Neurons and extracellular neurofibrillary tangles in the hippocampal subdivisions in early-onset familial Alzheimer's disease: A case study

Abstract  We have investigated morphometrically unaffected neurons, intracellular neurofibrillary tangles (I-NFT) and extracellular neurofibrillary tangles (E-NFT) in eight subdivisions of the hippocampal cortex in two cases of early-onset familial Alzheimer's disease (FAD) and six cases of early-onset sporadic Alzheimer's disease (SAD). The hippocampal subdivisions examined included: CA4, CA3, CA2, CAI, prosubiculum, subiculum and presubiculum (PRE), parasubiculum (PARA) and entorhinal cortex (ENT). CA3, CA2 and CAI in the FAD cases showed more severe neuronal loss and much greater E-NFT formation than in the SAD cases, while ENT in both the FAD cases showed less neuronal loss and less E-NFT formation. These data suggest that the cornu ammonis is affected more severely than the ENT in the FAD cases. These observations indicate that hippocampal pathology in the FAD cases is qualitatively as well as quantitatively different from that in sporadic cases. These results provide further evidence for pathological heterogeneity in AD, although the number of FAD cases examined is very small.     

Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late-onset sporadic Alzheimer's disease

To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i-NFT) and extracellular NFT (e-NFT) in 22 patients with late-onset sporadic Alzheimer's disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin-eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i-NFT and e-NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e-NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e-NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e-NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e-NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression.     

A Morphometric study of subcortical neurofibrillary tangles in Alzheimer's disease

The numbers of neurofibrillary tangles(NFT) in the subcortical nuclei detected in Gallyas-Nissl double stained sections was evaluated with computer-based image analysis techniques. This was undertaken to examine the susceptibility to NFT formation and to identify mutual correlations in NFT formation among the basal ganglia in Alzheimer's disease (AD). The numbers of NFT are insufficient to compare the regional differences of NFT in each nucleus of the AD brains because large subcortical gray nuclei tend to have more NFT, Incidences of NFT were given definitions in order to find the NFT incidences for the expected neuronal populations, The definitions used were: the ratio of total numbers of NFT observed in a given subcortical gray nucleus of AD brains to the total numbers of medium- to large-sized neurons(≥ 150μm²) in which the nucleoli were confirmed in the corresponding structure of control brains. A common order of susceptibility to NFT changes was found among the subcortical nuclei in advanced stages of AD cases, According to NFT incidences, subcortical nuclei were classified into four groups. The highest incidence of NFT (88%) was found in the nucleus basalis of Meynert. The severely affected group (NFT Incidences; 28–44%) included the raphe nucleus (superior central nucleus), anterior thalamic nucleus (anterior ventral thalamic nucleus), locus ceruleus and claustrum, The putamen, substantia nigra (zona compacta), medial thalamic nucleus (medio-dorsal thalamic nucleus) and lateral thalamic nucleus (ventro-lateral and ventro-anterior thalamic nuclei) comprised the moderately affected group (NFT incidences; 9–15%). The substantia nigra (zona reticulata), globus pallidus, subthalamic nucleus and red nucleus constituted the slightly affected group (NFT incidences;<5%). In spite of the group classifications, no significant mutual correlations in NFT incidences between any pair of subcortical nuclei were indicated. The present study suggests that the NFT formations in AD take place in the subcortical nuclei according to individual susceptibility, irrespective of the connections between the nuclei.     

Hypersialylation is a common feature of neurofibrillary tangles and granulovacuolar degenerations in Alzheimer's disease and tauopathy brains

