Neuronal inputs to hippocampal formation in Alzheimer's disease and in parkinsonism-dementia complex on Guam

Summary This study concerns the expression of synaptophysin in the hippocampal formation of normal controls, of patients with Alzheimer's disease (AD) and of patients with parkinsonism-dementia complex on Guam (P-D complex). A monoclonal antibody was used to visualize synaptophysin, an integral component of presynaptic vesicle membranes. In the normal controls, a strong synaptophysin immunoreactivity was seen in the stratum pyramidale, stratum radiatum and stratum lacunosum-moleculare of the hippocampus proper, in the subiculum and in the molecular layer of the dentate gyrus. In the dentate gyrus molecular layer, the reaction product was distributed in a laminar fashion. By contrast, in AD and in P-D complex a significant decrease in immunoreactivity was observed in all hippocampal strata, and especially of the hippocampal subfield CA1 and the subiculum. In both diseases, synaptophysin expression was also diminished in the molecular layer of the dentate gyrus of all patients examined, with the inner portion exhibiting almost normal and the outer portion a strikingly reduced synaptophysin immunoreactivity.     

Enhancement of immunoreactivity for NF-κB in the hippocampal formation and cerebral cortex of Alzheimer's disease

The distribution of nuclear factor-kappa B (NF-κB) was investigated immunohistochemically in the hippocampal formation, entorhinal cortex, middle temporal gyrus and visual cortex of Alzheimer's disease (AD) and control postmortem cases using a polyclonal antibody against the (NF-κB) p65 subunit. In AD cases, prominent staining for (NF-κB) was seen in neurons and their processes, neurofibrillary tangles and dystrophic neurites. In control cases, only weak staining of some neurons was obtained. The neuronal staining observed in AD was strongest in the hippocampal formation and entorhinal cortex, less in the middle temporal gyrus and least in the visual cortex. There was no difference between AD and control cases in the staining of glial cells and vascular walls. These results suggest that enhanced expression of neuronal (NF-κB) occurs in areas affected by AD pathology.     

Prenatal malnutrition effect on pyramidal and granule cell generation in the hippocampal formation

The effects of prenatal malnutrition produced by protein deprivation on the neurogenesis of granule and pyramidal cells in the rat hippocampal formation was investigated by injecting pregnant rats with tritiated thymidine on E12, E16, or E20 and sacrificing the pups on P30. Granule cell neurogenesis was significantly decreased in the pups injected on E20, but not in E12 or E16 groups. There was no effect on the generation of pyramidal cells at the times noted, indicating a differential effect of prenatal malnutrition on the generation of these two different neuronal types in the hippocampal formation.     

The laminar distribution of neuritic plaques in the fascia dentata of patients with Alzheimer's disease

Summary Neuritic plaques are prominent in the fascia dentata of the hippocampus and are often linearly oriented in stratum moleculare. Since the afferents to this region are also organized in a laminar pattern, the present study focused on the relative number and laminar distribution of plaques in this region to shed light on the genesis of the neuritic plaques. Examination of 19 brains from patients with Alzheimer's disease showed approximately the same number of plaques in the stratum moleculare of the fascia dentata and in CA1 (Sommer's sector) of the hippocampus, even though the area of the latter is much greater. Laminar analysis of plaque location showed that the plaques were centered on a band between 26% and 40% of the way between the border of stratum granulosum and the outer edge of stratum moleculare. The mean location was 35% of the way through the layer at the intersection of the inner and middle thirds. Plaques appear in approximately the same location, but in lesser numbers, in non-demented patients. The significance of this localization is discussed in terms of the normal anatomy of the fascia dentata and its possible reorganization in Alzheimer's disease. The predictability of plaque formation in this region could be useful in defining the pathogenesis of the neuritic plaque.Supported by a grant from the Duke University Alzheimer's Disease Research Center NIA SP50AGO5128-03     

Relationship between pigment accumulation and age in Alzheimer's disease and Down syndrome

Summary The amount of lipofuscin pigment within nerve cells of the nucleus basalis of Meynert and that of melanin pigment with nerve cells of locus ceruleus was measured in seven patients with Down syndrome, in 22 patients with Alzheimer's disease and in 18 controls ranging from 30 to 88 years of age. No significant differences in amount of either pigment in these cells at any age were noted between the patient groups and their age controls.Supported by a grant from the North Western Regional Health Anthority     

