Acetylcholine Muscarinic M2 Receptor Stimulated [35S]GTPγS Binding Shows Regional Selective Changes in Alzheimer's Disease Postmortem Brain

Oxotremorine-M stimulated [³⁵S]GTPγS binding was used to assess acetylcholine muscarinic M2 receptor mediated G-protein function in superior frontal cortical, superior temporal cortical and hippocampal membranes from a series of Alzheimer's disease and matched control subjects. No significant differences were seen in basal [³⁵S]GTPγS binding between the groups. The maximal level of oxotremorine-M stimulated [³⁵S]GTPγS binding over basal was significantly increased in Alzheimer's disease superior temporal cortex, suggesting an enhanced muscarinic M2 receptor-G-protein coupling efficiency in this region. In contrast, the maximal level of oxotremorine-M stimulated [³⁵S]GTPγS binding over basal was unaltered in Alzheimer's disease superior frontal cortex and significantly reduced in Alzheimer's disease hippocampus. Western immunoblotting using antisera towards the α-subunits of those G-protein types known to couple muscarinic receptors, revealed that G_qαand G_iα, but not G_oα, levels were significantly reduced in Alzheimer's disease superior temporal cortex. Neither G_qα, G_iαnor G_oαlevels were significantly altered in Alzheimer's disease superior frontal cortex or hippocampus. These results suggest that the efficacy of muscarinic M₂receptor G-protein coupling shows regional selective changes in Alzheimer's disease postmortem brain with deficits occurring only in a region that shows severe pathology.     

PROCEEDINGS OF THE SIXTY-NINTH MEETING OF THE BRITISH NEUROPATHOLOGICAL SOCIETY HELD AT THE UNIVERSITY OF BRISTOL 11–12 JULY 1985

Fluorescence activated cell sorting as a preparation method for neurofibrillary tangles in Alzheimer's disease Neurofilament epitopes are located on paired helical filaments from Alzheimer neurofibrillary tangles Pathophysiological significance of neurofibrillary tangle formation in mid-brain and brain stem nuclei in Alzheimer's disease Elemental analysis of isolated and in situ senile plaque cores Loss of nerve cells from locus caeruleus in Alzheimer's disease is topographically arranged Immunocytochemical studies on Alzheimer's Disease (AD) with anti-bodies t o neuropeptide Y (NPY) Pelizaeus-Merzbacher disease in a brother and sister Motor Neuron Disease and an insect baculovirus (nuclear polyhedrosis virus) Some neurological consequences of viraemia with herpes simplex virus in the mouse Transfection studies with DNA obtained from multiple sclerosis brain tissue Is there a regional distribution pattern of corpora amylacea in the human brain stem and spinal cord? Ultrastructural changes in the frontal cortex and hippocampus of the aging primate An in vitro study of rat cerebral capillary endothelium Immunocytochemical study of small pituitary tumours found incidentally at autopsy An immunocytochemical survey of glial and neural differentiation in 18 primitive neuroectodermal tumours Anti-Drosophila brain monoclonal anti-bodies as diagnostic markers for human cerebral tumours The characterization of medullo-blastomas with a monoclonal antibody panel Vascular permeability differences related t o morphological features in extracranial and intracerebral components of experimental murine gliomas Tumours in Meckel's cave Astroglial elements in oligodendro-gliomas and oligoastrocytomas Astrocytomas: a morphological and tissue culture study Oligodendroglioma-A clinicopatho-logical study of 40 cases diagnosed in a 20 year period Calcification in human choroid plexus, psammomamatous meningiomas and the pineal gland Diagnostic difficulty in Becker muscular dystrophy The use of allografts of muscle pre-cursor cells as a means of modifying the genotype and phenotype of skeletal muscle Failure to induce experimental allergic neuritis in T-cell deficient rats Alterations in the morphology of myelinated nerve fibres caused by Phoneutria, Leiurus or Centruroides venom are prevented by tetrodotoxin Energy depletion necrotic brainstem lesions caused by tribromoimidazole Clinical and experimental studies on brain hypoxia/ischaemia     

7.0T nuclear magnetic resonance evaluation of the amyloid beta(1–40) animal model of Alzheimer's disease: comparison of cytology verification