Glycosylation is one of the major post‐translational modifications of proteins. The status of sialylation of the neuropathological hallmarks of various neurodegenerative disorders was investigated in this study. Here, we report the novel findings that two phosphorylated tau (p‐tau)‐containing structures associated with Alzheimer's disease (AD), that is, neurofibrillary tangles (NFTs) and granulovacuolar degenerations (GVDs), were hypersialylated. The NFTs, GVDs and dystrophic neurites of senile plaques (SPs) in AD hippocampi were clearly visualized by immunohistochemistry using an anti‐sialic acid (SA) antibody. In contrast, the amyloid core of SPs was not sialylated at all. Interestingly, other p‐tau‐containing structures, that is, globose‐type NFTs in progressive supranuclear palsy and Pick bodies and ballooned neurons in frontotemporal lobar degeneration with Pick bodies, were also hypersialylated. Unlike the p‐tau‐containing structures observed in tauopathies, the hallmarks of other neurodegenerative disorders, such as Lewy bodies in Parkinson's disease, glial cytoplasmic inclusions in multiple system atrophy, Bunina bodies, skein‐like inclusions and round inclusions in amyotrophic lateral sclerosis, intranuclear inclusions in neuronal intranuclear inclusion disease and physiological bodies or granules (lipofuscin granules, corpora amylacea and melanin granules), were not immunolabeled by the anti‐SA antibody. Because this antibody specifically identified NFTs and GVDs, immunostaining for sialylation represents a useful tool to screen these structures in a diagnostic setting. These results clearly indicate that the pathological hallmarks of various tauopathies are commonly hypersialylated, and that sialylation plays an important role in the process of p‐tau accumulation in AD and other tauopathies.     

Entorhinal cortex pathology in Alzheimer's disease.

The anatomical distribution of pathological changes in Alzheimer's disease, although highly selective for only certain brain areas, can be widespread at the endstage of the illness and can affect many neural systems. Propriety for onset among these is a question of importance for clues to the etiology of the disease, but one that is formidable without an experimental animal model. The entorhinal cortex (Brodmann's area 28) of the ventromedial temporal lobe is an invariant focus of pathology in all cases of Alzheimer's disease with selective changes that alter some layers more than others. The authors' findings reveal that it is the most heavily damaged cortex in Alzheimer's disease. Neuroanatomical studies in higher mammals reveal that the entorhinal cortex gives rise to axons that interconnect the hippocampal formation bidirectionally with the rest of the cortex. Their destruction in Alzheimer's disease could play a prominent role in the memory deficits that herald the onset of Alzheimer's disease and that characterize it throughout its course.     

A quantitative study of neurofibrillary tangles, senile plaques and astrocytes in the hippocampal subdivisions and entorhinal cortex in Alzheimer's disease, normal controls and non-Alzheimer neuropsychiatric diseases

Abstract  The present quantitative study was performed in order to discriminate pathological substrates for dementia from Alzheimer changes in normal controls (NC) and non-Alzheimer neuropsychiatric diseases (NAND). Regional densities of senile plaques (SP), neurofibrillary tangles (NFT) and astrocytes in the cornu ammonis (CA), subiculum and entorhinal cortex were measured and differences in these densities among Alzheimer's disease (AD), NAND and NC were statistically compared. Densities of NFT in the CA and subiculum were significantly higher in AD than in NAND, and densities of SP in all regions were significantly higher in AD than in NAND. Similarly, NFT density in the subiculum and SP density in all regions were higher in AD than in NC. Regional densities of astrocytes in most regions were closely correlated with those of Alzheimer changes. In conclusion, the attribution of the Alzheimer changes, particularly of NFT, to dementia is neglected when they are confined to the entorhinal cortex. However, the attribution of the Alzheimer changes to dementia should be appreciated when they spread from the entorhinal cortex to the subiculum and/or CA.     

The relationship between alphaB-crystallin and neurofibrillary tangles in Alzheimer's disease

