Specialized cortical subnetworks differentially connect frontal cortex to parahippocampal areas

How information is manipulated and segregated within local circuits in the frontal cortex remains mysterious, in part because of inadequate knowledge regarding the connectivity of diverse pyramidal cell subtypes. The frontal cortex participates in the formation and retrieval of declarative memories through projections to the perirhinal cortex, and in procedural learning through projections to the striatum/pontine nuclei. In rat frontal cortex, we identified two pyramidal cell subtypes selectively projecting to distinct subregions of perirhinal cortex (PRC). PRC-projecting cells in upper layer 2/3 (L2/3) of the frontal cortex projected to perirhinal area 35, while neurons in L5 innervated perirhinal area 36. L2/3 PRC-projecting cells partially overlapped with those projecting to the basolateral amygdala. L5 PRC-projecting cells partially overlapped with crossed corticostriatal cells, but were distinct from neighboring corticothalamic (CTh)/corticopontine cells. L5 PRC-projecting and CTh cells were different in their electrophysiological properties and dendritic/axonal morphologies. Within the frontal cortex, L2/3 PRC-projecting cells innervated L5 PRC-projecting and CTh cells with similar probabilities, but received feedback excitation only from PRC-projecting cells. These data suggest that specific neuron subtypes in different cortical layers are reciprocally excited via interlaminar loops. Thus, two interacting output channels send information from the frontal cortex to different hierarchical stages of the parahippocampal network, areas 35 and 36, with additional collaterals selectively targeting the amygdala or basal ganglia, respectively. Combined with the hierarchical connectivity of PRC-projecting and CTh cells, these observations demonstrate an exquisite diversification of frontal projection neurons selectively connected according to their participation in distinct memory subsystems.     

Dementia of frontal lobe type: neuropathology and immunohistochemistry.

Brains from 12 patients dying with a clinical diagnosis of frontal lobe dementia have been examined at post mortem. In pathological terms four groups were encountered. Groups A and B showed severe frontal and temporal lobe atrophy characterised histologically in group A by severe neuronal loss, spongiform change of the superficial laminae, and mild astrocytosis; in group B severe neuronal loss was accompanied by intense gliosis but with little or no spongiform change. Two patients in this latter group also showed inclusions in frontal cortex and hippocampus typical of "Pick bodies"; such patients were considered as having classic "Pick''s disease". Group C patients showed severe striatal atrophy with variable cortical (frontal or temporal) involvement, with histological changes similar to patients in groups A and B. The single patient in group D showed mild frontotemporal atrophy with spongiform degeneration of the superficial laminae of the cortex and nigral damage, and was considered to have motor neuron disease with dementia. This study is consistent with previous reports showing that the clinical syndrome of frontal lobe dementia is pathologically heterogeneous. However, the nosological relationships within these pathological variants, and between them and conditions such as progressive aphasia were similar histopathological changes are present, remain uncertain.     

Calbindin D-28k and parvalbumin immunoreactivity in the frontal cortex in patients with frontal lobe dementia of non-Alzheimer type associated with amyotrophic lateral sclerosis.

The morphology and distribution of local-circuit neurons (interneurons) were examined, by calbindin D-28k and parvalbumin immunocytochemistry, in the frontal cortex (area 8) in two patients with frontal lobe dementia of non-Alzheimer type associated with classical amyotrophic lateral sclerosis (ALS), and in seven normal cases. The density of calbindin D-28k immunoreactive cells was dramatically reduced in ALS patients, but the density of parvalbumin-immunoreactive neurons was preserved. Decreased density of calbindin D-28k-immunoreactive neurons, which are mainly located in the upper cortical layers, may interfere with the normal processing of cortico-cortical connections, whereas integrity of parvalbumin-immunoreactive cells may be associated with the preservation of the major inhibitory intracortical circuits in patients with frontal lobe dementia.     

