting persistent behavioral alterations. Although METH-induced changes in the striatal dopaminergic system might play a role in these effects, the potential underlying neuroanatomical substrate for the chronic cognitive dysfunction in METH users is unclear. To investigate the involvement of non-dopaminergic systems in the neurotoxic effects of METH, we treated rats with an escalating dose-multiple binge regimen, which we have suggested may more closely simulate human METH exposure profiles. Combined neuropathological and stereological analyses showed that 30 days after the last binge, there was shrinkage and degeneration in the pyramidal cell layers of the frontal cortex and in the hippocampal CA3 region. Further immunocytochemical analysis showed that METH exposure resulted in loss of calbindin interneurons in the neocortex and selective damage to pyramidal neurons in the CA3 region of the hippocampus and granular cells in the dentate gyrus that was accompanied by microglial activation. Taken together, these studies suggest that selective degeneration of pyramidal neurons and interneurons in the neocortex and limbic system might be involved in the cognitive alterations in METH users.     

Regional vulnerability of hippocampal subfields and memory deficits in Parkinson's disease

Neuropathological studies show the hippocampus is affected in Parkinson's disease (PD), with the second subfield of the cornu armonis (CA2) being the most involved. Our aims were to assess in vivo volumes of different hippocampal subfields in patients with PD with and without visual hallucinations using MRI and test their association with verbal learning and long‐term recall. A total of 18 nondemented PD patients, 18 nondemented PD patients with visual hallucinations and 18 neurologically unimpaired elderly controls matched by age and gender were enrolled in this study. We assessed the volumes of seven hippocampal subfields on MRI, including the cornu armonis (CA) sectors, subiculum, presubiculum, and the dentate gyrus (DG) using a novel technique that enables automated volumetry. The CA2‐3 and CA4‐DG subfields were significantly smaller in both groups of patients, while the subiculum was only reduced in PD patients with visual hallucinations, compared to controls. Significant correlations were found between learning performance and CA2‐3 as well as CA4‐DG volumes in the whole patient sample. These data show there is regional atrophy of specific hippocampal subfields in PD, which is more severe and further extends to the subiculum in patients with visual hallucinations. Our findings indicate that learning deficits are associated with volume loss in subfields that act as input regions in the hippocampal circuit, suggesting that degeneration in these regions could be responsible for cognitive dysfunction in PD. © 2013 Wiley Periodicals, Inc.     

Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease

In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 μm-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = −0.56, 2P < 0.05), and a 32% mean reduction in the AD group compared with controls (P < 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = −0.84 2P < 0.0001) and subiculum (r = −0.49, 2P < 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P < 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes. J. Comp. Neurol. 379:482–494, 1997. © 1997 Wiley-Liss, Inc.     

Dendritic changes in the hippocampal formation of AIDS patients: a quantitative Golgi study

We have previously shown that in the hippocampal formation of patients with acquired immunodeficiency syndrome (AIDS) there is neuronal atrophy, without cell loss. Because reductions in neuronal size are suggestive of associated neuritic alterations, we decided to study the dendritic trees of the main neuronal populations in the hippocampal formation. Material was obtained in five male AIDS patients and five male controls. After Golgi impregnation, the dendritic arborizations of dentate granule and hilar basket cells, and of CA3 and CA1 pyramidal cells, were hand traced, and their segments classified, counted and measured. We found an impoverishment of the dendritic trees in all neuronal populations in the AIDS group, which was more striking in the hilus and CA3 field. Specifically, hilar neurons had fewer dendritic segments, and reduced branching density and dendritic extent; in CA3 pyramids there was a decrease in the number of terminal segments in the basal trees, and a reduction in the total number of segments, number of medium order terminals, dendritic branching density and dendritic extent in the apical trees. In CA1 pyramids, the terminals were shorter in the apical trees and the dendritic spine density decreased in the basal trees, whereas in granule cells only the dendritic spine density was reduced in AIDS patients. Subtle signs suggestive of dendritic reorganization were observed. These results point to a regional vulnerability of the hippocampal formation to HIV infection, and might contribute to explaining the occurrence of dementia, as a consequence of overall reduction in the hippocampal neuronal receptive surface.     

