Neurofibrillary changes confined to the entorhinal region and an abundance of cortical amyloid in cases of presenile and senile dementia

Summary Cases of old-aged demented individuals exhibited abundant cortical amyloid deposits but only small numbers of neurofibrillary changes. Neuritic plaques were rare or absent. Neither Ammon's horn nor isocortex revealed sufficiently large numbers of tangles to permit the diagnosis of fully developed Alzheimer's disease. Dense accumulations of neurofibrillary tangles and neuropil threads occurred only in layer Pre- (II) of the entorhinal region. This pattern of cortical destruction may represent a variant of Alzheimer's disease or an initial stage of this disorder.Supported by the Deutsche Forschungsgemeinschaft     

Alzheimer''s disease and senile dementia of Alzheimer type

Clinical and neuropsychological findings, EEG, and several blood and CSF parameters were investigated in 36 patients with Alzheimer's disease (AD) and 35 patients with senile dementia of Alzheimer type (SDAT). There were more women among senile patients and more familial cases among presenile patients. The average duration of the symptoms was longer in presenile patients (6.1 years) than in senile patients (3.9 years). This could be due to the lower resistance to the disease process in the senile group.
Extrapyramidal signs, especially rigidity, were found in over 60 % of all patients and in practically all patients with advanced dementia. Tremor was found in three patients only. Four presenile (11 %) and two senile (6 %) patients had epileptic seizures. All patients had abnormal EEG recordings, mainly in form of diffuse slowing. A positive correlation was found between the EEG abnormality and the severity of dementia in AD but not in SDAT. However, the difference between the correlation coefficients in AD and SDAT was insignificant. Between EEG and the duration of the disease there was no correlation. EEG was not more abnormal in very severe dementia than in severe dementia. Other findings were similar in AD and SDAT.
It is concluded that it is artificial to separate AD and SDAT at the age of 65 and that they clinically compose a single entity. This entity could well be called Alzheimer's disease.     

Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease

Neurofibrillary tangle predominant dementia (NFTPD) is a subset of late onset dementia, clinically different from traditional "plaque and tangle" Alzheimer disease (AD): later onset, shorter duration, less severe cognitive impairment, and almost absence of ApoE epsilon4. Neuropathology reveals abundant allocortical neurofibrillary pathology with no or few isocortical tau lesions, absence of neuritic plaques, absence or scarcity of amyloid deposits, but neurofibrillary changes comprising both 3 and 4 repeat (3R and 4R) tau immunohistochemistry are not significantly different from those in classical AD. Comparing 51 autopsy cases of NFTPD with 244 classical AD subjects, the nosology of NFTPD and its differences from AD are discussed.     

Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation

Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer’s disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala→Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Aβ amyloid protein. Numerous senile plaques consisted of large Aβ amyloid cores, often measuring more than 30 μm in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing familial, presenile AD and in patients with the APP693 mutation causing HCHWA-D. Received: 11 August 1997 / Revised, accepted: 9 February 1998     

Low prevalence of apolipoprotein E ε4 allele in the neurofibrillary tangle predominant form of senile dementia

Apolipoprotein E (apoE) genotypes were analyzed in a subset of demented very old patients who share a uniform neuropathological picture consisting of various numbers of neurofibrillary tangles (NFT) in allocortical areas of the inferomedial temporal lobe without significant numbers of either diffuse amyloid or neuritic plaques. Among 18 patients with this condition referred to as NFT-predominant senile dementia (average age at death 87 ± 4.7 years), we found allele frequencies of 0.11 ɛ2, 0.86 ɛ3 and 0.03 ɛ4, which are significantly different from allele frequencies reported in Alzheimer’s disease (0.04 ɛ2, 0.59 ɛ3 and 0.38 ɛ4). The low prevalence of the apoE ɛ4 allele in this subset of patients is striking and suggests that NFT-predominant senile dementia is a dementing neurodegenerative disease in which the deposition of Aβ-amyloid did not occur, possibly due to protective effects of ɛ2 and/or ɛ3 alleles or lack of a promoting effect of apoE ɛ4 on amyloidogenesis. We propose that NFT-predominant dementia is a variant of Alzheimer’s disease occurring in the very old. Received: 17 July 1997 / Accepted: 31 July 1997     

