Regional localization of the regulatory subunit (RII beta) of the type II cAMP-dependent protein kinase in human brain.

The distribution of the regulatory (RII beta) subunits of type II cAMP-dependent protein kinase in cortical and subcortical areas was examined in human control and Alzheimer's disease (AD) brains. Four monoclonal antibodies generated against bovine brain RII, which cross-reacted with human brain RII beta, detected RII-immunoreactivity in pyramidal neurons of the hippocampus and frontal, occipital, parietal and superior temporal cortices and in non-pyramidal neurons of the amygdala and putamen. RII beta immunoreactivity was localized to neuronal perikarya, proximal dendrites and cell processes. With the exception of rare processes in the ventroposterior lateral nucleus, RII-immunoreactivity was not seen in the thalamus. Other areas lacking RII-immunoreactivity included the midbrain, caudate nucleus and globus pallidus. RII-immunoreactivity was not detected in endothelia or glia. Except for the neocortex, the distribution of RII beta immunoreactivity was the same in AD and non-demented control brains; however, cell bodies and their processes stained more intensely and uniformly in the neocortical regions of non-demented controls compared to AD. In the neocortex of AD, RII beta immunoreactivity was substantially decreased in the superior temporal and occipital cortices, but not in the frontal cortex. Our data suggest that RII subunits are regionally distributed in the human brain. RII-immunoreactivity was decreased in some regions of neocortex in AD, but it did not preferentially colocalize with neurofibrillary tangles (NFT), senile plaques, or neuropil threads.     

Quantification of pathological lesions in the frontal and temporal lobe of ten patients diagnosed with Pick’s disease

The densities of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) in the frontal and temporal lobe were determined in ten patients diagnosed with Pick’s disease (PD). The density of PB was significantly higher in the dentate gyrus granule cells compared with the cortex and the CA sectors of the hippocampus. Within the hippocampus, the highest densities of PB were observed in sector CA1. PC were absent in the dentate gyrus and no significant differences in PC density were observed in the remaining brain regions. With the exception of two patients, the densities of SP and NFT were low with no significant differences in mean densities between cortical regions. In the hippocampus, the density of NFT was greatest in sector CA1. PB and PC densities were positively correlated in the frontal cortex but no correlations were observed between the PD and AD lesions. A principal components analysis (PCA) of the neuropathological variables suggested that variations in the densities of SP in the frontal cortex, temporal cortex and hippocampus were the most important sources of heterogeneity within the patient group. Variations in the densities of PB and NFT in the temporal cortex and hippocampus were of secondary importance. In addition, the PCA suggested that two of the ten patients were atypical. One patient had a higher than average density of SP and one familial patient had a higher density of NFT but few SP. Received: 9 March 1998 / Revised, accepted: 27 October 1998     

Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease

TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20-30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. In this report, we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal, and parietal neocortex, were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, six had TDP-43 positive NCIs in the amygdala only and seven had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases, TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most susceptible region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first, followed by higher order association cortices.     

Quantification of vacuolation ("spongiform change"), surviving neurones and prion protein deposition in eleven cases of variant Creutzfeldt-Jakob disease

Vacuolation ("spongiform change") and prion protein (PrP) deposition were quantified in the cerebral cortex, hippocampus, dentate gyrus and molecular layer of the cerebellum in 11 cases of variant Creutzfeldt-Jakob disease (vCJD). The density of vacuoles was greater in the cerebral cortex compared to the hippocampus, dentate gyrus and cerebellum. Within the cortex, vacuole density was significantly greater in the occipital compared to the temporal lobe and the density of surviving neurones was greatest in the occipital lobe. The density of the non-florid PrP plaques was greater in the cerebellum compared to the other brain areas. There were significantly more florid-type PrP plaques in the cerebral cortex compared to the hippocampus and the molecular layer of the cerebellum. No significant correlations were observed between the densities of the vacuoles and the PrP plaques. The densities of vacuoles in the parietal cortex and the non-florid plaques in the frontal cortex were positively correlated with the density of surviving neurones. The densities of the florid and the non-florid plaques were positively correlated in the parietal cortex, occipital cortex, inferior temporal gyrus and dentate gyrus. The data suggest: (i) vacuolation throughout the cerebral cortex, especially in the occipital lobe, but less evident in the hippocampus and molecular layer of the cerebellum; (ii) the non-florid plaques are more common than the florid plaques and predominate in the molecular layer of the cerebellum; and (iii) either the florid plaques develop from the non-florid plaques or both types are morphological variants resulting from the same degenerative process.     