AlphaB-crystallin is known as a small heat shock protein with a cytoprotective function. This study was undertaken to investigate the relationship between alphaB-crystallin and changes seen in Alzheimer's disease. The distribution and immunohistochemical characteristics of alphaB-crystallin positive neurones in the cerebral cortices of 4 patients with Alzheimer's disease were examined. AlphaB-crystallin positive neurones were mainly distributed in the limbic and paralimbic regions, namely parahippocampal gyrus, fusiform gyrus, cingulate cortex, middle and superior frontal gyrus, and insular cortex, which corresponded to commonly affected regions in Alzheimer's disease. Moreover, such neurones were present predominantly in the III or V layer of the cerebral cortex. The number of alphaB-crystallin positive neurones increased in parallel with the neuronal loss. Logistic regression analysis revealed a significant relation between the density of alphaB-crystallin positive neurones and that of extracellular neurofibrillary tangles (NFTs), with a correlation coefficient (r) of 0.57 and P < 0.0001 in 14 regions of the cerebral cortex. In contrast, the relation was not statistically significant between the density of alphaB-crystallin positive neurones and that of classical senile plaques, diffuse plaques or intracellular NFTs. Modified Gallyas-Braak (GB) staining on alphaB-crystallin positive neurone demonstrated several patterns of the structures: faint GB positive structures in the swollen perikaryon with straight neurites, fine granules compressed and contorted into fuzzy bundles, intensely GB positive filamentous structures together with fine granules and very intensely GB positive ring-like NFTs in a swollen perikaryon with curved neurites. In positive neurones, the density of ring-like NFTs correlated with that of atrophic perikaryon, or bent neurites and a decrease in the immunoreactivity of alphaB-crystallin. These data suggest that a close relationship exists between the appearance of alphaB-crystallin in neurones, extracellular NFTs, and neurofibrillary formation in alphaB-crystallin positive neurones in Alzheimer brain.     

Sequential expression of cell-cycle regulators and Alzheimer's disease-related proteins in entorhinal cortex after hippocampal excitotoxic damage

Growing evidence suggests that one of the earliest events in the neuronal degeneration of Alzheimer's disease (AD) is aberrant cell-cycle activation in postmitotic neurons, which may, in fact, be sufficient to initiate the neurodegenerative cascade. In the present study we examined whether cyclins and cyclin-dependent kinases, molecules normally associated with cell-cycle control, may be involved in delayed expression of altered Alzheimer's proteins in two interconnected areas, the entorhinal cortex (EC) and the dentate gyrus (DG), after a hippocampal excitotoxic lesion. Several cell-cycle proteins of the G1 and S phases and even of the G2 phase were found to be up-regulated in the EC after kainic acid evoked neuronal death in the hippocampus. In addition, we describe the progressive expression of two Alzheimer's-related proteins, PHF-1 and APP, which reached higher levels immediately after the increase in G1/S-phase markers. Hence, the results of the present study support the participation of cell-cycle dysregulation as a key component of the process that may ultimately lead to expression of AD proteins and neuronal death in a brain area when the target site for synaptic inputs in that area is damaged by an excitotoxic insult.     

Both N-terminal and C-terminal fragments of Presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer's disease

Presenilin 1 (PS1) is a causative gene for chromosome 14-linked familial Alzheimer's disease. The gene product is known to be cleaved into N-terminal fragments (PS1-N) and C-terminal fragments (PS1-C). To understand the pathophysiological role of PS1, we conducted immunohistochemical studies using antibodies specific for PS1-N and PS1-C in sporadic Alzheimer's disease (AD). Both antibodies showed punctuate staining exclusively in neurons and their processes in both control and AD brains. PS1-N immunolabeling colocalized with neurofibrillary tangles (NFTs) in 36% of NFT-bearing neurons and with dystrophic neurites in 28% of senile plaques (SPs). PS1-C immunolabeling colocalized with dystrophic neurites in 70% of NFT-bearing SPs and with intraneuronal NFTs in 32% of NFT-bearing neurons. Both antibodies did not detect PHF-tau-positive neuropil threads and Aβ amyloid fibrils. The colocalization was also found in 33–38% of NFT-bearing neurons in progressive supranuclear palsy. These results indicate that both PS1-N and PS1-C fragments are deposited in part of NFT-bearing neurons and dystrophic neurites in SPs; both are the pathologic hallmarks of AD. J. Neurosci. Res. 53:99–106, 1998. © 1998 Wiley-Liss, Inc.     

Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe in in vivo 3 Tesla MRI. The method performs segmentation on a T2‐weighted MRI scan with 0.4 × 0.4 × 2.0 mm³ resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi‐atlas label fusion and learning‐based error correction. In contrast to earlier work on automatic subfield segmentation in T2‐weighted MRI [Yushkevich et al., 2010], our approach requires no manual initialization, labels hippocampal subfields over a greater anterior‐posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross‐validation in 29 subjects from a study of amnestic mild cognitive impairment (aMCI) and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797), and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest nonuniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions. Hum Brain Mapp, 36:258–287, 2015. © 2014 Wiley Periodicals, Inc .     