Senile dementia of Alzheimer type: Astroglial reaction to extracellular neurofibrillary tangles in the hippocampus

Summary Two types of Alzheimer neurofibrillary tangles may be found in the hippocampus in senile dementia of the Alzheimer type. Besides classical flameshaped intraneuronal tangles, there are less compact tangles representing extracellular remnants of destroyed neurons with neurofibrillary change. Strong immunoreactivity for glial fibrillary acidic protein (GFA) was found in the second type of tangles, which was due to penetration of fine processes of fibrous astrocytes into bundles of paired helical filaments (PHF). PHF appear to be a strong stimulus for astrocytic reaction when they are not segregated from the neuropil by the neuronal cell membrane.     

The relationship between clinical dementia and neuropathological staging (Braak) in a very elderly community sample

The neuropathological staging model proposed by Braak and Braak (1991) implies that the evolution of neurofibrillary pathology follows a predictable sequence and can be ordered in a regular regional hierarchy. A total of 42 cases of an elderly population sample, which had been prospectively clinically assessed, were examined. Clinical diagnosis was made according to the CAMDEX criteria, and the sample reported here did not include cases were vascular dementia according to the criteria proposed by Chui et al. (1991). The neuropathological staging procedure was applied as originally proposed by Braak and Braak (1991). In addition, in all cortical laminae and regions which are essential for the staging model neurofibrillary tangles were quantified. Demented cases had significantly more areas involved and more advanced neuropathological stages. Cases with stages 1–3 tended to be non-demented, and cases with stages 4–6 tended to be demented. However, there was a considerable degree of overlap and no clear-cut threshold could be established. This brings into question the diagnostic value of the staging model.     

Tau,paired helical filaments and amyloid in the neocortex: a morphometric study of 15 cases with graded intellectual status in aging and senile dementia of Alzheimer type

Summary Tau immunoreactivity was studied in temporal neocortex, area 22, in 15 cases with graded intellectual status and compared with the immunoreactivity observed with an antiserum against paired helical filaments (PHF) and with the density of amyloid revealed by thioflavin S. Samples came from women over 75 years either intellectually normal or affected by senile dementia of the alzheimer type at various degrees of severity. Mental status had been prospectively assessed by the Blessed's test score. Antitau labelled a neuropil meshwork, the density of which increased with the severity of the disease. This meshwork was denser in layers II, III and V in the most affected cases. The number and the size of the taupositive fibers within the senile plaques increased with the intellectual deficit. Senile plaques were more numerous in layers II and III and neurofibrillary tangles in layers III and V whatever the staining technique: tau or PHF immunocytochemistry, and thioflavin S. The densities of senile plaques and of neurofibrillary tangles (NFT) were correlated with the severity of the disease whatever the staining method. The three methods revealed a systematically different number of changes. This systematic difference could greatly influence the neuropathological diagnosis. It could be the consequence of various factors: different sensitivities of the staining methods or changes in the antigenic and amyloid composition of the lesion according to the stage of the disease. In line with the last hypothesis, a higher proportion of amyloid-rich plaques was noted in the less affected cases, suggesting that tau and PHF epitopes appeared secondarily. Tau epitopes seemed to be present at least as early as PHF epitopes in the NFT. The pathological changes best linked to dementia were NFT revealed by tau antiserum.Supported by a fellowship from the European Community Commission (PD)     

Quantitative assessment of the density of neurofibrillary tangles and senile plaques in senile dementia of the Alzheimer type. Comparison of immunocytochemistry with a specific antibody and Bodian's protargol method

Summary Counts of neurofibrillary tangles and senile plaques were performed in two adjacent sections from the temporal lobe in 14 women aged over 75 years at death. The mental status of these cases had been prospectively assessed by the test score of Blessed, Tomlinson and Roth. They were either intellectually normal or had senile dementia of the Alzheimer type of various degrees of severity. The first section was silver-impregnated according to Bodian's method; the second one was immunolabeled with an antiserum raised against neurofibrillary tangles. Densities of neurofibrillary tangles and senile plaques evaluated by the two techniques were highly correlated but their means of differences and limits of agreement were large. The correlation with the clinical data was similar for the two methods. Both techniques can thus be used with the same accuracy in correlative studies but their results are not interchangeable without caution.     