3.0T magnetic resonance spectroscopic imaging is a commonly used method in the research of brain function in Alzheimer's disease.However,the role of 7.0T high-field magnetic resonance spectroscopic imaging in brain function of Alzheimer's disease remains unclear.In this study,7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer's disease rats,the N-acetylaspartate wave crest was reduced,and the creatine and choline wave crest was elevated.This finding was further supported by hematoxylin-eosin staining,which showed a loss of hippocampal neurons and more glial cells.Moreover,electron microscopy showed neuronal shrinkage and mitochondrial rupture,and scanning electron microscopy revealed small size hippocampal synaptic vesicles,incomplete synaptic structure,and reduced number.Overall,the results revealed that 7.0T high-field nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer's disease rats in vivo,allowing the possibility for assessing the success rate and grading of the amyloid beta(1–40) animal model of Alzheimer's disease.     

Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex

Neuronal dysfunction and synaptic loss are major hallmarks of Alzheimer's disease (AD) which correlate with symptom severity. Impairment of the γ-aminobutyric acid (GABA)ergic inhibitory interneurons, which form around 20% of the total neuronal network, may be an early event contributing to neuronal circuit dysfunction in neurodegenerative diseases. This study examined the expression of two of the main classes of inhibitory interneurons, parvalbumin (PV) and somatostatin (SST) interneurons in the temporal cortex and hippocampus of AD and control cases, using immunohistochemistry. We report a significant regional variation in the number of PV and SST interneurons with a higher number identified per mm² in the temporal cortex compared to the hippocampus. Fewer SST interneurons, but not PV interneurons, were identified per mm² in the temporal cortex of AD cases compared to control subjects. Our results support regional neuroanatomical effects on selective interneuron classes in AD, and suggest that impairment of the interneuronal circuit may contribute to neuronal dysfunction and cognitive decline in AD.     

Age-related changes of VIP, NPY and somatostatin-immunoreactive neurons in the cerebral cortex of aged rats

Recent studies have explored certain changes with aging of neurons containing neuropeptides. The degree of loss of vasoactive intestinal polypeptide (VIP)-, neuropeptide Y (NPY)- and somatostatin-containing neurons in the aged CNS has not yet been established with certainty however, and available data is often contradictory. Changes with aging of VIP- and NPY-containing neurons were demonstrated by immunocytochemistry in this study. A major loss of VIP-immunoreactive (ir) neurons in aged rat brain was observed in the frontal cortex area 3, parietal cortex area 1, hindlimb area, temporal cortex area 1 and 2, monocular part of occipital cortex area 1, occipital cortex area 2, and retrosplenial cortex. VIP-ir cells in the frontal cortex areas 1 and 2, parietal cortex area 2, forelimb area, binocular part of the occipital cortex area 1, and the dentate gyrus were moderately decreased. The axis of VIP neurons in the aged group showed an irregular orientation tendency, especially in layers II and III. Major loss of NPY-ir neurons in aged rat brain were observed in the retrosplenial cortex, frontal cortex areas 1 and 2, parietal cortex areas 1 and 2, occipital cortex areas 1 and 2, the temporal cortex, hippocampus proper and cingulate cortex. Loss of NPY-ir neurons was observed mostly in layers V and VI. The number and length of dendritic branches also appeared to have decreased and shortened in the aged group. There were only slight decreases of somatostatin-ir cell numbers in the parietal and occipital cortex of the aged group. These results indicate the involvement of VIP and NPY-ir neurons in the aging process of cerebral cortex, and provide the morphological evidence for the decreased number of VIP and NPY neurons by immunocytochemistry in each area of cerebral cortex of aged rats. © 1997 Elsevier Science B.V. All rights reserved.     

Cognitive,neuroimaging, and pathological studies in a patient with Pick's disease

We conducted cognitive, imaging, and neuropathological studies on a patient with Pick's disease. The patient was impaired at interpreting sentences with complex grammatical constructions, differing significantly from control subjects and patients with Alzheimer's disease (AD). Evaluation of regional brain functioning at rest, with positron emission tomography, revealed reduced left frontal activity compared with control subjects and AD patients. Autopsy demonstrated the classic pathology of Pick's disease, including massive neuron loss and gliosis in the frontal and cingulate cortex as well as numerous tau-positive hippocampal Pick bodies. The abnormal tau proteins were phosphorylated at the same amino acid residues as AD paired helical filament tau (PHFtau), but they exhibited a unique migration profile on western blot. Our observations support the hypothesis that a distinct variety of hyperphosphorylated tau in Pick's disease compromises the long-term viability of selectively vulnerable populations of neurons in frontal cortices that contribute to sentence processing.     

