[show abstract][hide abstract] ABSTRACT: Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
Journal of Neuropathology and Experimental Neurology 04/2012; 71(5):362-81. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: DNA damage accumulation in brain is associated with the development of Alzheimer disease (AD), but newly identified protein markers of DNA damage have not been evaluated in the diagnosis of AD and other forms of dementia.
Here, we analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N-acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia.
Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8% using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4% (β-amyloid) and 77.6% (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91%. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia.
Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.
[show abstract][hide abstract] ABSTRACT: To study whether neuronal regeneration occurs after laserinduced interstitial thermotherapy (LITT) of the brain, we examined lesions and their margins in adult Lewis rats with histological and immunohistochemical methods. We used the Bodian stain and antibodies against β-amyloid precursor protein (APP), which has been associated with trophic effects in neural regeneration and against heat-shock protein 72 (HSP 72) and neurofilament 68 (NF 68). The glial reaction was monitored with antibodies against glial fibrillary acidic protein (GFAP) and apolipoprotein E (Apo E). β-Amyloid precursor protein showed a distinct temporal profile in areas of lesion margins thought to be associated with neurite sprouting and regeneration. Axonal accumulation of APP started 1 h after LITT and reached a maximum after 3 days. Heat-shock protein 72 was weakly positive in isolated marginal neurons in the early postoperative period. Subsequent to GFAP expression, Apo E immunoreactivity was detected in reactive astrocytes but not in profiles thought to be axonal sprouts. The results showed that margins of LITT-induced lesions contain profiles which resemble sprouting neurites and are similar to those found after injury or ischemia but with differences in the time course of reactive proteins.
[show abstract][hide abstract] ABSTRACT: Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia. Tau protein-containing lesions known as argyrophilic grains and located predominantly in limbic regions of the brain characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD. The aim of this study is to determine the role of concurrent Alzheimer's disease (AD)-related pathology for the development of dementia in AGD patients. A total of 204 post-mortem brains from 30 demented and 49 nondemented AGD patients, 39 AD patients, and from 86 nondemented controls without AGD were staged for AD-related neurofibrillary tangles (NFTs) as well as amyloid beta-protein (Abeta) deposition. To identify differences in AD-related pathology between demented and nondemented AGD cases, and to differentiate the pattern of AD-related changes in demented and nondemented AGD cases from that seen in AD and nondemented controls, we statistically compared the stages of Abeta and NFT distribution among these groups. Using a logistic regression model, we showed that AGD has a significant effect on the development of dementia beyond that attributable to AD-related pathology (P < 0.005). Demented AGD cases showed lower stages of AD-related pathology than did pure AD cases but higher stages than nondemented AGD patients. AGD associated dementia was seen in the presence of NFT (Braak)-stages II-IV and Abeta-phases 2-3, whereas those stages were not associated with dementia in the absence of AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly contributes to the development of dementia by lowering the threshold for cognitive deficits in the presence of moderate amounts of AD-related pathology.
Neuropathology and Applied Neurobiology 07/2005; 31(3):270-9. · 4.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alzheimer's disease is a slowly but continuously progressive degenerative disorder of the human central nervous system seen in approximately 15% of elderly people over the age of 65 years. Morphological hallmarks of this process are intra- and extracellular protein aggregates. The intraneuronal protein aggregates are primarily made up of abnormal phosphorylated tau-protein, which builds neurofibrillary tangles, neuropil threads and dystrophic neurites in neuritic plaques. The extracellular deposits consist of amyloid beta-protein (Abeta) aggregates showing the characteristics of amyloid fibrils. The evolution of neurofibrillary changes as well as Abeta-deposition in brain regions follows a distinct hierarchical sequence spanning many decades. Abeta deposition begins in the neocortex whereas neurofibrillary pathology starts in the allocortical nerve cells of the transentorhinal region. Both transformations continue to increase in severity and expand into further areas and regions. The hierarchical pattern allows an easily understandable staging of neurofibrillary and Abeta pathology which in turn reflects the clinical gravity of the disease. According to these stages a dementing disorder can be diagnostically attributed to Alzheimer's disease.