Reduced expression of amyloid precursor protein, presenilin-1 and rab3a in cortical brain regions in Alzheimer's disease

To study the role of amyloid precursor protein (APP) in the pathogenesis of Alzheimer's disease (AD), the level of APP was analysed by quantitative immunoblotting in 6 AD patients and 6 age-matched controls in 9 brain regions. These were associative cortices (orbital frontal cortex, inferior temporal cortex, inferior parietal cortex), primary cortex (occipital cortex), limbic structures (anterior cingulate gyrus, hippocampus), subcortical structures (putamen, thalamus) and cerebellum. To assess a potential relationship between APP and presenilin-1 (PS-1) and/or synaptic proteins, the levels of PS-1 and rab3a, a specific synaptic vesicle protein, were also determined in the same tissue samples. The level of APP was almost the same in the association cortical regions, primary cortex, and limbic structures and in the subcortical structures, while the lowest level was found in the cerebellum. There were more marked differences in the level of PS-1 and rab3a between different brain regions. The highest levels of PS-1 and rab3a were found in the association cortical areas, while intermediate levels were found in primary cortex, limbic structures and subcortical structures. As for APP, the lowest level was found in cerebellum. We found significantly reduced levels of all three proteins in the association cortices and in hippocampus in AD. Our data show that the protein levels are reduced in specific areas, restricted to neuronal populations that are known to degenerate in AD. Due to the similarity of the expression of APP, PS-1 and rab3a, it is tempting to speculate whether there is a functional relationship between these proteins.     

Differences in the density and spatial distribution of florid and diffuse plaques in variant Creutzfeldt-Jakob disease (vCJD)

OBJECTIVE: To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently. MATERIAL: Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD. METHOD: The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis. RESULTS: The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters. CONCLUSION: The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.     

THE TOPOGRAPHY OF PLAQUES AND TANGLES IN DOWN''S SYNDROME PATIENTS OF DIFFERENT AGES

The topographical distribution of senile plaques and neurofibrillary tangles has been investigated in 12 patients with Down's syndrome ranging from 31 to 65 years of age. No plaques or tangles whatsoever were seen in the brain of the 31-year-old patient. The nine patients over 53 years of age, showed a similar pathological picture in which there were numerous mature plaques in all areas of cerebral cortex, hippocampus and amygdala and numerous tangles in these areas and in subcortical structures such as nucleus basalis, locus caeruleus, dorsal raphe, ventral tegmental area, substantia nigra, olfactory bulb and tracts. In the other two patients aged 37 and 51 years, an intermediate pathological picture was seen in which primitive plaques predominated within the cortex, with numerous mature plaques in hippocampus and amygdala. In the 37-year-old patient, tangles were numerous in the entorhinal cortex, but much less common in hippocampus and amygdala, rare in cerebral cortex and absent in the subcortical areas, olfactory bulbs and tracts. A similar pattern was seen in the 51-year-old patient though here some cells in the subcortex were also affected. These observations suggest that the primary focus of plaque and tangle formation in Down's syndrome may be in amygdala, entorhinal cortex and hippocampus, with a 'spreading out' to subsequently involve all areas of cortex, certain subcortical regions and the olfactory bulbs and tracts. It appears unlikely that the olfactory bulbs and tracts provide a portal of entry for any pathogenic agent that may be responsible for inducing plaque and tangle formation within the rest of the brain.     

Neural substrates of spatial and temporal disorientation in Alzheimer’s disease

To examine the neuroanatomical correlates of spatial and temporal disorientation in Alzheimer’s disease (AD), we performed an anterograde clinicopathological study of 29 patients with clinically and neuropathologically confirmed AD. Spatial and temporal disorientation was assessed using the locational orientation subtests of the Mini Mental State Examination and the Benton’s test for temporal orientation. Quantitative analysis of neurofibrillary tangles and senile plaques were performed in the CA1 field of the hippocampus, layers II and V of the entorhinal cortex, and layers II–III and V–VI of areas 9, 7, 39, 19, 37, 20 and 23 in the right hemisphere. Forward stepwise logistic regression was used to assess the relationship between lesion densities and the presence of either spatial or temporal disorientation; severity scores and brain weight were included as covariants. A statistically significant relationship was found between neurofibrillary tangle densities in Brodmann’s areas 7, 23 and the CA1 field of hippocampus and both spatial and temporal disorientation. Senile plaque counts did not correlate with any of the neuropsychological parameters. Both temporal and spatial disorientation in AD are related to the degeneration of the same pathways linking the hippocampus with the superior parietal and posterior cingulate cortex in the right hemisphere. These observations are discussed with respect to the notion of global corticocortical disconnection in AD. Received: 30 August 1999 / Revised, accepted: 3 November 1999     

The amygdala in Down's syndrome and familial Alzheimer's disease: four clinicopathological case reports.