Age-related changes in brain microanatomy: Sensitivity to treatment with the dihydropyridine calcium channel blocker darodipine (PY 108-068)

The influence of aging and of treatment with the dihydropyridine Ca²⁺ antagonist darodipine (PY 108-068) on the age-related microanatomical changes of rat brain were studied in male Wistar rats treated from the 18th to the 24th month of age with an oral dose of 5 mg/kg/day of darodipine. Twelve-month-old untreated rats were used as an adult reference group. A decreased number of nerve cells and of alkaline phosphatase-positive capillaries and an increased lipofuscin deposition were observed in the frontal and occipital cortex, in the hippocampus, and in the cerebellar cortex of rats of 24 months in comparison with 12-month-old animals. The number of nerve cells was higher in the occipital cortex and in the hippocampus, but not in the frontal cortex and in the cerebellar cortex, of darodipine-treated rats in comparison with age-matched untreated animals. Lipofuscin deposition is reduced in all the brain areas investigated. The density of alkaline phosphatase-reactive capillaries is also increased in the frontal and occipital cortex and in the hippocampus of aged rats treated with darodipine. The above results suggest that treatment with darodipine is able to counter some microanatomical changes occurring in the brain of aged rats and involving not only microvascular parameters. The occipital (visual) cortex and the hippocampus were the cerebral areas more sensitive to treatment with darodipine. The possible relevance of these findings is discussed.     

Presenilin-1 protein expression in familial and sporadic Alzheimer's disease

Mutations of the presenilin PS1 and PS2 genes are closely linked to aggressive forms of early-onset (<60 years) familial Alzheimer's disease. A highly specific monoclonal antibody was developed to identify and characterize the native PS1 protein. Western blot analyses revealed a predominant 32-kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PS1 complementary DNA, brain biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early-onset familial Alzheimer's disease cases (PS1 and PS2), lateonset sporadic Alzheimer's disease cases, and cases of other degenerative disorders. This truncated polypeptide contains the N-terminus of PS1 and appeared unchaged across cases. In 2 early-onset cases linked to missense mutations in the PS1 gene, a PS1 immunoreactive protein (～49 kd) accumulated in the frontal cortex. This protein was similar in size to full-length PS1 protein present in transfected cells overexpressing PS1 complementary DNA, and in lymphocytes from an affected individual with a deletion of exon 9 of the PS1 gene, suggesting that mutations of the PS1 gene perturb the endoproteolytic processing of the protein. Immunohistochemical studies of control brains revealed that PS1 is expressed primarily in neurons, with the protein localized in the soma and dendritic processes. In contrast, PS1 showed striking localization to the neuropathology in early-onset familial Alzheimer's disease and sporadic Alzheimer's disease cases. PS1 immunoreactivity was present in the neuritic component of senile plaques as well as in neurofibrillary tangles. Localization of PS1 immunoreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathophysiology involving PS1 protein.     

Developmental expression and subcellular localization of glutaminyl cyclase in mouse brain