Postnatal development of Rattus norvegicus B. cortical neurons and the influence of trauma]

The differentiation of the pyramid neurons during ontogenesis and the effects of a trauma on the process of neuron differentiation and synaptogenesis were investigated in the rat cerebral cortex after Golgi-impregnation. 1. There are temporal differences in the differentiation of the processes of cortical neurons. Axons differentiate earlier than dendrites, apical dendrites earlier than basal ones. 2. Varicosities in the processes of cortical neurons during the early postnatal period are regarded as a feature of growth processes. 3. The appearance of the dendritic spines is an important process in the ontogenetic and phylogenetic development of cortical neurons. 4. The different cortical layers show a different degree of differentiation during development. The deeper layers precede the upper layers in the process of differentiation. 5. Ingrowing afferents have an essential influence on the differentiation - especially on the differentiation of the dendritic postsynaptic structures. 6. The cortex of 6 month old rats shows no principle differences in comparison with 24 days old animals. It is concluded that the visible differentiation processes of cortical neurons are nearly finished 24 days post partum. 7. As an effect of the trauma a considerable loss of dendritic spines of layer III and V pyramid cells is found in addition to general degeneration features. 8. The following factors are thought to be responsible for the loss of spines: (i) transneuronal processes with spine degeneration and subsequent phagocytosis of the synaptosome. (ii) destruction of differentiation furthering afferents results in differentiation defects of the neuron with the failure of further postsynaptic differentiation (spines).     

Prenatal development of neurons in the human prefrontal cortex. II. A quantitative Golgi study.

The quantitative development of neurons in the human dorsolateral and lateral prefrontal cortex was studied in Golgi-impregnated tissue from postmortem brains ranging from 13.5 weeks of gestation up to the second postnatal month. Pyramidal neurons in the future layers III and V of the cortical plate, as well as different types of neurons in the transient subplate zone, were studied. The basal dendrites of the future layer III and V pyramidal neurons show a slow increase during the first two-thirds of the period of gestation. From 27-32 weeks of gestation on, there is a rapid increase in the length of basal dendrites of layer III and V pyramidal neurons, while the number of basal dendrites per pyramidal neuron appears to stabilize at 26/27 weeks of gestation. The increase in total length of basal dendrites per pyramidal neuron is mainly due to an increase in the number of bifurcations and the growth of terminal segments. Throughout the whole period studied, the size of the layer III pyramidal basal dendritic tree was smaller than that of layer V pyramidal neurons. Thus, not until postnatal life do the layer III pyramidal basal dendrites become larger than those of layer V. No statistically significant differences were found for data of the pyramidal neurons between the superior and middle frontal gyri. The dendritic size of subplate neurons, except for the subplate inverted pyramidal neurons, significantly exceeds the size of the basal dendrites of the pyramidal neurons up to the seventh gestational month, which indicates an earlier maturation of these subplate neurons. During the period examined, no clear decrease in the size of the subplate neurons was observed. The present study shows that the dendritic parameters of either subplate or cortical plate pyramidal neurons rapidly increase during the periods of ingrowth of afferent fibers into the subplate zone and cortical plate, respectively. In the Golgi preparations of the prefrontal cortex, the size of the subplate neurons does not show any clearly regressive changes at the end of the prenatal period.     

Presenile non-Alzheimer dementia with motor neuron disease and laminar spongiform degeneration

We describe the clinicopathological findings in three autopsy cases of presenile dementia with motor neuron disease. These patients had a relatively rapid course involving dementia and muscle weakness with a distal pattern of atrophy in the upper extremities. Postmortem examination revealed features of motor neuron disease and spongiform cortical degeneration. The latter change was most marked in the second layer of the frontal or temporal cortex and included minimal to mild neuronal cell loss and mild to moderate gliosis. In this report we relate these patients' laminar spongiform degeneration to three other conditions; frontal lobe dementia, primary progressive aphasia and dementia lacking a distinctive histology. These three conditions and presenile dementia with motor neuron disease may fall within the spectrum of the non-Alzheimer type frontotemporal degenerative dementia.     

Aging, senile dementia, and the intralaminar microchemistry of cerebral cortex

We compared the microchemical architecture or right frontal isocortex from patients with senile dementia and age-matched and younger controls. Neuronal connectivity within deep lamina of the cortical column (Brodmann area 9) tended to decline in normal aging and was profoundly depleted in senile dementia. In both aging and senile dementia, there was a significant 20% loss of total cells (neurons and glia) in cortical layers III to VI. In senile dementia, marked diminution of total ganglioside sialic acid per neuron and galactocerebroside per cell in the lower lamina far exceeded alterations associated with aging itself. This structural loss may imply deafferentation of the cortex, owing to loss of projections from subcortical areas such as nucleus basalis. Selective vulnerability of axodendritic arborization of neurons in lower lamina may be correlated to the impaired cognitive functions of senile dementia.     