Alzheimer paired helical filaments: Identification of polypeptides with monoclonal antibodies

Summary Paired helical filaments (PHF) were isolated from autopsied brain of cases of Alzheimer dementia, and their polypeptides were identified with monoclonal antibodies to PHF by Western blots. The PHF polypeptide profile consisted of several bands with a size difference of less than 5 kilodalton (kDa) between adjacent bands; the most prominent bands were in the 45–62 kDa region. These PHF polypeptides were also labeled with tangles reactive antisera to microtubules from normal brain but had electrophoretic patterns different from those of microtubules and neurofilaments. These studies define the molecular weight profile of PHF polypeptides and suggest that they might originate from normal brain proteins.Supported in part by NIH grants NS 18105, NS 17487 and P01 AG/NS 04220     

Monoamine metabolism in senile dementia of Alzheimer type

Monoamine metabolism in senile dementia of the Alzheimer-type (SDAT) was assessed by measuring the concentrations of the dopamine metabolite HVA, the noradrenaline metabolite MHPG and serotonin metabolite 5-hydroxy-3-indoleacetic acid (5-HIAA) in post-mortem brains of SDAT patients, a group of control subjects and a group of chronically depressed patients. Concentrations of MHPG and 5-HIAA were significantly reduced in hippocampus and cortical regions of the SDAT group. These changes did not correlate with clinical assessments of the degree of dementia or neuropathological assessment of the degree of Alzheimertype changes in the SDAT group. It is suggested that changes in monoamine metabolite concentrations are not primarily involved in the pathogenesis of SDAT, and may be secondary to the well established cholinergic deficits.     

Quantitative EEG in patients with presenile and senile dementia of the Alzheimer type

EEG data obtained from 27 patients with presenile Alzheimer's disease (AD) and 28 patients with senile dementia of the Alzheimer type (SDAT) were compared with data from 30 age- and sex-matched controls. Both patient groups exhibited more pronounced delta and theta activity and less prominent alpha and beta activity than the controls. AD, however, was accompanied by more severe slowing than SDAT. The slowing was distributed in the left temporal and frontal regions in AD, and bilaterally in the frontal regions in SDAT. As the severity of the dementia increased, delta activity alone increased in AD, whereas, there were significantly greater increases in both delta and theta activity and decreases in alpha and beta activity in SDAT. These EEG differences appear to be related to the degree of brain damage and the speed of progression of the disease process.     

Amyloid-induced neurofibrillary tangle formation in Alzheimer''s disease: insight from transgenic mouse and tissue-culture models

Of all forms of dementia, Alzheimer's disease is the most prevalent. It is histopathologically characterized by beta-amyloid-containing plaques, tau-containing neurofibrillary tangles, reduced synaptic density and neuronal loss in selected brain areas. For the rare familial forms of Alzheimer's disease, pathogenic mutations have been identified in both the gene encoding the precursor of the Abeta peptide, APP, itself and in the presenilin genes which encode part of the APP-protease complex. For the more frequent sporadic forms of Alzheimer's disease, the pathogenic trigger has not been unambiguously identified. Whether Abeta is again the main cause remains to be heavily discussed. In a related disorder termed frontotemporal dementia, which is characterized by tangles in the absence of beta-amyloid deposition, mutations have been identified in tau which also lead to neurodegeneration and dementia. For Alzheimer's disease the existence of familial forms lead to the proposition of the amyloid cascade hypothesis, which claims that beta-amyloid causes or enhances the tangle pathology. In this review, we describe tau transgenic mouse models in which aspects of the tau-associated pathology, including tangle formation, has been achieved. Moreover, tau transgenic mouse and tissue-culture models were used to test the amyloid cascade hypothesis. In addition, we discuss alternative hypotheses to explain the sporadic forms. The animal and tissue-culture models will provide insight into the underlying biochemical mechanisms of tau aggregation and nerve cell degeneration. These mechanisms may be partially shared between sporadic Alzheimer's disease, the familial forms and frontotemporal dementia. Eventually, Alzheimer's disease may be redefined based on biochemical events rather than phenotype.     

Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience

The progressive development of Alzheimer disease (AD)-related lesions, such as neurofibrillary tangles (NFT), amyloid deposits and synaptic loss, and the occurrence of microvascular and small macrovascular pathology within the cerebral cortex are conspicuous neuropathologic features of brain aging. Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia depends more on the severity and topography of pathological changes than on the presence of a qualitative marker. However, several methodological problems, such as selection biases, case–control design, density-based measures and masking effects, of concomitant pathologies persisted. In recent years, we performed several clinicopathologic studies using stereological counting of AD lesions. In order to define the cognitive impact of lacunes and microvascular lesions, we also analyzed pure vascular cases without substantial AD pathology. Our data revealed that total NFT numbers in the CA1 field, cortical microinfarcts and subcortical gray matter lacunes were the stronger determinants of dementia. In contrast, the contribution of periventricular and subcortical white matter demyelinations had a modest cognitive effect even in rare cases with isolated microvascular pathology. Importantly, in cases with pure AD pathology, more than 50% of Clinical Dementia Rating scale variability was not explained by NFT, amyloid deposits and neuronal loss in the hippocampal formation. In cases with microvascular pathology or lacunes, this percentage was even lower. The present review summarizes our data in this field and discusses their relevance within the theoretical framework of the functional neuropathology of brain aging and with particular reference to the current efforts to develop standardized neuropathological criteria for mixed dementia.     

Alzheimer paired helical filaments: Immunochemical identification of polypeptides

Summary Antisera to isolated Alzheimer neurofibrillary tangles (ANT) of paired helical filaments (PHF) were raised in rabbits. These anti-PHF sera immunolabeled both ANT in sections of Alzheimer hippocampus and ANT which were isolated and extracted with sodium dodecyl sulfate (SDS). The immunostaining of ANT in tissue sections was removed by absorption of the anti-PHF serum with small amounts of PHF and also with 40-fold the amount of a fraction prepared identically from normal brain; neurofilament and brain microtubule preparations used at the same concentration as the normal brain control fraction did not eliminate the tangle staining. Furthermore, the tangle staining was also not removed with glial filaments or actin and myosin filaments. No labeling of the neurofilaments of axons and cerebellar basket fibers by anti-PHF sera was observed in tissue sections from non-neurologic brain. On paper blots of SDS-polyacrylamide gels anti-PHF serum reacted with neither polypeptides of the normal brain control fraction nor major microtubule and neurofilament polypeptides. However, the immunoblots of PHF preparations with the anti-PHF serum revealed staining of several polypeptide bands in the 45,000–70,000 molecular weight (MW) region, material on top of the gel and diffuse staining of the high MW region. The tangles staining in tissue sections by the anti-PHF serum was abolished by its absorption with PHF polypeptides extracted from high and low molecular weight areas of SDS polyacrylamide gels but not with identically prepared neurofilament polypeptides. These results indicate that (1) the antigen(s) recognized by the anti-PHF serum is inherent to the PHF, (2) this PHF polypeptide(s) is at least partly soluble in SDS, and (3) this polypeptide(s) occurs in normal brain but is not associated with microtubules, neurofilaments, actin, or myosin.Parts of this paper have been reported at the 57th Annual Meeting of the American Association of Neuropathologists, 1981, Vancouver, Canada (Grundke-Iqbal et al. 1981) and at the IXth International Congress of Neuropathology, Vienna, 1982Supported by NIH grants NS 18105 and NS 17487     

Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.

Alois Alzheimer published two papers on the disease which was named after him by Emil Kraepelin in 1910. Each of these papers contains clinical and pathological data on a patient Alzheimer had seen at the hospital. We have previously reported on the rediscovery of tissue sections from Alzheimer's second published case of Alzheimer disease, Johann F., which probably gave the disease its name (Neurogenetics 1997; 1 : 73–80). Here, we describe the histopathology and APOE genotype of Alois Alzheimer's first patient, Auguste D. As in the case of Johann F., a large number of tissue sections belonging to Alzheimer's laboratory, which was later headed by Spielmeyer, were found among material kept at the Institute of Neuropathology of the University of Munich. As described by Alzheimer in his original report (Allg Zeitschr Psychiatr 1907; 64 : 146–148), there were numerous neurofibrillary tangles and many amyloid plaques, especially in the upper cortical layers of this patient. Yet, there was no microscopic evidence for vascular, i.e., arteriosclerotic, lesions. Interestingly, Alzheimer's histological preparations did not include the hippocampus or entorhinal region. The APOE genotype of this patient was shown to be ε3/ε3 by PCR-based restriction enzyme analysis, indicating that mutational screening of the tissue is feasible. The historical importance of the case of Auguste D. lies in the fact that it marks the beginning of research into Alzheimer disease. In addition, neurofibrillary tangles were first described in this brain. Received: 29 December 1997 / Accepted: 15 January 1998     