Glutaminyl cyclase (QC) converts N-terminal glutaminyl residues into pyroglutamate (pE), thereby stabilizing these peptides/proteins. Recently, we demonstrated that QC also plays a pathogenic role in Alzheimer's disease by generating the disease-associated pE-Abeta from N-terminally truncated Abeta peptides in vivo. This newly identified function makes QC an interesting pharmacological target for Alzheimer's disease therapy. However, the expression of QC in brain and peripheral organs, its cell type-specific and subcellular localization as well as developmental profiles in brain are not known. The present study was performed to address these issues in mice. In brain, QC mRNA expression was highest in hypothalamus, followed by hippocampus and cortex. In liver, QC mRNA concentration was almost as high as in brain while lower QC mRNA levels were detected in lung and heart and very low expression levels were found in kidney and spleen. In the developmental course, stable QC mRNA levels were detected in hypothalamus from postnatal day 5 to 370. On the contrary, in cortex and hippocampus QC mRNA levels were highest after birth and declined during ontogenesis by 20–25%. These results were corroborated by immunocytochemical analysis in mouse brain demonstrating a robust QC expression in a subpopulation of lateral and paraventricular hypothalamic neurons and the labeling of a significant number of small neurons in the hippocampal molecular layer, in the hilus of the dentate gyrus and in all layers of the neocortex. Hippocampal QC-immunoreactive neurons include subsets of parvalbumin-, calbindin-, calretinin-, cholecystokinin- and somatostatin-positive GABAergic interneurons. The density of QC labeled hippocampal neurons declined during postnatal development matching the decrease in QC mRNA expression levels. Subcellular double immunofluorescent analysis localized QC within the endoplasmatic reticulum, Golgi apparatus and secretory granules, consistent with a function of QC in protein maturation and/or modification. Our results are in compliance with a role of QC in hypothalamic hormone maturation and suggest additional, yet unidentified QC functions in brain regions relevant for learning and memory which are affected in Alzheimer's disease.     

Cognitive profiles and regional cerebral blood flow patterns in dementia of the Alzheimer type

Individual cognitive profiles and correlations between cognitive functions and regional cerebral blood flow (rCBF) were analyzed in 20 consecutive patients with a clinical diagnosis of probable Alzheimer's disease (AD). CBF was measured with high resolution single photon emission computed tomography (SPECT) and [^99mTc]d,l-HMPAO. The analysis of cognitive profiles was based on the composite scores for six cognitive domains, derived from a detailed neuropsychological test battery, as compared with corresponding test data obtained in a control group of 28 age-matched healthy volunteers. The cognitive profiles displayed a marked heterogeneity as concerned the general level of cognitive impairment, the number of significantly affected cognitive domains, the spectrum of affected and non-affected cognitive domains, and the severity of each cognitive dysfunction. Statistically significant correlations with rCBF were found for memory scores (right frontal and temporal cortex), abstraction scores (frontal/parietal ratio of rCBF), language scores (left frontal and temporal cortex), visual perception scores (rCBF throughout the right hemisphere), and for visuo-construction scores (side-to-side asymmetry of parietal rCBF). We conclude that the previously observed topographical heterogeneity of rCBF distribution patterns in probable AD was reflected by differences in cognitive profiles. The observed heterogeneities stress the relevance of analyzing individual cognitive and rCBF data, as a supplement to group comparisons of data, in the investigation of diseases with potential heterogeneous affections of the brain.     

MRI Temporal Lobe Volume Measures and Neuropsychologic Function in Alzheimer's Disease

The authors performed quantitation of the temporal lobes using magnetic resonance imaging in 20 patients with mild-tomoderate Alzheimer's disease, 20 age-matched aged control subjects, and 26 healthy young volunteers. Compared to young subjects, aged controls showed volume reductions in amygdala (17%, p=0.02), hippocampus (15%, p=0.0001) and temporal lobe (22%, p=0.0001). Compared to aged controls, Alzheimer's subjects showed further volume reductions in amygdala (33%, p=0.0001) and hippocampus (20%, p=0.006) but not temporal lobe (7%, p=0.15). In Alzheimer's subjects, left temporal lobe volume correlated strongly with the Mini Mental State (MMSE) score (adjusted r² =0.46, p=0.0006) whereas right amygdala volume correlated inversely with the noncognitive ADAS score (adjusted r²=0.46, p=0.0006). The authors conclude that significant volume changes occur in the temporal lobe in aging and in Alzheimer's disease, with the greatest percentage reductions in the amygdala in Alzheimer's disease. Temporal neocortical atrophy and temporal limbic atrophy might be associated with different patterns of performance and behavior in Alzheimer's patients.     

Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer's disease

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer''s disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-¹³C]glucose and [1,2-¹³C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using ¹H- and ¹³C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate–glutamine cycle were found in McGill-R-Thy1-APP rats.     