Der Pathologe 06/2005; 26(3):201-13. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Der Morbus Alzheimer ist eine langsam, jedoch stetig und unaufhaltsam voranschreitende neurodegenerative Erkrankung des menschlichen Zentralnervensystems, die etwa 15% aller ber 65-Jhrigen betrifft. Im Verlauf der Erkrankung entstehen sowohl intraneuronale als auch extrazellulre Ablagerungen pathologisch vernderter Proteine. Die intraneuronalen Aggregate bestehen berwiegend aus abnormem tau()-Protein. Sie fhren zur Bildung von neurofibrillren Vernderungen in den Perikaryen und von Neuropilfden in Zellfortstzen betroffener Neurone. Die Entwicklung der extrazellulren Amyloid-(A)-Ablagerungen und der intraneuronalen -Aggregate vollzieht sich in langsam voranschreitenden Prozessen. Innerhalb der Hirnrinde beginnt die Ablagerung von A im Neokortex, whrend die ersten neurofibrillren Vernderungen in den allokortikalen Nervenzellen der Regio transentorhinalis zu finden sind. Von hier ausgehend expandieren beide Vernderungen in immer weitere Felder und Regionen. Diese Ausbreitung erlaubt eine Gliederung der pathologischen Vernderungen in Stadien bzw. Phasen, entsprechend dem zunehmenden Schweregrad des klinischen Bildes. Nach dieser Einteilung kann beurteilt werden, inwieweit ein demenzielles Krankheitsbild durch den Morbus Alzheimer verursacht ist.Alzheimers disease is a slowly but continuously progressive degenerative disorder of the human central nervous system seen in ~15% of elderly people over the age of 65 years. Morphological hallmarks of this process are intra- and extracellular protein aggregates. The intraneuronal protein aggregates are primarily made up of abnormal phosphorylated -protein, which builds neurofibrillary tangles, neuropil threads and dystrophic neurites in neuritic plaques. The extracellular deposits consist of amyloid -protein (A) aggregates showing the characteristics of amyloid fibrils. The evolution of neurofibrillary changes as well as A-deposition in brain regions follows a distinct hierarchical sequence spanning many decades. A deposition begins in the neocortex whereas neurofibrillary pathology starts in the allocortical nerve cells of the transentorhinal region. Both transformations continue to increase in severity and expand into further areas and regions. The hierarchical pattern allows an easily understandable staging of neurofibrillary and A pathology which in turn reflects the clinical gravity of the disease. According to these stages a dementing disorder can be diagnostically attributed to Alzheimers disease.
Der Pathologe 01/2005; 26(3):201-213. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Different types of senile plaques occur in brains of Alzheimer’s disease (AD) patients. Senile plaques seen in early preclinical stages of AD differ from those in clinical stages both in their composition of Aβ-peptides of different lengths and other proteins, e.g., apoE. ApoE is involved in Aβ-transport and -uptake. Therefore, it is tempting to speculate that apoE plays a role in senile plaque generation. To characterize the association between apoE and Aβ-peptides of different lengths and its impact on initial Aβ-deposition, we studied the medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology as well as controls. Aβ-deposits in regions becoming newly involved in a given stage of β-amyloidosis exclusively consisted of new-formed plaques. In 36 cases, apoE was present in these new-formed plaques. Here, apoE was frequently co-localized with Aβ-deposits detectable with anti-Aβ42 but not with antibodies raised against N-terminal epitopes of Aβ. In contrast, immunoreactivity against apoE was completely absent in new-formed plaques of other cases where at the same time immunoreactivity against N-terminal epitopes of Aβ was present. The lacking co-localization of N-terminal epitopes of Aβ with apoE in new-formed plaques suggests that these deposits represent apoE-Aβ complexes in which the N-terminal epitopes of Aβ are often concealed after complexing with apoE, thus, preventing subsequent binding of antibodies.
[show abstract][hide abstract] ABSTRACT: A characteristic feature of Alzheimer's disease (AD) is the extracellular deposition of the amyloid β-protein (Aβ). Amyloid precursor protein (APP) transgenic mouse models for AD overexpress mutant APP and show Aβ plaques in the brain. Although neuronal loss has been observed in these mice at advanced stages of Aβ-plaque deposition it remains unclear if soluble forms of Aβ already lead to neurodegeneration before the onset of amyloid deposition. APP23-trangenic mice overexpressing mutant human APP and littermate controls were injected with DiI into the left frontocentral cortex. Traced commissural pyramidal neurons in layer III of the right frontocentral cortex were quantified in 5 months old mice, without Aβ deposits, and in 11 months old mice, with Aβ-plaques. To verify whether or not APP overexpression alone is responsible for changes in the neuronal network, DiI-crystals were injected into the left frontocentral cortex of APP51-transgenic mice overexpressing wild-type human APP and littermate controls at 5 and 11 months of age. These mice express the same levels of APP as APP23 mice but produce less Aβ and do not exhibit Aβ-deposits. Significant reduction of pyramidal neurons with a ramified dendritic tree was observed in APP23 compared to littermate controls at 5 months as well as at 11 months of age. No significant differences in the number of traced neurons were observed between APP51-transgenic mice and their littermate controls. Our results indicate that soluble forms of Aβ lead to neurodegeneration. This hypothesis is supported by the degeneration of ramified pyramidal cells in 5 months old APP23 mice in the absence of Aβ plaques. The overexpression of APP alone may not be responsible for this effect as demonstrated in APP51 mice.