CT study in senile dementia of Alzheimer type

We evaluated 14 patients with senile dementia of Alzheimer type (SDAT) and 15 age-matched normal elderly controls using psychological test and computed tomography scans. The low-density rate (LDR) was used as an index of brain atrophy. SDAT patients had significantly higher scores on the Hasegawa Dementia Scale (p< 0.01) and significantly lower scores on the Bender Gestalt Test (p<0.01) than control subjects. The LDRs of the left and right hemispheres were significantly higher in the SDAT group than in the control group in all three slices investigated (p<0.05/6 = 0.0083). In SDAT patients, significant diagnosis by hemisphere interaction was observed in one slice (p<0.05), with higher LDR on the left than on the right (p<0.05/6 = 0.0083). Our findings suggest that cortical atrophy is predominant on the left side in patients with SDAT.     

老年型阿尔茨海默病的病理与影像学对照研究

目的：我们通过4例老年型阿尔茨海默病（SDAT）的病理与其自身不同时期的影像学进行对照研究,探讨病理改变与影像的相关性。方法：病理用HE、Gallyas银染色及四种免疫组化方法,详细观察大脑皮层各叶、扣带回、杏仁核、海马、海马旁回、Meynert基底核、脑干的黑质、蓝斑、迷走神经背核的神经细胞丢失,老年斑、神经原纤维缠结等的变化。影像用4例剖检例自身生前不同时期的CT与病理的对照研究。结果：SDAT以颞叶及顶叶的变性为主：（1）额叶的皮质,以额叶中回的变性最明显;（2）岛叶的皮质,长回比短回的变性明显;（3）扣带回后性较前部变性明显,结论：SDAT的上述病理所见与影像学的改变基本一致。     

泛素在阿尔茨海默病神经原纤维缠结和老年斑中的表达

目的　观察泛素在阿尔茨海默病 (AD)患者和非痴呆 (ND)老年人脑海马神经原纤维缠结 (NFT)和老年斑 (SP)中的表达及分布特点 ,探讨泛素在AD发病机制中的意义。方法　采用免疫组织化学方法检测 7例AD、5例ND脑海马中泛素的表达及分布特点。结果　泛素在AD脑海马内的NFT和SP中特异性表达 ,而缠结前期神经元缺乏泛素免疫染色 ,同时海马CA1、CA2区泛素染色阳性的NFT神经元数目 (分别为 4 2 13± 0 6 5、30 5 7± 0 78)明显多于CA3、CA4区 (分别为 12 4 3±0 2 4、18 34± 0 81,P <0 0 1)。结论　泛素参与NFT形成的晚期发病机制 (晚期事件 ) ,失去正常功能的异常泛素可能是导致AD病理改变形成的重要因素之一 ;AD病理过程中海马CA1、CA2区病理改变较CA3、CA4区更为严重 ,提示CA1、CA2区神经元对AD的致病因素更为敏感     

Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer’s disease and Lewy body disorders

Amygdalae of patients with Alzheimer’s disease (AD), Parkinson’s disease, Down’s syndrome, diffuse Lewy body disease or a combination of these diseases were probed with antibodies to neurofilament proteins as well as with Lewy body (LB)- and paired helical filament-specific antibodies. The results indicate that the amygdala is severely affected by the accumulation of both neurofibrillary tangles (NFTs) and LBs in most cases of the diseases mentioned above, and that amygdala LBs have a similar epitope composition to that of LBs in the brain stem and cerebral cortex. While large numbers of both LBs and NFTs were seen in different neurons within the amygdala, these two lesions frequently occurred together in the same neurons of the amygdala. These findings are in contrast to other sites that accumulate LBs and NFTs, but rarely both lesions in the same neuron. Thus, amygdala neurons may be selectively vulnerable to developing both LBs and NFTs, and these inclusions may play a role in the massive degeneration of these neurons in AD and LB disorders of the elderly. Received: 6 September 1995 / Revised, accepted: 30 October 1995