An autopsy case of dementia with motor neuron disease accompanying Alzheimer's disease lesion]

We report the case of a 60-year-old man with autopsy-proven dementia with motor neuron disease (D-MND) and Alzheimer's disease lesion. The patient presented with clumsiness of his right hand at the age of 55 years old and subsequently developed dysarthria, weakness and atrophy of his upper limbs. He was unaffectionate towards his family, repeated the same phrase, and showed severe disorientation of time and place. Neurological examination on admission showed not only diffuse lower motor neuron signs, such as weakness, atrophy, fasciculation and areflexia in both upper limbs, but also dementia (HDS-R 9/30). He died of respiratory insufficiency. Neuropathological examination showed mild atrophy of the frontal and temporal lobes and anterior spinal roots. Microscopic examination of cortical sections revealed degenerative changes with simple atrophy and gliosis, and these changes were predominant in layers 1 and 2 of the frontal and temporal cortices. Using immunohistochemical staining, ubiquitin-positive but tau-negative inclusions were frequently found in neurons of the hippocampal granular cell layers and temporal lobes. Many senile plaques and neurofibrillary tangles were present in all sections of the brain. Our final diagnosis was dementia with motor neuron disease accompanying Alzheimer's disease lesion, because of hypoperfusion in the parietal lobe as well as the frontal lobe demonstrated by SPECT, and the presence of many senile plaques and neurofibrillary tangles in the cerebral cortex. Overlapping of pathologically-proven D-MND and Alzheimer's disease lesion is extremely rare, and this case may improve our understanding of the process of neurodegeneration.     

Laminar degeneration of the frontal and temporal cortex in neuronal intermediate filament inclusion disease (NIFID): a study original using alpha-internexin immunohistochemistry

OBJECTIVE: To determine the laminar distribution of the pathological changes in the frontal and temporal lobe in neuronal intermediate filament inclusion disease (NIFID). METHOD: The distribution of the alpha-internexin-positive neuronal cytoplasmic inclusions (NCI), surviving neurons, swollen achromatic neurons (SN) and glial cell nuclei was studied across the cortex in gyri of the frontal and temporal lobe in 10 cases of NIFID. RESULTS: The distribution of the NCI was highly variable within different gyri, a peak in the upper cortex, a bimodal distribution with peaks of density in the upper and lower laminae, or no significant variation in density across the cortex. The surviving neurons were either bimodally distributed or exhibited no significant change in density across the cortex. The SN and glial cell nuclei were most abundant in the lower cortical laminae. In half of the gyri, variations in density of the NCI across the cortex were positively correlated with the SN. In some gyri, the surviving neurons were positively correlated with the SN and negatively correlated with the glial cell nuclei. In addition, the SN and glial cell nuclei were positively correlated in over half the gyri studied. CONCLUSION: The data suggest that frontal and temporal lobe degeneration in NIFID characterized by NCI, SN, neuronal loss and gliosis extends across the cortical laminae with considerable variation between cases and gyri. alpha-internexin-positive neurons in the upper laminae appear to be particularly vulnerable. The gliosis appears to be largely correlated with the appearance of SN and with neuronal loss and not related to the NCI.     

Substance P-containing pyramidal neurons in the cat somatic sensory cortex.