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

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

Provoked confabulations in Alzheimer's disease

Confabulation in Alzheimer's disease (AD) has been the subject of limited investigation. When studied, the phenomenon has been found to share characteristics with memory distortions produced by neurologically intact individuals. Previous studies that have investigated confabulation in AD have failed to take into account the characteristics of the disease and the presence of confabulations in the retrieval of recent autobiographical memory (ABM). The aim of this study was to develop a test that could investigate the tendency to confabulate in recent autobiographical memory that was specifically created for eliciting confabulatory behaviours in patients with AD. Four experiments have been carried out. In Experiment 1, AD patients who have yet to show confabulatory behaviour were compared to elderly adults. The results revealed that AD patients produced significantly more confabulations on the new test compared to elderly adults. Experiment 2 investigated if the results of the initial experiment were due to AD patients having limited working memory capacity that would lead to difficulties in performing the test compared with elderly adults as AD patients would be in a condition of memory overload. The results showed that even when compared with the performance of elderly individuals under memory overload condition, AD patients still produced more confabulations than elderly adults. Using a correlational approach Experiments 3 and 4 revealed that a high production of provoked confabulatory answers were associated with poor scores on personal episodic memory measures but not with other measures of cognitive functioning such as working memory and/or executive function.     

The two faces of Alzheimer's disease

Correct classification of patients with dementia is pertinent to proper interpretation of research findings. However, the history of Alzheimer's disease (AD) is characterized by a continuing debate on its nosological status. Cerebrovascular pathology, Lewy bodies, or hippocampal sclerosis in combination with neuropathological signs of AD of only limited severity results in a disease that is essentially different from severe, purely degenerative AD. The clinical signs, course of the disease, and pathological correlates in elderly patients suffering from “mixed dementia of the Alzheimer type,” may differ from those with “purely degenerative Alzheimer's disease” as encountered in relatively young patients. Both clinicians and researchers have much to gain from a perspective that acknowledges the differences between these subgroups of AD patients. It may provide a more realistic perspective, and it holds promise for new opportunities for prevention and treatment. Received: 16 October 1999, Received in revised form: 13 December 1999, Accepted: 12 January 2000     

Calcification of the basal ganglia in Down's syndrome and Alzheimer's disease

Summary The prevalance and severity of calcification in the basal ganglia (BGC) has been examined histopathologically in 194 patients divided into ten diagnostic categories. The prevalence and severity of BGC was greater (for age) in Down's syndrome and in patients under 75 years of age with Alzheimer's disease. The severity, but not the prevalance, of BGC was greater in Down's syndrome than in patients of similar age with Alzheimer's disease. Both the prevalence and the severity of BGC in patients over 75 years of age with Alzheimer's disease were as expected for age alone. The increased prevalence and severity of BGC in Down's syndrome and in younger patients with Alzheimer's disease appeared not to be related to the presence of dementia or degenerative disease per se, nor was it affected by the presence of cerebral infarction. BGC may result from an age-related disturbance of the structure of arteries within the globus pallidus, which is accelerated (or occurs prematurely) in Down's syndrome and in younger patients with Alzheimer's disease, but probably does not form part of that spectrum of changes that constitutes the pathological basis of Alzheimer's disease.     

Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease

We quantified by microdensitometry the immunoreactivity (IR) to monoclonal antibodies (SP6, SP12, SP15 and SP18) against various synaptic proteins in the molecular layers of the dentate gyrus, CA4, CA3, CA1, subiculum and entorhinal cortex in Alzheimer's disease (AD), Lewy body variant of AD (LBV) and diffuse Lewy body disease (DLBD). A significant decrease in SP6 IR was observed in almost all regions in AD (28.4–70.1%, mean 41.3%), LBV (19.0–42.5%, mean 26.8%) and DLBD (19.9–31.7%, mean 27.1%) compared to controls. In addition, SP6 IR in the outer molecular layer of the dentate gyrus was strongly correlated with tangle count in the entorhinal cortex (r = −0.70, P < 0.002), suggesting loss of perforant pathway projection. Although the decrease in SP12 and SP15 IR was less pronounced, the mean values were decreased in dementia. Furthermore, SP12 and SP15 labeled a large number of neuritic plaques, and SP15 occasionally stained cortical LBs. The present findings indicate (i) that in the hippocampal-entorhinal formation, the decrease of synapse protein IR in AD is more severe than that in LBV and DLBD, (ii) that synaptic markers detect a subset of dystrophic neurites in the plaques and (iii) that synapse proteins are involved in the formation of cortical LBs.     

Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer's disease

We examined the effects of voluntary (16 weeks of wheel running) and forced (16 weeks of treadmill running) exercise on memory-related behavior, hippocampal volume, thioflavine-stained plaque number, and soluble Aβ levels in brain tissue in the Tg2576 mouse model of Alzheimer's disease (AD). Voluntary running animals spent more time investigating a novel object in a recognition memory paradigm than all other groups. Also, voluntary running animals showed fewer thioflavine S stained plaques than all other groups, whereas forced running animals showed an intermediate number of plaques between voluntary running and sedentary animals. Both voluntary and forced running animals had larger hippocampal volumes than sedentary animals. However, levels of soluble Aβ-40 or Aβ-42 did not significantly differ among groups. The results indicate that voluntary exercise may be superior to forced exercise for reducing certain aspects of AD-like deficits — i.e., plaque deposition and memory impairment, in a mouse model of AD.     

The effects of cooling and rewarming on the neuronal activity of pyramidal neurons in guinea pig hippocampal slices

To investigate the reversibility of neuronal functions during deep and mild hypothermia, we have examined changes in membrane properties of pyramidal neurons of the CA3 region of hippocampal slices during cooling and rewarming (8 approximately 37 degrees C) of the perfusion medium. Hypothermia reduced the excitatory postsynaptic potential (EPSP) slope in a temperature dependent manner, but the EPSP amplitude was enhanced transiently between 30 and 25 degrees C. In observing spikes generated by either orthodromic stimulation or by direct intracellular current injection, the critical threshold for spike generation was decreased transiently at a temperature of 30 degrees C. In addition, the numbers of spikes were increased transiently regardless of the progressive prolongation of spike duration and latency with cooling. The resting membrane potential was stable from 37 to 20 degrees C. However, this potential showed a depolarizing shift at 15 degrees C. The neuronal activities, including membrane properties, recovered fully when the temperature was raised to 35 degrees C even from a low of 15 degrees C. In addition, field population spikes (PS) recorded in the pyramidal cell layer showed a complete reversibility after long-term severe hypothermia (8 degrees C). These results suggest that synaptic function, neuronal excitability and membrane properties maintain reversibility during deep hypothermia, as well as in mild hypothermia.     

Sequestration of Tubulin in Neurons in Alzheimer's disease

In Alzheimer's disease (AD), a variety of populations of neurons exhibits cytoskeletal abnormalities, including neurofibrillary tangles (NFT) in perikarya, Hirano bodies in dendrites and filament-distended axons/terminals/dendrites (neurites) in senile plaques. Some nerve cells, particularly pyramidal neurons of the hippocampus, also develop Hirano bodies (paracrystalline arrays of actin) and granulovacuolar degeneration (GVD; granular inclusions in cytoplasmic vacuoles). Since abnormalities of cytoskeletal elements have been implicated in the formation of NFT, neurites and Hirano bodies, the present study was designed to determine whether GVD also may represent a type of cytoskeletal pathology. Sections of hippocampus from controls and from individuals with AD were stained by immunocytochemical methods using monoclonal and polyclonal antibodies directed against a variety of cytoskeletal antigens. Granules of GVD contained tubulin-like immunoreactivity and absorption with purified tubulin abolished staining. Other antigens were not demonstrated in granules when antibodies directed against other cytoskeletal antigens were used. The observation of sequestration of tubulin in granules is consistent with the concept that abnormalities of the neuronal cytoskeleton are an important part of the cellular pathology of AD.     

A computed tomography study of Alzheimer's disease by regional volumetric and parenchymal density measurements

Summary Seventeen patients with clinically diagnosed Alzheimer's disease and 13 healthy age-matched controls were studied by means of computed tomography (CT). To assess cerebral atrophy, regional volumetric measurements and parenchymal density measurements were performed. The results indicate that: (1) Alzheimer patients show diffuse cerebral atrophy in the early stage; (2) the evaluation of lobar atrophy by means of CT is useful for the clinical diagnosis of Alzheimer's disease; (3) the evaluation of parenchymal density by means of CT is not as sensitive as the evaluation of lobar atrophy.     