Senile plaques and neurofibrillary tangles were quantified in 14 subnuclei of the amygdala in the brains of 3 patients with Down's syndrome (DS), aged 19, 56, and 64 years, and in 1 patient with familial Alzheimer's disease (AD), aged 54 years. The amygdala of the 19-year-old Down's case contained numerous senile plaques (SPs) but no neurofibrillary tangles (NFTs). The distribution of neuropathological change in the amygdala was similar among the Down's and the Alzheimer's cases. Medical and ventral regions contained more SPs and NFTs than did lateral regions, and the SPs in ventromedial subnuclei generally were the "mature" type with a prominent amyloid core. In general, the numbers of SPs and NFTs were parallel in a given subnucleus with the striking exceptions of the deep medial basal, deep cortical, and lateral central nuclei that contained far more SPs than NFTs, and the medial and lateral superficial cortical nuclei that contained numerous NFTs but few SPs. Several subnuclei strongly interconnected with hippocampus and entorhinal cortex were more heavily involved than subnuclei related to the nucleus basalis of Meynert. The patterns of SP and NFT deposition are consistent with amygdaloid abnormalities found by others in sporadic AD. These findings demonstrate the similarity in amygdaloid pathology among Down's syndrome, familial Alzheimer's disease, and sporadic AD. The presence of senile plaques in the amygdala of the 19-year-old patient with DS suggests that the amygdala is a focus of early pathological change in DS and possibly AD.     

Laminar distribution of Pick bodies, Pick cells and Alzheimer disease pathology in the frontal and temporal cortex in Pick's disease

Lesions in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have distinct laminar distributions in the cortex. The objective of the present study was to test the hypothesis that the lesions characteristic of Pick's disease (PD) and AD have distinctly different laminar distributions in cases of PD. Hence, the laminar distribution of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) was studied in the frontal and temporal cortex in nine patients with PD. In 57% of analyses of individual cortical areas, the density of PB was maximal in the upper cortex while in 25% of analyses, the distribution of PB was bimodal with density peaks in the upper and lower cortex. The density of PC was maximal in the lower cortex in 77% of analyses while a bimodal distribution was present in 5% of analyses. The density of NFT was maximal in the upper cortex in 50% of analyses, in the lower cortex in 15% of analyses, with a bimodal distribution in 4% of analyses. The density of SP did not vary significantly with cortical depth in 86% of analyses. The vertical densities of PB and PC were negatively correlated in 12/21 (57%) of brain areas. The maximum density of PB in the upper cortex was positively correlated with the maximum density of PC in the lower cortex. In 17/25 (68%) of brain areas, there was no significant correlation between the vertical densities of PB and NFT. The data suggest that the pathogenesis of PB may be related to that of the PC. In addition, although in many areas PB and NFT occur predominantly in the upper cortex, the two lesions appeared to affect different neuronal populations.     

A case of progressive supranuclear palsy with widespread senile plaques

Summary A case of progressive supranuclear palsy (PSP) with frontal lobe atrophy is reported, in which many senile plaques were widely distributed in the neocortex, the entorhinal cortex, the amygdala, and, to a lesser extent, the cerebellar cortex, but not in the hippocampus. Most of the plaques were of the diffuse and primitive types. They were well visualized by -protein immunostaining, modified Bielschowsky staining and methenamine silver staining, but were not seen by Bodian staining. The widespread distribution of senile plaques in the cerebral and cerebellar cortices was far beyond that seen in normal aging, and was reminiscent of concomitant Alzheimer's disease (AD). Unlike AD, however, this case had neither senile changes in the hippocampus nor neurofibrillary tangles in the amygdala and entorhinal cortex. It seems that many senile plaques may appear widely in the cerebral cortex and even, to a lesser extent, in the cerebellar cortex of some patients with PSP. Additional case studies using sensitive silver and amyloid antibody preparations are required to elucidate the presence of senile plaques in the cerebral cortex of PSP.     

Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease.

