RESUMEN
AIM: Granulovacuolar degeneration (GVD) in Alzheimer's disease (AD) involves the necrosome, which is a protein complex consisting of phosphorylated receptor-interacting protein kinase 1 (pRIPK1), pRIPK3 and phosphorylated mixed lineage kinase domain-like protein (pMLKL). Necrosome-positive GVD was associated with neuron loss in AD. GVD was recently linked to the C9ORF72 mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with transactive response DNA-binding protein (TDP-43) pathology (FTLD-TDP). Therefore, we investigated whether GVD in cases of the ALS-FTLD-TDP spectrum (ALS/FTLD) shows a similar involvement of the necrosome as in AD, and whether it correlates with diagnosis, presence of protein aggregates and cell death in ALS/FTLD. METHODS: We analysed the presence and distribution of the necrosome in post-mortem brain and spinal cord of ALS and FTLD-TDP patients (n = 30) with and without the C9ORF72 mutation, and controls (n = 22). We investigated the association of the necrosome with diagnosis, the presence of pathological protein aggregates and neuronal loss. RESULTS: Necrosome-positive GVD was primarily observed in hippocampal regions of ALS/FTLD cases and was associated with hippocampal TDP-43 inclusions as the main predictor of the pMLKL-GVD stage, as well as with the Braak stage of neurofibrillary tangle pathology. The central cortex and spinal cord, showing motor neuron loss in ALS, were devoid of any accumulation of pRIPK1, pRIPK3 or pMLKL. CONCLUSIONS: Our findings suggest a role for hippocampal TDP-43 pathology as a contributor to necrosome-positive GVD in ALS/FTLD. The absence of necroptosis-related proteins in motor neurons in ALS argues against a role for necroptosis in ALS-related motor neuron death.
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Demencia Frontotemporal/patología , Hipocampo/patología , Necroptosis/fisiología , Degeneración Nerviosa/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Médula Espinal/patologíaRESUMEN
OBJECTIVE: 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. METHODS: 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. RESULTS: 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% (ß-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. CONCLUSIONS: 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.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/enzimología , Quitinasas/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Daño del ADN/fisiología , Demencia/líquido cefalorraquídeo , Demencia/diagnóstico , Demencia/enzimología , Diagnóstico Diferencial , Femenino , Hexosaminidasas/líquido cefalorraquídeo , Humanos , Masculino , Persona de Mediana Edad , Factor 1 de Elongación Peptídica/líquido cefalorraquídeo , Estatmina/líquido cefalorraquídeo , Telómero/fisiologíaRESUMEN
Cerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid-ß protein (Aß) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Aß refers to Aß depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aß depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Aß(40) and Aß(42) in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Aß precursor protein show parenchymal Aß and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Aß enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Aß, respectively. We suggest that pericapillary Aß represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Aß. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated.
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Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Péptidos beta-Amiloides/metabolismo , Animales , Capilares/patología , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/patología , Infarto Cerebral/patología , Demencia/etiología , Demencia/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Siderosis/complicaciones , Siderosis/patologíaAsunto(s)
CADASIL/complicaciones , Enfermedad de Parkinson Secundaria/complicaciones , Sustancia Negra/metabolismo , CADASIL/patología , Cuerpo Estriado/patología , Dopamina/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson Secundaria/patología , Piel/patología , Piel/ultraestructura , Sustancia Negra/patologíaRESUMEN
We here describe the case of a boy with an atypical teratoid-rhabdoid tumor (ATRT) of the 4th ventricle at 1 year of age and a local tumor recurrence at 19 months of age. Due to brainstem infiltration, only incomplete tumor resection was possible each time. High-dose chemotherapy, stem cell transplantation and irradiation resulted in complete tumor remission on a control MRI. At 8 years of age, another tumor appeared extending from the cerebellopontine angle along the right trigeminal nerve through Meckel's cave into the cavernous sinus. The trigeminal tumor was not in continuity with the primary ATRT but was located within the field of prior irradiation, neuroradiologically mimicking a schwannoma or a meningioma. The origin of the trigeminal tumor as a late metastasis of the former ATRT or as a less likely irradiation-induced secondary ATRT and the operative approach are discussed.