Light and electron microscopic immunocytochemical methods were used to verify the possibility that neocortical pyramidal neurons in the first somatic sensory cortex of cats contain substance P. At the light microscopic level, substance P-positive neurons accounted for about 3% of all cortical neurons, and the vast majority were nonpyramidal cells. However, 10% of substance P-positive neurons had a large conical cell body, a prominent apical dendrite directed toward the pia, and basal dendrites, thus suggesting they are pyramidal neurons. These neurons were in layers III and V. At the electron microscopic level, the majority of immunoreactive axon terminals formed symmetric synapses, but some substance P-positive axon terminals made asymmetric synapses. Labelled dendritic spines were also present. Combined retrograde transport-immunocytochemical experiments were also carried out to study whether substance P-positive neurons are projection neurons. Colloidal gold-labelled wheat germ agglutinin conjugated to enzymatically inactive horseradish peroxidase was injected either in the first somatic sensory cortex or in the dorsal column nuclei. In the somatic sensory cortex contralateral to the injection sites, a few substance P-positive neurons in layers III and V also contained black granules, indicative of retrograde transport. This indicates that some substance P-positive neurons project to cortical and subcortical targets. We have therefore identified a subpopulation of substance P-positive neurons that have most of the features of pyramidal neurons, are the probable source of immunoreactive axon terminals forming asymmetric synapses on dendritic spines, and project to the contralateral somatic sensory cortex and dorsal column nuclei. These characteristics fulfill the criteria required for classifying a cortical neuron as pyramidal.     

Layer-specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex

The dendritic field of pyramidal neurons in cortical layers IIIc and V of the prefrontal cortex in ageing humans was studied. The three-dimensional branching pattern of the basilar dendrites of Golgi–Cox impregnated neurons was analysed in the middle frontal gyrus (areas 9 and 46) in eight subjects between the ages of 49 and 90 years, all without a neurological or psychiatric disorder. The results revealed a significant regression of the layer V dendritic pattern with increasing age, but the layer IIIc neurons did not show any age-related changes. Together with our earlier data on the postnatal development of the same cell types in the prefrontal cortex, we hypothesize that the layer V neurons in the prefrontal cortex start to regress from the fifth decade onwards, in contrast to the layer IIIc neurons which remain stable from puberty on. We conclude that pyramidal cells in layer IIIc and V in a similar cortical region undergo a differential ageing effect.     

Upper motor neuron predominant degeneration with frontal and temporal lobe atrophy

The autopsy findings of a 78-year-old man mimicking primary lateral sclerosis (PLS) are reported. He showed slowly progressive spasticity, pseudobulbar palsy and character change, and died 32 months after the onset of symptoms. Autopsy revealed severe atrophy of the frontal and temporal lobes, remarkable neuronal loss and gliosis in the precentral gyrus, left temporal lobe pole and amygdala, mild degeneration of the Ammon’s horn, degeneration of the corticospinal tract, and very mild involvement of the lower motor neurons. The anterior horn cells only occasionally demonstrated Bunina body by cystatin-C staining, and skein-like inclusions by ubiquitin staining. This is a peculiar case with concomitant involvement in the motor cortex and temporal lobe in motor neuron disease predominantly affecting the upper motor neuron. Received: 18 November 1997 / Revised, accepted: 2 April 1998     

Synaptic termination of afferents from the ventrolateral nucleus of the thalamus in the cat motor cortex. A light and electron microscopy study

The synaptic termination in the cat motor cortex of afferents from the ventrolateral nucleus of the thalamus (VL) has been studied with experimental light and electron microscopic methods. The distribution of normal synapses on motor cortex pyramidal, stellate, and Betz cells was also examined. Synapses in the motor cortex can be classified into two general types. The first and most prominent type contains flat vesicles, lacks a compact postsynaptic density, and corresponds to Colonnier's ('68) symmetrical synapse. Stellate neurons receive synapses of both types on their cell bodies and proximal dendritic shafts, while pyramidal cells have only symmetrical synapses at these sites. The dendritic spines of both stellate and pyramidal cells are contacted by predominantly asymmetrical synapses. Betz cells, like smaller pyramidal neurons, receive only symmetrical synapses on their cell bodies. The proximal portions of the Betz cells apical dendrites, however, receive both asymmetrical and symmetrical synapses. Following VL lesions, degenerating synapses were mainly found in three cortical layers: the upper third of layer I (18%), layer III (66%), and layer VI (13%). Degenerating synapses were not seen in the lower two-thirds of layer I or in layer II, and were only rarely seen in layer V (3%). Ninety-one percent of the VL synapses were found on spines and 8% on stellate-type dendritic shafts. Stellate cell bodies rarely received VL synapses (1%) and none occurred on pyramidal or Betz cell bodies and their proximal dendrites. A VL synapse within layer III was found on two dendritic spines of a Betz cell apical dendrite. Thus, part of the VL input to layer III synapses on the processes of both motor cortex output neurons (Betz cells in layer V) and cortical interneurons (stellate cells in layer III).     