We studied the topographic distribution of Alzheimer's disease (AD)-type pathologic changes in the brains of 25 presumed nondemented elderly individuals. Neurofibrillary tangles (NFT) and senile plaques (SP) were evaluated quantitatively in nine to 20 cytoarchitectural fields using thioflavine S, Alz-50, and anti-beta/A4 amyloid immunohistochemistry. Our observations suggest that (1) most individuals over the age of 55 have at least a few NFT and SP; (2) the topographic distribution of NFT and SP in nondemented elderly individuals follows a consistent pattern of vulnerability in different cytoarchitectural areas; (3) NFT occur most frequently in the entorhinal and perirhinal cortices and the CA1/subiculum field of the hippocampus, while neocortical areas are less frequently affected; (4) immunohistochemically defined subtypes of SP have distinct patterns of distribution. beta/A4 immunoreactive SP are present in neocortical areas much greater than limbic areas. Alz-50 immunoreactive SP are infrequent and limited to those areas that contain Alz-50-positive neurons and NFT. These patterns closely match the hierarchical topographic distribution of NFT and SP observed in AD, suggesting a commonality in the pathologic processes that lead to NFT and SP in both aging and AD.     

Interaction between Amyloid-β Pathology and Cortical Functional Columnar Organization

Amyloid-β plaques are one of the major neuropathological features in Alzheimer's disease (AD). Plaques are found in the extracellular space of telencephalic structures, and have been shown to disrupt neuronal connectivity. Since the disruption of connectivity may underlie a number of the symptoms of AD, understanding the distribution of plaques in the neuropil in relation to the connectivity pattern of the neuronal network is crucial. We measured the distribution and clustering patterns of plaques in the vibrissae-receptive primary sensory cortex (barrel cortex), in which the cortical columnar structure is anatomically demarcated by boundaries in Layer IV. We found that the plaques are not distributed randomly with respect to the barrel structures in Layer IV; rather, they are more concentrated in the septal areas than in the barrels. This difference was not preserved in the supragranular extensions of the functional columns. When comparing the degree of clustering of plaques between primary sensory cortices, we found that the degree of plaques clustering is significantly higher in somatosensory cortex than in visual cortex, and these differences are preserved in Layers II/III. The degree of areal discontinuity is therefore correlated with the patterns of neuropathological deposits. The discontinuous anatomical structure of this area allows us to make predictions about the functional effects of plaques on specific patterns of computational disruption in the AD brain.     

Senile plaques in cortex of aged normal monkeys

The density, type, and distributions of cortical senile plaques were determined in 6 aged rhesus monkeys. Plaque densities were highest in prefrontal and temporal cortices and lowest in occipital cortex. Neurite plaques contained many argentophilic neurites and little amyloid, mixed plaques had both neurites and amyloid, and amyloid plaques showed significant amounts of amyloid and fewer numbers of neurites. As total plaque density increased, there was a linear increase in the density of amyloid plaques, suggesting that plaques evolve from neurite, to mixed, to amyloid types.     

The duality of the cingulate gyrus in monkey. Neuroanatomical study and functional hypothesis

According to most behavioural, electrophysiological, and clinical studies, the cingulate gyrus is widely thought to be involved in regulation of emotional life, reactivity to painful stimuli, memory processing, and attention to sensory stimuli. Anatomically the cingulate cortex is composed of two distinct areas numbered 24 and 23 in Brodmann's classification. We have investigated the connections of the cingulate gyrus in monkeys, using horseradish peroxydase and radioautographic techniques, in order to verify the hypothesis of an anatomical complementarity of these cytoarchitectonic subdivisions. The posterior cingulate gyrus (area 23) is specifically connected with the associative temporal cortex, the medial temporal and orbitofrontal cortices, and with the medial pulvinar. The anterior cingulate gyrus (area 24) is related to the intralaminar, mediodorsal, and ventral anterior thalamic nuclei, the amygdala, and the nucleus accumbens septi. The two cingulate areas were found to be interconnected and to have, in common, connections with the 'limbic' thalamic nuclei (AM, AV, LD), the caudate nucleus, the claustrum, the lateral frontal and the posterior parietal (area 7) cortices.     

Magnetic resonance studies in Alzheimer's dementia. What routine scanning shows

Magnetic resonance images of the brain acquired in relationship to the commissural plane have been analyzed in twenty cases classified as Probable Alzheimer's disease (Pr. AD). These examinations have been compared to normal aged matched subjects. All examinations have been made in strict correlation with the planes defined by Talairach and Tournoux (1988). The analysis of brain cortical damage was made by evaluating the sulci of the brain mainly on coronal sections correlated with simultaneous image review of the same area on the two other orthogonal planes. In Pr. AD, an asymmetric atrophic pattern was found mainly on the following areas: amygdaloid nucleus, para hippocampal gyrus, hippocampus, areas 22 and 21, temporal pole, insula, dorso frontal cortex, angular gyrus, superior parietal lobule. The primary motor and visual areas were normal in all cases.     