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Neoplasias Encefálicas/diagnóstico , Neoplasias de los Nervios Craneales/diagnóstico , Tumor Rabdoide/diagnóstico , Teratoma/diagnóstico , Enfermedades del Nervio Trigémino/diagnóstico , Neoplasias Encefálicas/terapia , Quimioterapia Adyuvante , Niño , Neoplasias de los Nervios Craneales/cirugía , Cuarto Ventrículo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/terapia , Tumor Rabdoide/terapia , Trasplante de Células Madre , Teratoma/terapia , Enfermedades del Nervio Trigémino/cirugíaRESUMEN
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.
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Enfermedad de Alzheimer/complicaciones , Encéfalo/patología , Cuerpos de Inclusión/patología , Enfermedades Neurodegenerativas/complicaciones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/patología , Ovillos Neurofibrilares/patologíaRESUMEN
AIMS: To study the immunohistochemical and histological features of 158 gastrointestinal stromal tumours (GISTs), consisting of 137 tumours with mutations in c-kit and platelet-derived growth factor receptor-alpha (PDGFRalpha) genes and 21 wt-GISTs. Additionally, we evaluated the localization of PDGFRalpha in the normal intestine. PDGFRalpha gene mutations were recently described in a subset of GISTs and it has been hypothesized that PDGFRalpha-mutated tumours represent a distinctive entity among GISTs. RESULTS: PDGFRalpha was expressed in ganglion bodies of the myenteric plexus and in Schwann cells but not in interstitial cells of Cajal. In contrast to other GISTs, tumours with PDGFRalpha mutations had an epithelioid phenotype and multinuclear giant cells. Kit was down-regulated in PDGFRalpha-mutated GISTs and PDGFRalpha expression was decreased in c-kit mutated tumours. Dot-like staining of Kit and PDGFRalpha was associated very frequently with mutation within the respective gene. CONCLUSIONS: Features of PDGFRalpha-mutated GISTs are multinuclear giant cells and dot-like staining for PDGFRalpha. In contrast, c-kit-mutated GISTs display a spindle cell phenotype and Kit-dots on immunohistochemistry. Our findings not only help to distinguish distinctive entities of GISTs using histological and immunhistochemical features, but also indicate that Kit and PDGFRalpha are differentially regulated in a subset of GISTs.
Asunto(s)
Tumores del Estroma Gastrointestinal/patología , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Anciano , Western Blotting , Análisis Mutacional de ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Femenino , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
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.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Anciano , Enfermedad de Alzheimer/fisiopatología , Autopsia , Humanos , Ovillos Neurofibrilares/patología , Placa Amiloide/patologíaRESUMEN
A common polymorphism of the gene encoding acyl-coenzyme A: cholesterol acyltransferase 1 (SOAT1), which is involved in the regulation of beta-amyloid peptide generation, is associated with low brain amyloid load (P=0.03) and with low cerebrospinal fluid levels of cholesterol (P=0.005). This polymorphism of SOAT1 is also associated with reduced risk for Alzheimer's disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4-0.8).
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/enzimología , Colesterol/líquido cefalorraquídeo , Esterol O-Aciltransferasa/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
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.
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Proteínas Relacionadas con Receptor de LDL/genética , Polimorfismo Genético , Tauopatías/genética , alfa-Macroglobulinas/genética , Anciano , Anciano de 80 o más Años , Alelos , Apolipoproteína E2 , Apolipoproteínas E/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Tinción con Nitrato de PlataRESUMEN
The formation of amyloid plaques is a hallmark of Alzheimer's disease (AD). Amyloid plaques and vascular amyloid deposits in cerebral amyloid angiopathy (CAA) consist of the beta-amyloid protein (Abeta) in association with other proteins. These Abeta-deposits can be visualized by thioflavin S, Congo red staining, silver staining methods and immunohistochemistry. Senile plaques also have been shown to exhibit blue autofluorescence. Here we report that UV light-induced autofluorescence is restricted to full-length Abeta-containing amyloid plaques and is also seen in blood vessels affected by CAA. Different types of samples from AD and control cortices were examined: native samples, formalin-fixed paraffin and polyethylene glycol-embedded tissue sections. These samples were viewed with a fluorescence microscope under UV light excitation (360 - 370 nm). By emitting blue fluorescence (>420 nm), amyloid plaques and blood vessels affected by CAA were detected in AD and CAA samples. Combination with immunofluorescence against anti-Abeta1-42, anti-Abeta17-24, and anti-Abeta8-17 demonstrated co-localization of the autofluorescent deposits with full-length Abeta containing Abeta-deposits. N-terminal truncated Abeta-deposits, such as the fleecy amyloid, do not exhibit autofluorescence. In doing so, Abeta-autofluorescence is a suitable method for screening native tissue samples for full-length Abeta-deposits. In contradistinction to conventional and immunohistochemical procedures, detection of plaques and CAA by autofluorescence enables the recognition of full-length Abeta-deposits in the human brain without any chemical interaction whatsoever on the part of Abeta.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Rayos Ultravioleta , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Encéfalo/patología , Fluorescencia , Técnica del Anticuerpo Fluorescente , Humanos , Placa Amiloide/metabolismo , Placa Amiloide/patologíaRESUMEN
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.