Entorhinal cortex structure and functional MRI response during an associative verbal memory task

Entorhinal cortex (ERC) volume in adults with mild cognitive impairment has been shown to predict prodromal Alzheimer's disease (AD). Likewise, neuronal loss in ERC has been associated with AD, but not with normal aging. Because ERC is part of a major pathway modulating input to the hippocampus, structural changes there may result in changes to cognitive performance and functional brain activity during memory tasks. In 32 cognitively intact older adults, we examined the relationship between left ERC thickness and functional magnetic resonance imaging (fMRI) activity during an associative verbal memory task. This task has been shown previously to activate regions that are sensitive to aging and AD risk. ERC was manually defined on native space, high resolution, oblique coronal MRI scans. Subjects having thicker left ERC showed greater activation in anterior cingulate and medial frontal regions during memory retrieval, but not encoding. This result was independent of hippocampal volume. Anterior cingulate cortex is directly connected to ERC, and is, along with medial frontal cortex, implicated in error detection, which is impaired in AD. Our results suggest that in healthy older adults, processes that engage frontal regions during memory retrieval are related to ERC structure. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross‐sectional study, we employed ¹¹C‐Pittsburgh Compound‐B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta‐amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large‐scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30–55, median age = 43.5) and a stark lack of anti‐correlation. However, in contrast to typically developing controls (n = 20, ages 30–55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB‐negative Down's syndrome group (n = 19, ages 30–48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB‐positive (n = 15, ages 39–55, median age = 48.0) and PiB‐negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome.     

Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats

Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimer's disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1‐ and CA3‐dorsal hippocampus (DH) as well as CA1‐ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18‐month‐old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi‐Cox stain procedure, followed by Sholl analysis on 20‐month‐old rats. In all resveratrol‐treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimer's disease. Synapse, 2016. © 2016 Wiley Periodicals, Inc. Synapse 70:206–217, 2016. © 2016 Wiley Periodicals, Inc.     

Hippocampal release of dopamine and norepinephrine encodes novel contextual information

The detection and processing of novel information encountered in our environment is crucial for proper adaptive behavior and learning. Hippocampus is a prime structure for novelty detection that receives high‐level inputs including context information. It is of our interest to understand the mechanisms by which the hippocampus processes contextual information. For this, we performed in vivo microdyalisis in order to monitor extracellular changes in neurotransmitter levels during Object Location Memory (OLM), a behavioral protocol developed to evaluate contextual information processing in recognition memory. Neurotransmitter release was evaluated in the dorsal hippocampus and insular cortex during OLM in 3‐month‐old B6129SF2/J mice. We found a simultaneous release of dopamine and norepinephrine in hippocampus during OLM, while neurochemical activity remained unaltered in the cortex. Additionally, we administered 6‐hydroxy‐dopamine (6‐OHDA), a neurotoxic compound selective to dopaminergic and noradrenergic neurons, in the dorsal hippocampus in a different group of mice. Depletion of catecholaminergic terminals in the hippocampus by 6‐OHDA impaired OLM but did not affect novel object recognition. Our results support the relevance of hippocampal catecholaminergic neurotransmission in recognition memory. The significance of catecholaminergic function may be extended to the clinical field as it has been reported that innervation of hippocampus by the noradrenergic and dopaminergic system is reduced and atrophied in aging and Alzheimer's disease brain. © 2017 Wiley Periodicals, Inc.     

Differential changes of nicotinic receptors in the ratbrain following ibotenic acid and 192-IgG saporin lesionsof the nucleus basalis magnocellularis

