Association of cortical microinfarcts and cerebral small vessel pathology in the ageing brain.

AIMS: Cortical microinfarcts (CMI) are frequently observed in the ageing brain independent of cognitive decline, but their aetiology is not fully elucidated. To examine the potential role of different vessel pathologies, including cerebral amyloid angiopathy (CAA), arteriolosclerosis-hyalinosis and thromboembolism in the development of CMI, we examined 80 autopsy cases with more than one CMI on routine neuropathological examination. METHODS: Pial and intracortical vessels around CMI were assessed for their integrity with haematoxylin-eosin staining and antibodies against amyloid-ß protein and fibrinogen using a semiquantitative four-level rating scale (absent to severe) in the hippocampus, and the frontal, temporal and occipital cortex. Four histological categories of changes were defined: CAA, vessel pathology other than CAA, thromboembolism and absence of vessel pathology near CMI. RESULTS: A differential distribution of microvascular pathology was observed depending on brain regions. In the occipital cortex, CAA was commonly associated with CMI. In contrast, in the hippocampus and the frontal cortex, cases without any vascular pathology in pial and intracortical vessels were significantly more frequent. CONCLUSIONS: The aetiology of CMI differs depending on brain location. CAA may play a role principally in the occipital cortex. The large number of intact vessels around the CMI (mainly in the frontal cortex and hippocampus) raises the possibility that pathologies other than structural microangiopathy, including hypoperfusion/arterial hypotension or large vessel atherosclerosis, play a role in the development of microvascular lesions. These results are relevant in the context of aetiopathogenesis of vascular changes associated with conditions like vascular dementia.

Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.

The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.

Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities.

AIMS: The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data, however, are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development. METHODS: We investigated the dorsal anterior cingulate cortex (dACC) in 13 men with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neurone and glial numbers, and glia/neurone index (GNI) in both layers II-III and V-VI. RESULTS: We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neurone numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development. CONCLUSIONS: Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post mortem histopathological studies and in vivo brain imaging findings in patients.

The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.

AIMS: Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid ß protein (Aß) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer's disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a 1-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva. MATERIALS AND METHODS: Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal and occipital cortex, using an antibody against Aß, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established. RESULTS: CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age, followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters. CONCLUSION: The present data show that CAA plays a role in the development of microvascular lesions in the ageing brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contribute importantly to the pathogenesis of microvascular changes.

Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex.

AIMS: Previous neuroimaging reports described morphological and functional abnormalities in anterior cingulate cortex (ACC) in schizophrenia and mood disorders. In earlier neuropathological studies, microvascular changes that could affect brain perfusion in these disorders have rarely been studied. Here, we analysed morphological parameters of capillaries in this area in elderly cases affected by these psychiatric disorders. METHODS: We analysed microvessel diameters in the dorsal and subgenual parts of the ACC in eight patients with schizophrenia, 10 patients with sporadic bipolar disorder, eight patients with sporadic major depression, and seven age- and gender-matched control cases on sections stained with modified Gallyas silver impregnation using a stereological counting approach. All individuals were drug-naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Statistical analysis included Kruskal-Wallis group comparisons with Bonferroni correction as well as multivariate regression models. RESULTS: Mean capillary diameter was significantly decreased in the dorsal and subgenual parts of areas 24 in bipolar and unipolar depression cases, both in layers III and V, whereas schizophrenia patients were comparable with controls. These differences persisted when controlling for age, local neuronal densities, and cortical thickness. In addition, cortical thickness was significantly smaller in both layers in schizophrenia patients. CONCLUSIONS: Our findings indicate that capillary diameters in bipolar and unipolar depression but not in schizophrenia are reduced in ACC. The significance of these findings is discussed in the light of the cytoarchitecture, brain metabolism and perfusion changes observed in ACC in mood disorders.

Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates.

Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer's disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia.

Stereology of the neocortex in Odontocetes: qualitative, quantitative, and functional implications.