[show abstract][hide abstract] ABSTRACT: Cerebrovascular pathology is common in Alzheimer's disease (AD) and is considered to contribute to cerebral malfunction. However, distinct antiangiogenic proteins that accumulate in AD brains have not yet been identified. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII that, when added exogenously, inhibits endothelial proliferation and migration in vitro and angiogenesis and tumor growth in vivo by inducing apoptosis in endothelial cells. We produced a monoclonal antibody directed against endostatin and observed significantly more (p < 0.0001) immunoreactive cortical neurons in AD brains compared with age-matched neuropathologically unaltered controls. High numbers of extracellular and frequently perivascular endostatin deposits were detected in the cerebral hemispheres. Double-labeling experiments revealed colocalization of endostatin in amyloid-beta(1-40) (Abeta(1-40)), tau protein, and periodic acid-Schiff stain-positive plaques that were surrounded by focal gliosis. Western blotting revealed more 20 kDa endostatin in an AD patient compared with a control. In unstimulated SKNSH supernatants, endostatin was detected that increased predominantly after hypoxia in supernatants and cellular lysates. Abeta(1-40) (80 microg/ml) supplementation to SKNSH neurons for 24 hr completely abolished the release of endostatin. These data show that endostatin is released by neurons to accumulate in amyloid plaques in Alzheimer's disease. Induction by hypoxia and complete abrogation of endostatin release after Abeta(1-40) challenge reveals intricate interactions between the two proteins and opens new avenues for the development of novel treatment strategies of AD patients.
Journal of Neuroscience 01/2003; 22(24):10621-6. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Argyrophilic grain disease (AGD) is a neurodegenerative disorder of the aged human brain associated with the formation of abnormal tau protein in specific neurones and macroglial cells. Previously, we reported the association between AGD and the epsilon2 allele of apolipoprotein E (ApoE). Here, the polymorphisms of the alpha-2 macroglobulin gene (A2M) and those of the low-density lipoprotein receptor-related protein gene (LRP) were assessed in 115 AGD cases and compared with 170 controls. The results reveal an association between AGD and the C766T polymorphism of LRP (P=0.001). In addition, the present study shows that the valine to isoleucine (Val1000Ile) polymorphism of A2M is linked with AGD (P=0.03). By comparison, no relationship between AGD and the intronic 5-bp deletion/insertion polymorphism of A2M is demonstrable (P=0.8). Finally, this report corroborates and extends our earlier finding in that the frequency of the epsilon2 allele of ApoE is higher in AGD cases than in controls (17.4% vs. 8.5%, P=0.003), whereas the epsilon4 allele frequency approximates that in control cases (13.9% vs. 13.2%, P=0.93). This association, however, is only apparent in the presence of the LRP CC genotype. In conclusion, the present study shows that AGD is associated with the LRP, A2M and ApoE genes.
Neuropathology and Applied Neurobiology 09/2002; 28(4):308-13. · 4.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: The nuclei of the pontine parabrachial region (medial parabrachial nucleus, MPB; lateral parabrachial nucleus, LPB; subpeduncular nucleus, SPP) together with the intermediate zone of the medullary reticular formation (IRZ) are pivotal relay stations within central autonomic regulatory feedback systems. This study was undertaken to investigate the evolution of the Alzheimer's disease-related cytoskeletal pathology in these four sites of the lower brain stem. We examined the MPB, LPB, SPP and IRZ in 27 autopsy cases and classified the cortical Alzheimer-related cytoskeletal anomalies according to an established staging system (neurofibrillary tangle/neuropil threads [NFT/NT] stages I-VI). The lesions were visualized either with the antibody AT8, which is immunospecific for the abnormally phosphorylated form of the cytoskeletal protein tau, or with a modified Gallyas silver iodide stain. The MPB, SPB, and IRZ display cytoskeletal pathology in stage I and the LPB in stage II, whereby bothstages correspond to the preclinical phase of Alzheimer's disease (AD). In stages III-IV (incipient AD), the MPB and SPP are severely affected. In all of the stage III-IV cases, the lesions in the LPB and IRZ are well developed. In stages V and VI (clinical phase of AD), the MPB and SPP are filled with the abnormal intraneuronal material. At stages V-VI, the LPB is moderately involved and the IRZ shows severe damage. The pathogenesis of the AD-related cytoskeletal lesions in the nuclei of the pontine parabrachial region and in the IRZ conforms with the cortical NFT/NT staging sequence I-VI. In the event that the cytoskeletal pathology observed in this study impairs the function of the nerve cells involved, it is conceivable that autonomic mechanisms progressively deteriorate with advancing cortical NFT/NT stages. This relationship remains to be established, but it could provide insights into the illusive correlation between the AD-related cytoskeletal pathology and the function of affected neurons.
[show abstract][hide abstract] ABSTRACT: To assess the impact of apolipoprotein E (APOE) polymorphism on AD-related neurofibrillary tangle (NFT) formation and senile plaques (SP).
A sample of 729 routine autopsy brains (359 men, 370 women; age range, 60 to 99 years) was investigated. All brains were classified neuropathologically according to a procedure permitting differentiation of six NFT stages and three SP stages. APOE genotyping was performed on all cases.
The epsilon4 allele of APOE was associated not only with SP (p < 0.0001) but also with NFT formation (p < 0.0001). The effect of the epsilon4 allele on NFT formation was noted at ages > or =80 years (p < 0.0001) but not between ages 60 and 79 years (p = 0.12). An association between the epsilon4 allele and SP for women was found at ages 60 to 79 years (p < 0.0001) but not at > or =80 years of age (p = 0.063). By comparison, men showed an association in both age categories (p = 0.001 and p = 0.001).
The results confirm the association between the epsilon4 allele and both types of AD-related lesions and show that this association is differentially modified by age and gender.