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Enfermedad de Alzheimer/patología , Sistema Nervioso Autónomo/patología , Tronco Encefálico/patología , Citoesqueleto/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales , Sistema Nervioso Autónomo/metabolismo , Tronco Encefálico/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Citoesqueleto/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/patología , Ovillos Neurofibrilares/patología , Puente/patología , Formación Reticular/metabolismo , Formación Reticular/patología , Fijación del TejidoRESUMEN
OBJECTIVE: To assess the impact of apolipoprotein E (APOE) polymorphism on AD-related neurofibrillary tangle (NFT) formation and senile plaques (SP). METHODS: 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. RESULTS: 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). CONCLUSION: 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.
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Factores de Edad , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Factores Sexuales , Anciano , Alelos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Giant cell arteritis (GCA) is a disease chiefly found in elderly patients. Intracranial vessels are rarely involved in GCA. Here we report the case of a 19-year-old woman with GCA in the basilar and vertebral arteries. Two weeks after the first symptoms, she developed an aneurysmatical dilatation of the right vertebral artery which ruptured leading to subarachnoid hemorrhage. Although the ruptured right vertebral artery was clipped neurosurgically, she died two days later. Autopsy revealed GCA with focal medial necrosis and intimal thickening of the vertebral arteries and the basilar artery. No other arteries were affected. In the involved vessels, the media exhibited C1q immunoreactivity. At the intimal site of the internal elastic lamina there were increased levels of elastase. Other arterial diseases showing the pattern of GCA were excluded. This case demonstrates that GCA is not necessarily restricted to elderly people. Moreover, this case shows that a GCA-induced aneurysm is a very rare reason for subarachnoid hemorrhage even in young adults.
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Aneurisma Roto/patología , Arteritis de Células Gigantes/patología , Arteria Vertebral/patología , Insuficiencia Vertebrobasilar/patología , Adulto , Arteria Basilar/patología , Tronco Encefálico/patología , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Complicaciones Posoperatorias/patología , Hemorragia Subaracnoidea/patologíaRESUMEN
Three studies, designed to examine use of word order and animacy for interpretation of sentences by 21 typically-developing two-year-old, 23 typically-developing two-and-one-half-year-old, 16 typically-developing three-year-old, 17 language-delayed two-and-one-half-year-old and 19 language-delayed three-year-old children were carried out. Results indicated that typically-developing two-year olds used neither cue consistently to interpret sentences. Typically-developing two-and-one-half-year olds, on the other hand used a coalition of word order and animacy cues and language-delayed two-and-one-half-year olds used neither cue. At three years of age both groups of children used word order exclusively to interpret sentences.