We investigated the quantitative morphology of the neocortex (gray matter) in 2 toothed whale (odontocete) species (harbor porpoise, Phocoena phocoena; bottlenose dolphin, Tursiops truncatus) with stereological methods. The 4 primary projection areas (motor, somatosensory, auditory, and visual fields) are analyzed for their cell densities in layers III and V with standard design-based stereology methods. Along cortical areas M1, S1, A1, and V1 in Tursiops, neuron density is always higher in layer III than in layer V, whereas the data in Phocoena are variable. Moreover, neuron density in layer III is generally around 1.5 times higher in Tursiops than in Phocoena. Maximal density values are seen in layer III of A1 and V1 in Tursiops and the ratio of layer III/layer V density is maximal in A1 of this species. Thus, layer III could have a higher capacity in the bottlenose dolphin with regard to intrinsic connectivity. Extant knowledge on toothed whale neurobiology and behavior suggests that quantitative/stereological differences between the 2 odontocete species regarding the neuron density of standard cortical units may be correlated with specific adaptations to their respective habitats. In contrast to layers V and VI which mainly serve as an executive system, layer III could represent an intermediate level in sensory and premotor processing which works more tangentially in the cortices via horizontal connections with other cortical areas, respectively. The generally higher density of cortical layer III in Tursiops suggests a higher connectivity of this layer in view of the more agile and complicated behavior of these gregarious animals including versatile phonation by complex sound and ultrasound signals.

Alterations of white matter tracts following neurotoxic hippocampal lesions in macaque monkeys: a diffusion tensor imaging study.

Diffusion tensor imaging (DTI) is a valuable tool for assessing presumptive white matter alterations in human disease and animal models. The current study used DTI to examine the effects of selective neurotoxic lesions of the hippocampus on major white matter tracts and anatomically related brain regions in macaque monkeys. Two years postlesion, structural MRI, and DTI sequences were acquired for each subject. Volumetric assessment revealed a substantial reduction in the size of the hippocampus in experimental subjects, averaging 72% relative to controls, without apparent damage to adjacent regions. DTI images were processed to yield measures of fractional anisotropy (FA), apparent diffusion coefficient (ADC), parallel diffusivity (lADC), and perpendicular diffusivity (tADC), as well as directional color maps. To evaluate potential changes in major projection systems, a region of interest (ROI) analysis was conducted including the corpus callosum, fornix, temporal stem, cingulum bundle, ventromedial prefrontal white matter, and optic radiations. Lesion-related abnormalities in the integrity of the fiber tracts examined were limited to known hippocampal circuitry, including the fornix and ventromedial prefrontal white matter. These findings are consistent with the notion that hippocampal damage results in altered interactions with multiple memory-related brain regions, including portions of the prefrontal cortex.

Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.

AIMS: Previous neuropathological studies documented that small vascular and microvascular pathology is associated with cognitive decline. More recently, we showed that thalamic and basal ganglia lacunes are associated with post-stroke depression and may affect emotional regulation. The present study examines whether this is also the case for late-onset depression. METHODS: We performed a detailed analysis of small macrovascular and microvascular pathology in the post mortem brains of 38 patients with late-onset major depression (LOD) and 29 healthy elderly controls. A clinical diagnosis of LOD was established while the subjects were alive using the DSM-IV criteria. Additionally, we retrospectively reviewed all charts for the presence of clinical criteria of vascular depression. Neuropathological evaluation included bilateral semi-quantitative assessment of lacunes, deep white matter and periventricular demyelination, cortical microinfarcts and both focal and diffuse gliosis. The association between vascular burden and LOD was investigated using Fisher's exact test and univariate and multivariate logistic regression models. RESULTS: Neither the existence of lacunes nor the presence of microvascular ischaemic lesions was related to occurrence of LOD. Similarly, there was no relationship between vascular lesion scores and LOD. This was also the case within the subgroup of LOD patients fulfilling the clinical criteria for vascular depression. CONCLUSIONS: Our results challenge the vascular depression hypothesis by showing that neither deep white matter nor periventricular demyelination is associated with LOD. In conjunction with our previous observations in stroke patients, they also imply that the impact of lacunes on mood may be significant solely in the presence of acute brain compromise.

Species-specific distributions of tyrosine hydroxylase-immunoreactive neurons in the prefrontal cortex of anthropoid primates.

In this study, we assessed the distribution of cortical neurons immunoreactive for tyrosine hydroxylase (TH) in prefrontal cortical regions of humans and nonhuman primate species. Immunohistochemical methods were used to visualize TH-immunoreactive (TH-ir) neurons in areas 9 (dorsolateral prefrontal cortex) and 32 (anterior paracingulate cortex). The study sample included humans, great apes (chimpanzee, bonobo, gorilla, orangutan), one lesser ape (siamang), and Old World monkeys (golden guenon, patas monkey, olive baboon, moor macaque, black and white colobus, and François' langur). The percentage of neurons within the cortex expressing TH was quantified using computer-assisted stereology. TH-ir neurons were present in layers V and VI and the subjacent white matter in each of the Old World monkey species, the siamang, and in humans. TH-ir cells were also occasionally observed in layer III of human, siamang, baboon, colobus, and François' langur cortex. Cortical cells expressing TH were notably absent in each of the great ape species. Quantitative analyses did not reveal a phylogenetic trend for percentage of TH-ir neurons in these cortical areas among species. Interestingly, humans and monkey species exhibited a bilaminar pattern of TH-ir axon distributions within prefrontal regions, with layers I-II and layers V-VI having the densest contingent of axons. In contrast, the great apes had a different pattern of laminar innervation, with a remarkably denser distribution of TH-ir axons within layer III. It is possible that the catecholaminergic afferent input to layer III in chimpanzees and other great apes covaries with loss of TH-ir cells within the cortical mantle.