Untangling Alzheimer's disease from fibrous lesions of neurofibrillary tangles and senile plaques

Neuropathological evidence suggests that the two fibril lesions of neurofibrillary tangles (NFT) and senile plaques are the major findings in brain tissue of Alzheimer's disease (AD) and that their occurrence is strongly associated with the symptoms of dementia. Genetic findings have indicated that the pathological molecules from the lesions function as causal agents. There is little evidence, however, to directly indicate that fibril lesions themselves kill neuronal cells in vivo. In spite of such limitations it is important to consider the molecular events involved in AD etiology. In this review of the contribution of Japanese neuropathologists to studies of AD, I will introduce briefly their work and highlight some current topics for consideration on the etiology of AD, and the basis of cell death, and will offer my perspective on outstanding conflicting issues.     

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non‐demented elderly brains: Comparison with late‐onset Alzheimer's disease brains

We quantitatively investigated the formation process of neurofibrillary tangles (NFT) in the hippocampus of 32 brains from non‐demented elderly persons using tau‐immunohistochemistry, compared with 13 brains from patients with late‐onset Alzheimer's disease (AD). The 32 non‐demented elderly brains were classified into 16 brains in group I and 16 brains in group II mainly based on the distribution of tau‐positive neurons in the hippocampus. Tau‐positive neurons were found predominantly in the CA2 in group I, while they were found predominantly in the subiculum～pre‐CA1 in group II. Most late‐onset AD brains showed a distribution of tau‐positive neurons similar to that in group II. In addition, the distribution pattern of tau‐positive neurons in the hippocampus was closely related to degeneration of the perforant pathway with the accumulation of tau. These findings suggest that NFT occur first in the CA2 and extend to the subiculum～pre‐CA1 in group I, while they occur first in the subiculum～pre‐CA1 and extend to the CA2 later in group II, and that the NFT occurring in the subiculum～pre‐CA1 are mainly related to degeneration of the perforating route and in the CA2 are related to the degeneration of the non‐perforating route.     

Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases

Summary Head trauma has been associated with the occurrence of Alzhiemer's disease and plays a clear role in the etiopathogenesis of the boxers encephalopathy referred to as dementia pugilistica. Neurofibrillary tangles (NFT), one of the pathological hallmarks of Alzheimer's disease are observed in very high densities in the brains of former professional boxers suffering from dementia pugilistica. In Alzheimer's disease, NFT display striking regional and laminar distribution patterns that have been correlated with the localization of neurons forming specific corticocortical connections. In dementia pugilistica cases, NFT were concentrated in the superficial layers in the neocortex, whereas in Alzheimer's disease they predominated in the deep layers. Thus, the association cortex of brains from dementia pugilistica patients demonstrated an inverse NFT distribution as compared to Alzheimer's disease. This finding suggests that a more circumscribed population of cortical pyramidal neurons might be affected in dementia pugilistica than in Alzheimer's disease.Supported by the Brookdale Foundation, the American Health Assistance Foundation, and NIH grants AG06647 and AG05138     

An entorhinal cortex sulcal pattern is associated with Alzheimer's disease

Objectives:

Magnetic resonance (MRI) studies rely on sulcal boundaries to delineate the human entorhinal cortex (EC) and typically show that EC size is reduced in Alzheimer's disease (AD) and a predictor of future dementia. However, it is unknown if variations in the EC sulcal patterns are associated with AD. We classified the lateral EC sulcal boundary as either a rhinal or collateral pattern and tested the hypotheses that the rhinal pattern was (1) more common in AD and (2) associated with a smaller EC size.

Experimental Design:

MRI was used to determine the prevalence of the rhinal and collateral EC patterns in 421 subjects (212 AD, 107 old normal (ONL), and 102 young NL (YNL). Anatomical validation studies of normal subjects were conducted at postmortem in 34 brain hemispheres and in vivo with 21 MRI volume studies. EC pattern reliability was studied with MRI in both cross‐sectional and longitudinal designs.