The basal forebrain cholinergic neurons are implicated in the pathogenesis ofneurodegenerative diseases including Alzheimer^fn2s disease (AD). The nicotinic acetylcholine receptors (nAChRs) have been found to besignificantly afflicted in AD. To study the underlying mechanisms for dysfunction of the basalforebrain cholinergic neurons development of suitable animal models is warranted. In this studywe investigated the effects of bilateral lesions of the nucleus basalis magnocellularis on nAChRs inthe rat brain using the cholinergic system selective immunotoxin 192-IgG saporin andnon-selective excitotoxin ibotenic acid. Changes in nAChRs were measured by ³H-cytisineand ³H-epibatidine, two ligands with different selectivity for nAChRs subtypes. Inthe parietal cortex of ibotenic acid lesioned rates, the choline acetyltransferase activity (ChAT)was decreased by 24% while no changes were detected in the frontal cortex or hippocampus.Similarly, a 40% decrease was observed in the number of nAChRs labelled by ³H-cytisine,but not by ³H-epibatidine, in the parietal cortex, while no changes were found in thefrontal cortex or hippocampus. Although the 192-IgG saporin induced lesions reduced the ChATactivity in the frontal cortex, parietal cortex and hippocampus by 77, 50 and 21%, respectively, nochanges were observed in the number of nAChRs as studied by ³H-cytisine or ³H-epibatidine. The results indicate a difference in vulnerability of the cortical nAChRsubtypes to experimental lesions of the nucleus basalis magnocellularis. The findings in this studysuggest that a major portion of the nAChRs might be located on non-cholinergic neurons in thebrain.     

MORPHOLOGICAL AND MORPHOMETRIC ALTERATIONS OF CAJAL-RETZIUS CELLS IN EARLY CASES OF ALZHEIMER'S DISEASE: A GOLGI AND ELECTRON MICROSCOPE STUDY

Cajal-Retzius cell is the prominent neuron of layer I of the cortex, playing a crucial role in cellular development and neuronal circuit formation, by secretion of reelin. In early cases of Alzheimer's disease the morphological and morphometric study of layer I of the temporal isocortex, based on silver impregnation techniques and electron microscopy, revealed a dramatic decline of the number of Cajal-Retzius cells. Because Cajal-Retzius cells and reelin are important factors for the synaptogenesis in the hippocampus and the brain isocortex, their loss may be implicated in the synaptic pathology and the multifactorious pathogenetic pathways of Alzheimer's disease.     

5-Hydroxytryptamine-sensitive [H]imipramine binding of protein nature in the human brain.: II. Effect of normal aging and dementia disorders

Recently, a high-affinity [³H]imipramine binding site of protein nature that appeared related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated in the rat brain. In a preceding paper a similar [³H]imipramine binding site of protein nature and displaceable by 5-HT was demonstrated in the human brain. Most previous [³H]imipramine binding studies of the human brain have used desipramine-sensitive binding, which appears to contain a significant amount of additional binding not related to 5-HT neurons. Therefore this study of the human brain in the normal aging, in Alzheimer's disease/senile dementia of Alzheimer type (AD/SDAT) and in multiinfarction dementia (MID) presents data on 5-HT-sensitive [³H]imipramine binding. The influence of normal aging (17–100 years) was studied in the frontal and cingulate cortices, in the putamen, caudate nucleus, amygdala and in the hippocampus. An age-related change in 5-HT-sensitive [^{3H]imipramine binding was only noted in the cingulate cortex with a 50% loss in B_max over the adult age range. In contrast, desipramine-sensitive [3H]imipramine binding studied in the frontal cortex and in the putamen showed marked increases in B_max with age which correlated with increases in K_d}. It is suggested that these increases are related to an increased binding to lipophilic membrane components not related to 5-HT neurons. The 5-HT-sensitive [³H]imipramine binding ( B_max) was reduced to 60% of control in the cingulate cortex and to 50% in the putamen in AD/SDAT. In MID there was a 50% loss of [³H]imipramine binding sites ( B_max) in the putamen, but a 30% loss in the cingulate cortex did not reach statistical significance. It is concluded that the losses of 5-HT-sensitive [³H]imipramine binding sites reflect a corresponding loss of 5-HT neurites.     

The superficial white matter in Alzheimer's disease

White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short‐range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern‐matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02 ± 5.84, 16M/28F) and 47 healthy controls (Age 69.23 ± 4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P < 0.001) with increases in diffusivity of more than 20% in the bilateral parahippocampal regions and the temporal and frontal lobes. Furthermore, diffusivity correlated with the cognitive deficits measured by the Mini‐Mental State Examination scores (P < 0.001). The superficial white matter has a unique microstructure and is critical for the integration of multimodal information during brain maturation and aging. Here we show that there are major abnormalities in patients and the deterioration of these fibers relates to clinical symptoms in Alzheimer's disease. Hum Brain Mapp 37:1321‐1334, 2016. © 2016 Wiley Periodicals, Inc.