Cranial irradiation impairs intrinsic excitability and synaptic plasticity of hippocampal CA1 pyramidal neurons with implications for cognitive function

Radiation therapy is a standard treatment for head and neck tumors. However, patients often exhibit cognitive impairments following radiation therapy. Previous studies have revealed that hippocampal dysfunction, specifically abnormal hippocampal neurogenesis or neuroinflammation, plays a key role in radiation-induced cognitive impairment. However, the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized. We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min. Furthermore, we observed a remarkable reduction in spike firing and excitatory synaptic input, as well as greatly enhanced inhibitory inputs, in hippocampal CA1 pyramidal neurons. Corresponding to the electrophysiological adaptation, we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT. Furthermore, in irradiated mice, long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited. These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.     

Correlation of cognitive functions with voxel-based morphometry in patients with hippocampal sclerosis

Material-specific memory dysfunction is a feature of mesial temporal lobe epilepsy (mTLE) and has lateralizing potential. We used voxel-based morphometry (VBM) and partial regression analysis of whole-brain tissue class volumes to test if there are correlations between material-specific cognitive dysfunction and localized gray matter loss. In a cohort of 89 patients with mTLE and hippocampal sclerosis (HS), we found correlations between global gray matter and cerebrospinal fluid volume and cognitive test scores in the group with left HS. These findings, however, were poorly anatomically localized; no global changes were detected in the group with right HS. Thus, correlations between gray matter loss and cognitive dysfunction were present and suggested the involvement of widespread neural networks.     

Reduced hippocampal N-acetylaspartate without volume loss in schizophrenia.

Quantitative magnetic resonance imaging (MRI) can measure total gray matter volume but cannot discriminate between neurons and glia. Proton magnetic resonance spectroscopic imaging (1H MRSI) measures N-acetylaspartate (NAA) which is a selective marker of neuronal loss or neuronal dysfunction. The objective of this study was to obtain quantitative measures of hippocampal volume and hippocampal NAA to determine if there was evidence for hippocampal neuronal dysfunction or neuronal loss in schizophrenia. Quantitative MRI and 1H MRSI was performed on the right and left hippocampal regions in 23 chronic schizophrenic patients and 18 control subjects. Relative to the control group, the patients with schizophrenia demonstrated no change in hippocampal volumes bilaterally, but significantly decreased NAA in the hippocampal regions bilaterally. There was also no correlation between hippocampal volumes and NAA in either the schizophrenics or controls. These findings suggest that: (1) hippocampal NAA may be a more sensitive measure of neuronal loss than volumetric measurements; and (2) reduced hippocampal NAA may be measuring neuronal dysfunction or damage rather than neuronal loss in this sample of schizophrenics.     

颞叶癫(癎)后认知功能障碍与海马萎缩的相关性

目的 比较颞叶癫(癎)患者与健康者认知障碍、海马萎缩的差异,探讨颞叶癫(癎)患者认知障碍与海马萎缩的相关性.方法 随机选取颞叶癫(癎)患者49例和健康对照者20名,神经心理量表评价其认知状态并测量双侧海马体积.结果 与健康者相比,颞叶癫(癎)患者的记忆商(83.2±21.0)和智商(91.0±12.3)显著下降(t=-3.365,-4.291,P=0.001,0.000),双侧海马显著萎缩(P=0.000),不对称指数显著增高(t=3.975,P=0.000),差异有统计学意义.颞叶癫(癎)患者记忆力与癫(癎)病程显著负相关(r=-0.339,P=0-017),左右两侧海马萎缩程度与认知指数均显著负相关(左侧:r=-0.297,P=0.038;右侧:r=-0.305,P=0.033),不对称指数与认知指数显著负相关(r=-0.441,P=0.002).结论 颞叶癫(癎)患者双侧海马的萎缩程度越高、对称性越差,认知损伤也就越显著.海马体积测量可以作为颞叶癫(癎)患者智力下降的评价因子.     