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Lenguaje Infantil , Cognición , Lenguaje , Conducta Verbal , Aprendizaje Verbal , Preescolar , Femenino , Estudios de Seguimiento , Humanos , MasculinoRESUMEN
The cross-sectional analyses currently available show that the Alzheimer's disease (AD)-related cytoskeletal alterations within the human brain affect variously susceptible areas of the cerebral cortex in a uniform sequence with very little interpatient variability. This sequence has been divided for research and comparative purposes into six stages (cortical NFT/NT-stages I-VI). Among the subcortical nuclei affected in AD are those belonging to the raphe system. Efforts were focused on the lesions present in these nuclei to see in which of the six stages the AD-related cytoskeletal anomalies begin and whether a correlation exists between the AD-related pathology developing within the cerebral cortex and the cytoskeletal damage that occurs in the nuclei of the raphe system. To this end, serial sections from the brainstems of 27 post-mortem cases with stages I-VI of cortical cytoskeletal lesions were examined. The cytoskeletal pathology was visualized using the modified silver iodide-Gallyas staining technique and the antibody AT8. The latter is directed specifically against the abnormally phosphorylated cytoskeletal protein tau. The dorsal raphe nucleus manifests the cytoskeletal lesions early on (stages I-II). The central and linear raphe nuclei, by contrast, do so initially in stages III-IV, and the caudal raphe nuclei register the first changes in stages V-VI. In stages V and VI, the dorsal raphe nucleus displays the most severe cytoskeletal pathology within the raphe system, followed by the central and linear raphe nuclei, whereas the cytoskeletal anomalies in the caudal raphe nuclei are slight. The developing damage within the nuclei of the raphe system correlates with the stages I-VI and, furthermore, progresses in the oral raphe nuclei in close connection with the evolution of the pathological process in cortical projection destinations of these nuclei. As the source of the ascending serotonergic system, the involvement of the oral raphe nuclei may be partially responsible for the early manifestation of the non-cognitive and emotional deficiencies possibly traceable to dysfunctions within the ascending serotonergic system.
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Enfermedad de Alzheimer/patología , Citoesqueleto/patología , Núcleos del Rafe/patología , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales , Corteza Cerebral/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Ovillos Neurofibrilares/patología , Neurópilo/patologíaRESUMEN
The deposition of the amyloid beta-protein (Abeta) is a pathological hallmark of Alzheimer's disease (AD). Abeta is a peptide consisting of 39-43 amino acids and is derived by beta- and gamma-secretase cleavage from the Abeta protein precursor (AbetaPP). An N-terminal-truncated form of Abeta can occur following alpha- and gamma-secretase cleavage of AbetaPP. Fleecy amyloid is a recently identified distinct type of Abeta deposits occurring in the internal layers (pri-alpha, pri-beta and pri-gamma) of the human entorhinal cortex. Fleecy amyloid consists exclusively of N-terminal-truncated Abeta and is a transient form of Abeta deposits, which disappears in late-stage beta-amyloidosis. In this study, the entorhinal cortex of 15 cases with AD-related pathology was used to examine astrocytes in the vicinity of N-terminal-truncated Abeta in fleecy amyloid of the layers pri-alpha, pri-beta, and pri-gamma in comparison to astrocytes in the vicinity of full-length Abeta in layers pre-beta and pre-gamma. Immunohistochemistry was performed with antibodies directed against AbetaPP, Abeta40, Abeta42, APbeta17-24, Abeta1-17 and Abeta8-17 as well as by double-labeling with antibodies directed against Abeta17-24, Abeta42, and glial fibrillary acid protein (GFAP). A large number of GFAP-positive astrocytes containing N-terminal-truncated Abeta fragments appeared in the vicinity of N-terminal-truncated Abeta, whereas Abeta-containing astrocytes were rarely seen in the vicinity of full-length Abeta. These results suggest that N-terminal-truncated Abeta peptide may be cleared preferentially from the extracellular space by astrocytic uptake and processing. Such an astroglial uptake of N-terminal-truncated Abeta may account for the transient nature of fleecy amyloid and point to the use of N-terminal truncation of Abeta in potential therapeutic strategies aimed at preventing the brain from amassing full-length Abeta deposits.
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Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Corteza Entorrinal/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Estructura Terciaria de Proteína/fisiologíaRESUMEN
The validity of the Fundación MacArthur Inventario del Desarrollo de Habilidades Comunicativas: Palabras y Enunciados (IDHC:PE) was examined with twenty 20- and nineteen 28-month-old, typically developing, monolingual, Spanish-speaking children living in Mexico. One measure of vocabulary (number of words) and two measures of grammar (mean of the three longest utterances and grammatical complexity score) from the IDHC:PE were compared to behavioral measures of vocabulary (number of different words from a language sample and number of objects named in a confrontation naming task) and one behavioral measure of grammar (mean length of utterance from a language sample). Only vocabulary measures were assessed in the 20-month-olds because of floor effects on the grammar measures. Results indicated validity for assessing expressive vocabulary in 20-month-olds and expressive vocabulary and grammar in 28-month-olds.