Columnar organization of dendrites and axons of single and synaptically coupled excitatory spiny neurons in layer 4 of the rat barrel cortex.

Cortical columns are the functional units of the neocortex that are particularly prominent in the "barrel" field of the somatosensory cortex. Here we describe the morphology of two classes of synaptically coupled excitatory neurons in layer 4 of the barrel cortex, spiny stellate, and star pyramidal cells, respectively. Within a single barrel, their somata tend to be organized in clusters. The dendritic arbors are largely confined to layer 4, except for the distal part of the apical dendrite of star pyramidal neurons that extends into layer 2/3. In contrast, the axon of both types of neurons spans the cortex from layer 1 to layer 6. The most prominent axonal projections are those to layers 4 and 2/3 where they are largely restricted to a single cortical column. In layers 5 and 6, a small fraction of axon collaterals projects also across cortical columns. Consistent with the dense axonal projection to layers 4 and 2/3, the total number and density of boutons per unit axonal length was also highest there. Electron microscopy combined with GABA postimmunogold labeling revealed that most (>90%) of the synaptic contacts were established on dendritic spines and shafts of excitatory neurons in layers 4 and 2/3. The largely columnar organization of dendrites and axons of both cell types, combined with the preferential and dense projections within cortical layers 4 and 2/3, suggests that spiny stellate and star pyramidal neurons of layer 4 serve to amplify thalamic input and relay excitation vertically within a single cortical column.     

Atypical amyotrophic lateral sclerosis with dementia mimicking frontal Pick's disease: a report of an autopsy case with a clinical course of 15 years

This report concerns an autopsy case of atypical amyotrophic lateral sclerosis (ALS) with dementia mimicking frontal Pick's disease. The patient was a Japanese woman without hereditary burden who was 45 years old at the time of death. She developed abnormal behavior and amnesia at age 30, followed by disinhibition, aspontaneity, urinary incontinence, abulia, and rectal incontinence. Neurological signs compatible with ALS developed about 14 years after the disease onset. No respirator was used throughout the clinical course. Macroscopically, neuropathological examination showed atrophy of the frontotemporal lobes with accentuation in the convexities of the frontal lobes. Histologically, there was neuronal loss in the cerebral cortex, parahippocampal gyrus, amygdala, caudate nucleus, substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord, in addition to marked degeneration of the pyramidal tracts. Ubiquitin-immunoreactive neuronal inclusions were present in the frontotemporal cortical layer II neurons and motor neurons in the brain stem and spinal cord. In the hippocampal dentate granular cells, many ubiquitin-immunoreactive neurites were present without ubiquitin-immunoreactive intraneuronal inclusions. Based on these clinicopathological findings and a review of the literature, we concluded that our case was atypical ALS with dementia of long disease duration. We also note the possibility that motor neuron disease-inclusion dementia with a long clinical course may develop into ALS in the final stage of the illness.     

Hereditary spastic paraparesis with dementia, amyotrophy and peripheral neuropathy. A neuropathological study

Hereditary, probably autosomal recessive, spastic paraparesis in two siblings was associated with dementia of frontal lobe type, amyotrophy and peripheral sensory and motor polyneuropathy. Neuropathological findings correlate with neurological deficits, although neuron loss in the caudate and putamen, substantia nigra, and loss of Purkinje cells were clinically silent. Loss of neurons occurred in all cortical layers of the prefrontal lobe and superior temporal gyrus. Immunohistochemical studies showed reduced parvalbumin immunoreactivity in dendrites, and reduced numbers of calbindin D28k-immunoreactive cells, thus suggesting involvement of cortical local-circuit neurons. Myelin loss, ubiquitin-immunoreactive granular deposits, and nerve fibre degeneration in the white matter of the frontal lobes and corpus callosum were also observed. Cerebral and sub-cortical white matter abnormalities, together with atrophy of the thalamic dorsomedial complex and anterior nucleus, may have accounted for the development of severe dementia in this patient.     