Hippocampal shape and cognitive performance in amnestic mild cognitive impairment

Previous studies have carried out hippocampal shape analysis of amnestic mild cognitive impairment (aMCI) patients using automated segmentation techniques. However, the relationships between hippocampal deformations and various episodic memory impairments were not clear. The aim of this study was to investigate hippocampal shape changes and their relationships with various episodic memory impairments in aMCI. Hippocampal volumes and deformations were compared between the aMCI and the controls. In addition, we explored the correlation pattern between hippocampal deformations and cognitive dysfunctions in aMCI using a comprehensive neuropsychological battery. Patients with aMCI exhibited significant hippocampal deformations in the right cornu ammonis 1 (CA1) and subiculum areas compared with healthy individuals. Significant correlations were observed between constructional recall scores and the right CA1 and subiculum areas in aMCI. Verbal delayed recall scores were also significantly correlated with the left CA1 and subiculum areas in aMCI. This study was the first to explore the relationships between hippocampal deformations and various types of cognitive performances in aMCI. These structural changes in the hippocampal CA1 and subiculum areas might be at the core of underlying neurobiological mechanisms of hippocampal dysfunction and their relevance to verbal and visuospatial delayed recall in aMCI.     

Effect of prenatal protein malnutrition on numbers of neurons in the principal cell layers of the adult rat hippocampal formation

Malnutrition has been associated with a variety of functional and anatomical impairments of the hippocampal formation. One of the more striking of these is widespread loss of hippocampal neurons in postnatally malnourished rats. In the present study we have investigated the effect of prenatal malnutrition on these same neuronal populations, neurons that are all generated during the period of the dietary restriction. In prenatally protein deprived rats, using design-based stereology, we have measured the regional volume and number of neurons in the hilus of the dentate gyrus and the pyramidal cell layers of CA3, CA2, CA1, and the subiculum of 90-day-old animals. These results demonstrated a statistically significant reduction of 20% in neuron numbers in the CA1 subfield, while numbers in the other subfields were unchanged. There was a corresponding significant reduction of 22% in the volume of the CA1 subfield and a significant 14% decrease in the volume of the pyramidal layer of the subiculum. The change in volume of the pyramidal layer of the subiculum without neuron loss may reflect loss of CA1 afferent input to the pyramidal layer. Although the effect of nutritional deprivation on the neuronal population appears to be different in pre- and postnatal malnutrition, both dietary paradigms highlight the vulnerability of key components of the hippocampal trisynaptic circuit (consisting of the dentate granule cell mossy fibers projection to CA3 pyramids and the CA3 projection to the CA1 pyramids), which is an essential circuit for memory and learning.     

Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease

BACKGROUND: Prior studies have shown that cyclooxygenase 2 (COX-2), an enzyme involved in inflammatory mechanisms and neuronal activities, is up-regulated in the brain with Alzheimer disease (AD) and may represent a therapeutic target for anti-inflammatory treatments. OBJECTIVE: To explore COX-2 expression in the brain as a function of clinical progression of early AD. DESIGN AND MAIN OUTCOME MEASURES: Using semiquantitative immunocytochemistry, we analyzed COX-2 protein content in the hippocampal formation in 54 postmortem brain specimens from patients with normal or impaired cognitive status. SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: The immunointensity of COX-2 signal in the CA3 and CA2 but not CA1 subdivisions of the pyramidal layers of the hippocampal formation of the AD brain increased as the disease progressed from questionable to mild clinical dementia as assessed by Clinical Dementia Rating. COX-2 signal was increased in all 3 regions examined among cases characterized by severe dementia. CONCLUSION: Neuronal COX-2 content in subsets of hippocampal pyramidal neurons may be an indicator of progression of dementia in early AD.     