Principal Observations:

The rhinal pattern was more frequent in the right hemisphere in AD (47%) compared with ONL (28%, odds ratio = 2.25, P = 0.001). EC pattern was not related to ApoE genotype. The validations showed that the EC sulcal pattern was not associated with the neuronal number, surface area, or volume of the EC. In patients with antemortem MRI studied at postmortem it was equivalently determined, that EC patterns are reliably determined on MRI and do not change with the progressive atrophy of AD.

Conclusions:

The data indicate that the right hemisphere rhinal pattern is over represented in AD as compared with control. However, in normal subjects the EC rhinal pattern is not associated with a diminished EC tissue size. It remains to be demonstrated if the right EC rhinal sulcus pattern association with AD reflects genetic or developmental influences. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

     

Aging and Alzheimer's disease pathology

The number of people with dementia worldwide is predicted to increase to 131.5 million by 2050. When studying dementia, understanding the basis of the neuropathological background is very important. Taking Alzheimer's disease (AD) neuropathology as an example, we know that the accumulation of abnormal structures such as senile plaques and neurofibrillary tangles is a hallmark. Macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. Braak advocates the spread of tau deposits from the entorhinal to associative regions of the neocortex as the disease progresses. If the AD has only tau pathology, the degree and distribution of tau deposition may be associated with clinical symptoms. However, AD is also accompanied by amyloid-β deposition and even atrophy. Although it is possible to make a neuropathological diagnosis of AD from the spread of amyloid and tau depositions, neuropathological abnormal protein accumulation cannot explain all clinical symptoms of AD. There is an ambiguity between clinical symptoms and neuropathological findings. It is important to understand neuropathological findings while understanding that this ambiguity exists. So, for the reader's help, first we briefly explain the changes in the brain with age, and then describe AD as a typical disease of dementia; finally we will describe the diseases that mimic AD for neurologists who are not experts in neuropathology.     

Motor neuron disease with neurofibrillary tangles in a non-Guamanian patient

Neurofibrillary tangles are described in Guamanian and post-encephalitic forms of motor neuron discase (MND) but not in sporadic MND. We report the neuropathological findings in a 79-year-old man who died after a 1-year history of MND without extrapyramidal features or dementia. There was no family history of neurological disease and he had not visited Guam. The spinal cord showed loss of anterior horn cells, and skeletal muscle typical changes of denervation. The brain appeared macroscopically normal but histology revealed many neurofibrillary tangles, particularly in medial temporal lobe structures, insula, nucleus basalis, hippocampus, oculomotor nucleus, raphe nuclei and locus ceruleus. Neurofibrillary tangles were not seen in the primary motor cortex, which appeared histologically unremarkable. Occasional tangles were present in the substantia nigra and pontine nuclei. None were seen in the cerebellum, medulla or spinal cord. The tangles were argyrophilic, and, in sections stained with thioflavin-S, both the intracellular and the extracellular tangles fluoresced strongly under ultraviolet light. The intracellular neurofibrillary tangles reacted strongly with an antibody to tau protein, and only occasional tangles showed weak ubiquitin immunoreactivity. Scattered neuropil threads were present in the cortex in the areas of neurofibrillary tangle formation. No plaques were present in any part of the brain and no A4/ protein immunoreactivity was detected. Ultrastructural examination revealed Alzheimer-type neurofibrillary tangles composed of paired helical filaments. The present findings further extend the spectrum of diverse neurological disorders associated with neurofibrillary tangles.     

Distribution and ultrastructure of Alzheimer's neurofibrillary tangles in postencephalitic parkinsonism of Economo type

Summary The distribution and ultrastructure of Alzheimer's neurofibrillary tangles (ANT) in the brain stem, hypothalamus, and Ammon's horn were studied in four patients with postencephalitic parkinsonism of Economo type (PEPE). The distribution of ANT was as previously reported; the pattern of distribution resembled to that of amine-containing nerve cells. Ultrastructurally, ANT revealed twisted tubules (TT), but straight tubules (ST) of 150 Å width were also found in the locus ceruleus of three cases; sometimes, TT and ST were mixed in a single neuron. Whether the coexistence of TT and ST in the locus ceruleus is a characteristic ultrastructural feature of ANT in PEPE or a regional peculiarity could not be determined. Ultrastructurally, ANT in PEPE were identical to those found in the brains of patients with Alzheimer's disease or senile dementia.     

Adult neurogenesis in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.