Functional classes of cortical projection neurons develop dendritic distinctions by class-specific sculpting of an early common pattern.

We demonstrate in rat neocortex that the distinct laminar arrangements of the apical dendrites of two classes of layer 5 projection neurons, callosal and corticotectal, do not arise de novo, but are generated later in development from a common tall pyramidal morphology. Neurons of each class initially elaborate an apical dendrite in layer 1. Layer 5 callosal neurons later lose the segments of their apical dendrite superficial to layer 4, generating their characteristic short pyramidal morphology. The apical dendrite of layer 5 callosal neurons later lose the segments of their apical dendrite superficial to layer 4, generating their characteristic short pyramidal morphology. The apical dendrite of layer 5 callosal neurons is actively eliminated, rather than passively displaced, as superficial cortical layers expand. Corticotectal neurons and callosal neurons superficial to layer 5 maintain their apical dendrite to layer 1. Therefore, this selective dendritic loss occurs in a neuron class-specific manner and, within the callosal population, in a lamina-specific manner. Based on our additional observations and other studies, this phenomenon can be extended to other types of cortical projection neurons. These findings show that selective dendritic elimination plays a major role in shaping the functional architecture characteristic of the adult cortex.     

Bunina body in frontal lobe dementia without clinical manifestations of motor neuron disease

We report here an early autopsy case of a 60-year-old woman clinically diagnosed as having frontal lobe dementia without other neurological deficits. Postmortem examination revealed mild spongiosis in layers II and III of the frontal cortex, together with depletion of melanin-containing neurons in the substantia nigra. In addition to ubiquitin-positive neurites, ubiquitin-positive, tau-negative inclusions, which were previously considered to be a hallmark for motor neuron disease with or without dementia, were identified in neurons of the hippocampal dentate gyrus and of the temporal cortex. Although the patient lacked lower motor symptoms, the presence of Bunina bodies identified in the hypoglossal nuclei further supported the relationship of this case to motor neuron disease. Bunina bodies might be present in some cases of frontal lobe dementia. The presence or absence of Bunina bodies should be scrutinized even in cases without motor symptoms. In this case, creatine kinase of skeletal muscle origin was elevated, which might also be a potential indicator that suggests subclinical involvement of lower motor neurons.     

Aberrant dendritic development in the human agyric cortex: a quantitative and qualitative Golgi study of two cases

A quantitative and qualitative Golgi comparison of the visual cortex from two agyric brains and of two age-matched controls is reported. In the camera lucida drawings, most pyramidal cells were oriented vertically to the pial surface in the external cellular layer, frequently with their apical dendrites directed toward the deep layers (inverted pyramidal neurons). The deep cellular layer contained pyramidal and polymorphic neurons normally found in the second to fourth cortical layers. In quantitative analysis of the agyric cortex of a ten-month-old patient, relative immaturity of basal dendritic arborization was apparent together with a bipolar configuration of dendritic development of the pyramidal neurons. The 3-year-old patient had a significant delay in apical dendritic arborization (shorter branch length, decreased number of dendritic intersections) compared with his age-matched normal control. The pathogenesis of the abnormal dendritic development in agyria is discussed.     

Fibrous astrocytes in Alzheimer's disease and senile dementia of Alzheimer's type

In four patients with Alzheimer's disease (AD), on patient with senile dementia of Alzheimer's type (SDAT) and five age-matched controls, occipital cortex, frontal cortex, and hippocampus were evaluated for the distribution of fibrous astrocytes (FA), using peroxidase-anti-peroxidase for glial fibrillary acidic protein (GFAP). FA, neuronal cells, neurofibrillary tangles (NFT), and senile plaques (SP) have been quantified in the occipital cortex. In AD and SDAT there was a significant increase in the number of FA in the molecular layer as well as in the other layers of the cortex. No correlation was found between the increase in FA and the number of neurons, NFT or SP.The GFAP positivity was most pronounced around small blood vessels. Electron-microscopic studies of four cortical biopsies of AD revealed dense perivascular gliosis in 48.8% of the capillaries examined as opposed to 17.8% of capillaries in three controls without dementia. The significance of increased perivascular gliosis in AD and SDAT is unknown. It may be related to a defect in the blood-brain barrier.