Piracetam reverses hippocampal membrane alterations in Alzheimer's disease

Summary. The in vitro effects of piracetam treatment on the fluidity of membranes from the hippocampus of Alzheimer's Disease patients (AD) and non-demented controls were studied. Hippocampal membranes of AD patients showed a significant lower hydrocarbon core fluidity compared with membranes from elderly non-demented controls. Preincubation with piracetam enhanced the hydrocarbon core fluidity of hippocampal membranes from AD-patients as well as elderly controls in a concentration depending fashion, although the effect was more pronounced for the AD membranes. In the presence of piracetam, the difference of the membrane fluidity between AD and control membranes was not longer apparent. Received January 18, 1999; accepted April 13, 1999     

Effects of age and Alzheimer's disease on hippocampal subfields

Growing interest has developed in hippocampal subfield volumetry over the past few years and an increasing number of studies use the automatic segmentation algorithm implemented in FreeSurfer. However, this approach has not been validated on standard resolution T1‐weighted magnetic resonance (MR) as used in most studies. We aimed at comparing hippocampal subfield segmentation using FreeSurfer on standard T1‐weighted images versus manual delineation on dedicated high‐resolution hippocampal scans. Hippocampal subfields were segmented in 133 individuals including 98 cognitively normal controls aged 19–84 years, 17 mild cognitive impairment and 18 Alzheimer's disease (AD) patients using both methods. Intraclass correlation coefficients (ICC) and Bland–Altman plots were computed to assess the consistency between both methods, and the effects of age and diagnosis were assessed from both measures. Low to moderate ICC (0.31–0.74) were found for the subiculum and other subfields as well as for the whole hippocampus, and the correlations were very low for cornu ammonis (CA)1 (<0.1). FreeSurfer CA1 volume estimates were found to be much lower than those obtained from manual segmentation, and this bias was proportional to the volume of this structure so that no effect of age or AD could be detected on FreeSurfer CA1 volumes. This study points to the differences in the anatomic definition of the subfields between FreeSurfer and manual delineation, especially for CA1, and provides clue for improvement of this automatic technique for potential clinical application on standard T1‐weighted MR. Hum Brain Mapp 36:463–474, 2015. © 2014 Wiley Periodicals, Inc.     

Alzheimer's disease: Distribution of protein on sucrose density gradient centrifugation

Summary Material has been examined from eighteen brains, postmortem and from 3 cortical biopsies. The cases were classified on clinical and morphological criteria and include cases of dementia and of non-neurological disease. Fractions were isolated from homogenates of neocortex and caudate nucleus by means of discontinuous sucorse density gradient centrifugation. The fractions were analysed for protein content.The mean protein content of fraction 1, at the interphase between 0.32 M and 0.8 M sucrose, from the cortex of the 6 Alzheimer cases was reduced. (P<0.005) by 25%. This deficit in protein content represents less than 5% of the total tissue protein. There were no significant differences in the protein content between other fractions from the control and Alzheimer cases.     

高胆固醇对AD大鼠海马神经元缺失和Tau蛋白异常磷酸化的影响

目的 研究高胆固醇饮食对阿尔茨海默病(AD)大鼠海马神经元缺失和Tau(ser202)异常磷酸化的影响.方法 海马齿状同注射B淀粉样蛋白(A13)建立AD大鼠模型,根据不同饮食,将动物分为高胆同醇AD组、高胆同醇磷酸盐缓冲液(PBS)组、标准饮食AD组和标准饮食PBS组;采用尼氏染色方法检测海马神经元缺失率,应用免疫组织化学方法检测海马及皮层Tau(ser202)磷酸化水平.结果 高胆固醇饮食增加海马神经元缺失,高胆固醇饮食AD组海马神经元缺失率(30.9%±4.6%)明显大于标准饮食AD组(22.7%±1.9%)、高胆同醇饮食PBS组(7.O%±1.5%)和标准饮食PBS组(5.4%±1.1%),差异均有统计学意义(P＜0.05);高胆固醇AD组、标准饮食AD组、高胆固醇PBS组、标准饮食PBS组海马齿状回(Pser202)Tau阳性细胞数分别为65.5±6.2、48.8±4.8、22.5±3.1和12.7±1.7,比较差异均有统计学意义(P＜0,05).结论 高胆固醇饮食促进Aβ诱导神经元缺失和Tau蛋白异常磷酸化.