Does Alzheimer's disease begin in the brainstem?

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high-order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake-sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging - Reagan Institute (NIA-RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, beta-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes.

Life and death of neurons in the aging brain.

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Cortical dopaminergic innervation among humans, chimpanzees, and macaque monkeys: a comparative study.

In this study, we assessed the possibility that humans differ from other primate species in the supply of dopamine to the frontal cortex. To this end, quantitative comparative analyses were performed among humans, chimpanzees, and macaques using immunohistochemical methods to visualize tyrosine hydroxylase-immunoreactive axons within the cerebral cortex. Axon densities and neuron densities were quantified using computer-assisted stereology. Prefrontal areas 9 and 32 were chosen for evaluation due to their roles in higher-order executive functions and theory of mind, respectively. Primary motor cortex (area 4) was also evaluated because it is not directly associated with cognition. We did not find an overt quantitative increase in cortical dopaminergic innervation in humans relative to the other primates examined. However, several differences in cortical dopaminergic innervation were observed among species which may have functional implications. Specifically, humans exhibited a sublaminar pattern of innervation in layer I of areas 9 and 32 that differed from that of macaques and chimpanzees. Analysis of axon length density to neuron density among species revealed that humans and chimpanzees together deviated from macaques in having increased dopaminergic afferents in layers III and V/VI of areas 9 and 32, but there were no phylogenetic differences in area 4. Finally, morphological specializations of axon coils that may be indicative of cortical plasticity events were observed in humans and chimpanzees, but not macaques. Our findings suggest significant modifications of dopamine's role in cortical organization occurred in the evolution of the apes, with further changes in the descent of humans.

Cerebral [18 F]T807/AV1451 retention pattern in clinically probable CTE resembles pathognomonic distribution of CTE tauopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [18F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [18F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [18F]florbetapir was negative for amyloidosis. The [18F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter-white matter junction, a distribution considered pathognomonic for CTE. [18F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [18F]T807/AV1451 retention requires postmortem correlation, our data suggest that [18F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects.

Design-based stereology in neuroscience.

Quantitative morphology of the CNS has recently undergone major developments. In particular, several new approaches, known as design-based stereologic methods, have become available and have been successfully applied to neuromorphological research. However, much confusion and uncertainty remains about the meaning, implications, and advantages of these design-based stereologic methods. The objective of this review is to provide some clarification. It does not comprise a full description of all stereologic methods available. Rather, it is written by users for users, provides the reader with a guided tour through the relevant literature. It has been the experience of the authors that most neuroscientists potentially interested in design-based stereology need to analyze volumes of brain regions, numbers of cells (neurons, glial cells) within these brain regions, mean volumes (nuclear, perikaryal) of these cells, length densities of linear biological structures such as vessels and nerve fibers within brain regions, and the cytoarchitecture of brain regions (i.e. the spatial distribution of cells within a region of interest). Therefore, a comprehensive introduction to design-based stereologic methods for estimating these parameters is provided. It is demonstrated that results obtained with design-based stereology are representative for the entire brain region of interest, and are independent of the size, shape, spatial orientation, and spatial distribution of the cells to be investigated. Also, it is shown that bias (i.e. systematic error) in results obtained with design-based stereology can be limited to a minimum, and that it is possible to assess the variability of these results. These characteristics establish the advantages of design-based stereologic methods in quantitative neuromorphology.

New techniques for imaging, digitization and analysis of three-dimensional neural morphology on multiple scales.