Stereologic investigation of the posterior part of the hippocampus in schizophrenia

Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections. Compared to the controls, the patients with schizophrenia showed a significant decrease in the mean number of oligodendrocytes in the left and right CA4. This is the first finding of reduced numbers of oligodendrocytes in CA4 of the posterior part of the hippocampus in schizophrenia. Our results are in line with earlier findings in the literature concerning decreased numbers of oligodendrocytes in the prefrontal cortex in schizophrenia. Our results may indicate disturbed connectivity of the CA4 of the posterior part of the hippocampus in schizophrenia and, thus, contribute to the growing number of studies showing the involvement of posterior hippocampal pathology in the pathophysiology of schizophrenia. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

No loss of hippocampal neurons in AIDS patients

Acquired immunodeficiency syndrome (AIDS) is often accompanied by neurological disorders and neuropathological abnormalities. A loss of up to 30% of the neocortical neurons in brains from AIDS patients has been demonstrated in several studies. This neuron loss appeared to have no relationship with either the presence of clinical dementia or HIV encephalitis. The hippocampal region of the brain is an essential component of learning and memory processes and it is severely affected in a number of diseases, including temporal lobe epilepsy and Alzheimer’s dementia. In view of the reports of a considerable loss of neocortical neurons, the aim of the present study was to investigate the degree to which neurons may be lost in hippocampus of AIDS patients. A stereological method, the optical fractionator, was used to estimate the total number of neurons in the five subregions of the hippocampus of nine AIDS patients and ten controls. There were no statistically significant differences in the group means of the number of neurons in any of the subdivisions. This result is discussed in the light of the large loss of neurons in the neocortex reported to take place in AIDS patients. Received: 21 June 1999 / Revised, accepted: 17 August 1999     

Distribution,morphological features,and synaptic connections of parvalbumin- and calbindin D28k-immunoreactive neurons in the human hippocampal formation

Calcium binding proteins calbindin D_28k (CaBP) and parvalbumin (PV) are known to form distinct subpopulations of gamma-aminobutyric acid (GABA)ergic neurons in the rodent hippocampal formation. Light and electron microscopic morphology and connections of these protein-containing neurons are only partly known in the primate hippocampus. In this study, CaBP and PV were localized in neurons of the human hippocampal formation including the subicular complex (prosubiculum, subiculum, and presubiculum) in order to explore to what extent these subpopulations of hippocampal neurons differ in phylogenetically distant species. CaBP immunoreactivity was present in virtually all granule cells of the dentate gyrus and in a proportion of pyramidal neurons in the CA1 and CA2 regions. A distinct population of CaBP-positive local circuit neurons was found in all layers of the dentate gyrus and Ammon's horn. Most frequently they were located in the molecular layer of the dentate gyrus and the pyramidal layer of Ammon's horn. In the subicular complex pyramidal neurons were not immunoreactive for CaBP. In the prosubiculum and subiculum immunoreactive nonpyramidal neurons were equally distributed in all layers, whereas in the presubiculum they occurred mainly in the superficial layers. Electron microscopy showed typical somatic and dendritic features of the granule, pyramidal, and local circuit neurons. CaBP-positive mossy fiber terminals in the hilus of the dentate gyrus and terminals of presumed pyramidal neurons of Ammon's horn formed asymmetric synapses with dendrites and spines. CaBP-positive terminals of nonprincipal neurons formed symmetric synapses with dendrites and dendritic spines, but never with somata or axon initial segments. PV was exclusively present in local circuit neurons in both the hippocampal formation and subicular complex. Most of the PV-positive cell bodies were located among or close to the principal cell layers. However, large numbers of immunoreactive neurons were also found in the molecular layer of the dentate gyrus and in strata oriens of Ammon's horn. PV-positive cells were equally distributed in all layers of the subicular complex. Electron microscopy showed the characteristic somatic and dendritic features of local circuit neurons. PV-positive axon terminals formed exclusively symmetric synapses with somata, axon initial segments and dendritic shafts, and in a few cases with dendritic spines. The CaBP- and PV-containing neurons formed similar subpopulations in rodents, monkeys, and humans, although the human hippocampus displayed the largest variability of these immunoreactive neurons in their morphology and location. Calcium binding protein-containing neurons frequently occurred in the molecular layer of the human dentate gyrus and in the stratum lacunosum-moleculare of Ammon's horn. The corresponding areas of the rat or monkey hippocampus were devoid of such neurons. In both rodents and primates similar populations of principal neurons contained CaBP. In addition, CaBP and PV were localized in distinct and nonoverlapping populations of nonprincipal cells. Their target selectivity did not change during phylogeny (e.g., PV-positive cells mainly innervate the perisomatic region and CaBP-positive cells the distal dendritic region of principal cells). © 1993 Wiley-Liss,Inc.     