Distribution of dopamine D1 receptors in rat cortical areas, neostriatum, olfactory bulb and hippocampus in relation to endogenous dopamine contents

The tritiated dopamine D1 antagonist SCH23390 was employed to determine the densities of D1 receptors in seven discrete and functionally identified cortical areas (cingulate, frontal, parietal, primary somatosensory, primary visual, retrosplenial and entorhinal-piriform) as well as in the neostriatum, hippocampus and olfactory bulbs. In addition, the tissue levels of the catecholamines NA, AD, DA, the indoleamine 5-HT and their main metabolites (MHPG, DOPAC, HVA, 3-MT, 5-HTP and 5-HIAA) were measured in the different regions by HPLC with electrochemical detection. The Scatchard analysis of saturation curves revealed the highest density of [3H]SCH23390 binding sites for the neostriatum, while the densities were 10-20 times lower for total cerebral cortex and hippocampus respectively. For the olfactory bulb and other cortical areas, D1 receptor densities were determined by equilibrium binding at a fixed radioligand concentration approaching saturation. The distribution of D1 receptors was heterogeneous with the greatest densities in entorhinal-piriform and cingulate cortices. The endogenous DA levels measured for all regions correlated with their metabolite (DOPAC, HVA and 3-MT) contents (r = 0.999; P less than 0.001). There was also a very good correlation (r = 0.981; P less than 0.001) between tissue DA and D1 receptor densities. This quantitative information reflects particular features of the organization of the DA systems and is discussed in relation to turnover and recently established aspects of the DA innervation.     

Is right hemisphere specialization for face discrimination specific to humans?

Patterns of neural activation during face recognition were investigated in sheep by quantifying altered c-fos mRNA expression in situations where faces (sheep vs. human) can (faces upright) and cannot (faces inverted) be discriminated. Exposure to upright faces selectively increased expression significantly more in the right inferior temporal cortex than in the left, and active choice between upright faces additionally increased expression bilaterally in basal amygdala and hippocampus (CA1-4). Exposure to inverted faces did not lead to enhanced activation in the right inferior temporal cortex, amygdala or hippocampus but instead increased expression levels in the diagonal band of Broca, parietal and cingulate cortices. These results show that discrimination of upright faces in sheep preferentially engages the right temporal cortex, as it does in humans, and that performance of active choices between such faces may additionally involve the basal amygdala and hippocampus.     

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease

OBJECTIVE: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. BACKGROUND: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. METHODS: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. RESULTS: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. CONCLUSIONS: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.     

Cortical afferents of the perirhinal,postrhinal, and entorhinal cortices of the rat

We have divided the cortical regions surrounding the rat hippocampus into three cytoarchitectonically discrete cortical regions, the perirhinal, the postrhinal, and the entorhinal cortices. These regions appear to be homologous to the monkey perirhinal, parahippocampal, and entorhinal cortices, respectively. The origin of cortical afferents to these regions is well-documented in the monkey but less is known about them in the rat. The present study investigated the origins of cortical input to the rat perirhinal (areas 35 and 36) and postrhinal cortices and the lateral and medial subdivisions of the entorhinal cortex (LEA and MEA) by placing injections of retrograde tracers at several locations within each region. For each experiment, the total numbers of retrogradely labeled cells (and cell densities) were estimated for 34 cortical regions. We found that the complement of cortical inputs differs for each of the five regions. Area 35 receives its heaviest input from entorhinal, piriform, and insular areas. Area 36 receives its heaviest projections from other temporal cortical regions such as ventral temporal association cortex. Area 36 also receives substantial input from insular and entorhinal areas. Whereas area 36 receives similar magnitudes of input from cortices subserving all sensory modalities, the heaviest projections to the postrhinal cortex originate in visual associational cortex and visuospatial areas such as the posterior parietal cortex. The cortical projections to the LEA are heavier than to the MEA and differ in origin. The LEA is primarily innervated by the perirhinal, insular, piriform, and postrhinal cortices. The MEA is primarily innervated by the piriform and postrhinal cortices, but also receives minor projections from retrosplenial, posterior parietal, and visual association areas. J. Comp. Neurol. 398:179–205, 1998. © 1998 Wiley-Liss, Inc.