Cognitive impairment in normal aging and neurodegenerative diseases is accompanied by altered morphologies on multiple scales. Understanding of the role of these structural changes in producing functional deficits in brain aging and neuropsychiatric disorders requires accurate three-dimensional representations of neuronal morphology, and realistic biophysical modeling that can directly relate structural changes to altered neuronal firing patterns. To date however, tools capable of resolving, digitizing and analyzing neuronal morphology on both local and global scales, and with sufficient throughput and automation, have been lacking. The precision of existing image analysis-based morphometric tools is restricted at the finest scales, where resolution of fine dendritic features and spine geometry is limited by the skeletonization methods used, and by quantization errors arising from insufficient imaging resolution. We are developing techniques for imaging, reconstruction and analysis of neuronal morphology that capture both local and global structural variation. To minimize quantization error and evaluate more precisely the fine geometry of dendrites and spines, we introduce a new shape analysis technique, the Rayburst sampling algorithm that uses the original grayscale data rather than the segmented images for precise, continuous radius estimation, and multidirectional radius sampling to represent non-circular branch cross-sections and anisotropic structures such as dendritic spine heads, with greater accuracy. We apply the Rayburst technique to 3D neuronal shape analysis at different scales. We reconstruct and digitize entire neurons from stacks of laser-scanning microscopy images, as well as globally complex structures such as multineuron networks and microvascular networks. We also introduce imaging techniques necessary to recover detailed information on three-dimensional mass distribution and surface roughness of amyloid beta plaques from human Alzheimer's disease patients and from the Tg2576 mouse that expresses the "Swedish" mutation of the amyloid precursor protein. By providing true three-dimensional morphometry of complex histologic structures on multiple scales, the tools described in this report will enable multiscale biophysical modeling studies capable of testing potential mechanisms by which altered dendritic structure, spine geometry and network branching patterns that occur in normal aging and in many brain disorders, determine deficits of functions such as working memory and cognition.

Hemispheric asymmetry, modular variability and age-related changes in the human entorhinal cortex.

The verrucae areae entorhinalis (VAE) are a characteristic feature of the human brain that occupy the anterior and posterolateral parts of the parahippocampal gyri and correspond to the islands of layer II neurons. We analyzed VAE in 60 neurologically normal subjects ranging from 23 to 85 years of age using a casting method. In 10 of these subjects the total number of neurons in the entorhinal islands was estimated stereologically using the optical fractionator. The number and surface area of VAE were higher in the left hemisphere compared with the right, and this leftward asymmetry was highly significant. Regression analysis showed a negative correlation between average VAE area and age in both hemispheres, representing a rate loss of about 800 microm2 per year. The estimated number of neurons obtained with the optical fractionator showed no significant difference between the left and the right hemisphere (468,000+/-144,000 vs. 405,000+/-117,000). There was a highly significant negative correlation between neuron numbers and age in both sides. In addition, clusters of small, undifferentiated layer II neurons ('heterotopias') were frequently observed in the rostral part of the entorhinal cortex in young and elderly adults. Layer II entorhinal neurons are among the first to show neurofibrillary changes during normal aging. The present data confirm the occurrence of age-related neuron loss in the entorhinal cortex. Considering the consistent projections from ipsilateral auditory association areas that, together with Broca's motor-speech area (Brodmann areas 44 and 45), show leftward asymmetry from early infancy (such as Brodmann area 22, planum temporale, and area 52 in the long insular gyrus), we speculate that functional lateralization of the human entorhinal cortex may be associated with specialization for memory processing related to language. Due to the dependence of hippocampal formation on entorhinal projections, this finding is also consistent with the greater capacity of the left hippocampus for verbal episodic memory.

A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy.

A comprehensive three-dimensional digital atlas database of the C57BL/6J mouse brain was developed based on magnetic resonance microscopy images acquired on a 17.6-T superconducting magnet. By using both manual tracing and an atlas-based semi-automatic segmentation approach, T2-weighted magnetic resonance microscopy images of 10 adult male formalin-fixed, excised C57BL/6J mouse brains were segmented into 20 anatomical structures. These structures included the neocortex, hippocampus, amygdala, olfactory bulbs, basal forebrain and septum, caudate-putamen, globus pallidus, thalamus, hypothalamus, central gray, superior colliculi, inferior colliculi, the rest of midbrain, cerebellum, brainstem, corpus callosum/external capsule, internal capsule, anterior commissure, fimbria, and ventricles. The segmentation data were formatted and stored into a database containing three different atlas types: 10 single-specimen brain atlases, an average brain atlas and a probabilistic atlas. Additionally, quantitative group information, such as variations in structural volume, surface area, magnetic resonance microscopy image intensity and local geometry, were computed and stored as an integral part of the database. The database augments ongoing efforts with other high priority strains as defined by the Mouse Phenome Database focused on providing a quantitative framework for accurate mapping of functional, genetic and protein expression patterns acquired by a myriad of technologies and imaging modalities.