In vivo analysis of hippocampal subfield atrophy in mild cognitive impairment via semi-automatic segmentation of T2-weighted MRI

The measurement of hippocampal volumes using MRI is a useful in-vivo biomarker for detection and monitoring of early Alzheimer's disease (AD), including during the amnestic mild cognitive impairment (a-MCI) stage. The pathology underlying AD has regionally selective effects within the hippocampus. As such, we predict that hippocampal subfields are more sensitive in discriminating prodromal AD (i.e., a-MCI) from cognitively normal controls than whole hippocampal volumes, and attempt to demonstrate this using a semi-automatic method that can accurately segment hippocampal subfields. High-resolution coronal-oblique T2-weighted images of the hippocampal formation were acquired in 45 subjects (28 controls and 17 a-MCI (mean age: 69.5 ± 9.2; 70.2 ± 7.6)). CA1, CA2, CA3, and CA4/DG subfields, along with head and tail regions, were segmented using an automatic algorithm. CA1 and CA4/DG segmentations were manually edited. Whole hippocampal volumes were obtained from the subjects' T1-weighted anatomical images. Automatic segmentation produced significant group differences in the following subfields: CA1 (left: p = 0.001, right: p = 0.038), CA4/DG (left: p = 0.002, right: p = 0.043), head (left: p = 0.018, right: p = 0.002), and tail (left: p = 0.019). After manual correction, differences were increased in CA1 (left: p < 0.001, right: p = 0.002), and reduced in CA4/DG (left: p = 0.029, right: p = 0.221). Whole hippocampal volumes significantly differed bilaterally (left: p = 0.028, right: p = 0.009). This pattern of atrophy in a-MCI is consistent with the topography of AD pathology observed in postmortem studies, and corrected left CA1 provided stronger discrimination than whole hippocampal volume (p = 0.03). These results suggest that semi-automatic segmentation of hippocampal subfields is efficient and may provide additional sensitivity beyond whole hippocampal volumes.     

Morphological alterations in amygdalo-hippocampal substructures in narcolepsy patients with cataplexy

Although the role of hypocretin-mediated amygdalo-hippocampal dysfunction is hypothesized to be linked with narcolepsy, there have been no human MRI studies investigating the relationship between their regional volume and key symptoms of narcolepsy. To investigate the morphological changes of amygdalo-hippocampus and its relationship with clinical features in patients with narcolepsy, point-wise morphometry that allowed for measuring the regional volumes of amygdalo-hippocampus on T1-weighted MRI was applied. Participants were 33 drug-naïve patients and 35 age-/gender-matched controls (mean ± SD: 27?±?6 years). We compared hippocampal and amygdalar subfields volumes between patients and controls and correlated between volume and clinical and neuropsychological features in patients. Bilateral hippocampal atrophy (183 vertices) was identified mainly located within the CA1 subfield (FDR?<?0.05). Significant amygdalar volume reduction was found in the areas of the centromedial (102 vertices) and laterobasal nuclear groups (LB, 35 vertices). There was no volume increase in patients relative to controls (FDR >0.2). After controlling depressive mood, sleep quality, age, and gender, hippocampal CA1 atrophy and amygdalar centromedial atrophy were associated with longer duration of daytime sleepiness and shorter mean REM sleep latency (|r| >0.44, p?<?0.01). The amygdalar centromedial atrophy was associated with longer duration of cataplexy (|r| >0.47, p?<?0.005). Subfields atrophy of amygdalo-hippocampus in untreated patients with narcolepsy that was found relative to controls suggests that CA1 of the hippocampus and centromedial area of amygdala are closely related to the severity of narcolepsy and play a crucial role in the circuitry of cataplexy.