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ABSTRACT: Cerebral deposits of amyloid-β peptides (Aβ) form the neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In the brain, Aβ can aggregate as insoluble fibrils present in amyloid plaques and vascular amyloid, or as diffuse plaques consisting of mainly non-fibrillar Aβ. Previously, magnetic resonance imaging (MRI) has been shown to be capable of detecting individual amyloid plaques, not only via the associated iron, but also Aβ itself has been suggested to be responsible for a decrease in the image intensity. In this current study we aim to investigate the MRI properties of the different cerebral Aβ deposits including diffuse plaques and vascular amyloid. Postmortem 60-μm-thick brain sections of AD, CAA, and Down's syndrome patients, known to contain Aβ, were studied. High resolution T2*- and T2-weighted MRI scans and quantitative relaxation maps were acquired using a microcoil on a Bruker 9.4T MRI system. Specific MRI characteristics of each type of Aβ deposit were examined by co-registration of the MRI with Congo Red and Aβ-immunostainings of the same sections. Our results show that only fibrillar Aβ, present in both vascular and parenchymal amyloid, induced a significant change in T2* and T2 values. However, signal changes were not as consistent for all of the vessels affected by CAA, irrespective of possible dyshoric changes. In contrast, the non-fibrillar diffuse plaques did not create any detectable MRI signal changes. These findings are relevant for the interpretation and further development of (quantitative) MRI methods for the detection and follow-up of AD and CAA.
Journal of Alzheimer's disease: JAD 01/2013; · 3.74 Impact Factor
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ABSTRACT: Epidemiological studies indicate that the incidence of Alzheimer's disease (AD) is higher in women than in men. There is evidence that changes in metabolites in the brain associated with the development of AD are present earlier than structural brain changes. The effect of sex on the metabolic profile during the development of AD has not yet been studied. In this study we longitudinally monitored and compared in vivo metabolic changes in male and female AβPPswe, PSEN1dE9 transgenic mice brains using magnetic resonance spectroscopy. Our results show a lower level of glutamate as well as of N-acetylaspartate (NAA) in transgenic mice. The decline in NAA with age was more apparent in female mice. The level of taurine was higher in female mice and showed a faster decline over time. In conclusion, our study is the first to suggest that changes in the metabolic profile during AD development are influenced by sex.
Journal of Alzheimer's disease: JAD 01/2013; · 3.74 Impact Factor
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Jannik Fonager,
Erica M Pasini,
Joanna A M Braks,
Onny Klop,
Jai Ramesar,
Edmond J Remarque,
Irene O C M Vroegrijk, Sjoerd G van Duinen,
Alan W Thomas,
Shahid M Khan,
Matthias Mann,
Clemens H M Kocken,
Chris J Janse,
Blandine M D Franke-Fayard
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ABSTRACT: Adherence of parasite-infected red blood cells (irbc) to the vascular endothelium of organs plays a key role in the pathogenesis of Plasmodium falciparum malaria. The prevailing hypothesis of why irbc adhere and sequester in tissues is that this acts as a mechanism of avoiding spleen-mediated clearance. Irbc of the rodent parasite Plasmodium berghei ANKA sequester in a fashion analogous to P. falciparum by adhering to the host receptor CD36. To experimentally determine the significance of sequestration for parasite growth, we generated a mutant P. berghei ANKA parasite with a reduced CD36-mediated adherence. Although the cognate parasite ligand binding to CD36 is unknown, we show that nonsequestering parasites have reduced growth and we provide evidence that in addition to avoiding spleen removal, other factors related to CD36-mediated sequestration are beneficial for parasite growth. These results reveal for the first time the importance of sequestration to a malaria infection, with implications for the development of strategies aimed at reducing pathology by inhibiting tissue sequestration.
Journal of Experimental Medicine 12/2011; 209(1):93-107. · 13.85 Impact Factor
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ABSTRACT: For the interpretation of magnetic resonance imaging (MRI) abnormalities in brain pathology, often ex vivo tissue is used. The purpose of this study was to determine the pathological substrate of several distinct forms of MR hypointensities that were found in formalin-fixed brain tissue with amyloid-beta deposits. Samples of brain cortex were scanned using effective transverse relaxation time-weighted protocols at several resolutions on a 9.4 T MRI scanner. High resolution MRI showed large coarse hypointensities throughout the cortical gray and white matter, corresponding to macroscopic discolorations and microscopic circumscribed areas of granular basophilic neuropil changes, without any further specific tissue reactions or amyloid-beta related pathology. These coarse MRI hypointensities were identified as localized areas of absent neuropil replaced by membrane/myelin sheath remnants using electron microscopy. Interestingly, the presence/absence of these tissue alterations was not related to amyloid deposits, but strongly correlated to the fixation time of the samples in unrefreshed formalin. These findings show that prolonged storaged of formalin fixed brain tissue results in subtle histology artifacts, which show on MRI as hypointensities that on first appearance are indistinguishable from genuine brain pathology. This indicates that postmortem MRI should be interpreted with caution, especially if the history of tissue preservation is not fully known.
Magnetic Resonance in Medicine 02/2011; 65(6):1750-8. · 2.96 Impact Factor
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ABSTRACT: A simple inductively coupled microcoil has been designed to image tissue samples placed on a microscope slide, samples which can subsequently be stained histologically. As the exact same tissue is used for MRI and histology, the two data sets can be compared without the need for complicated image registration techniques. The design can be integrated into any MRI system using existing commercial hardware. Compared with a commercial 25-mm-diameter birdcage, the signal-to-noise ratio was increased by a factor of 3.8, corresponding to an approximate 15-fold reduction in the data acquisition time. An example is shown of ex vivo samples from patients with Alzheimer's disease, in which the coregistration of highly sensitive iron staining and amyloid-β deposits is confirmed. Copyright © 2010 John Wiley & Sons, Ltd.
NMR in Biomedicine 10/2010; 24(4):351-7. · 3.21 Impact Factor
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ABSTRACT: Muscle-specific tyrosine kinase (MuSK) is essential for clustering of acetylcholine receptors (AChRs) at embryogenesis and likely also important for maintaining synaptic structure in adult muscle. In 5 to 7% of myasthenia gravis (MG) cases, the patients' blood contains antibodies to MuSK. To investigate the effect of MuSK-MG antibody on synapse regeneration, notexin was used to induce damage to the flexor digitorum brevis muscle. We administered aliquots of MuSK-MG patients' plasma to the flexor digitorum brevis twice daily for a period up to 21 days, and muscles were investigated ex vivo in contraction experiments. AChR levels were measured with (125)I-alpha-bungarotoxin, and endplates were studied with quantitative immunohistochemistry. In normal muscles and in 14-day regenerated muscles, MuSK plasma caused impairment of nerve stimulus-induced contraction in the presence of 0.35 and 0.5 mmol/L Ca(2+) with or without 100 to 400 nmol/L tubocurarine. Endplate size was decreased in regenerated muscles relative to controls; however, we did not observe such differences in muscle not treated with notexin. MuSK plasma had no effect on the amount and turnover rate of AChRs. Our results suggest that anti-MuSK antibodies influence the activity of MuSK molecules without reducing their number, thereby diminishing the size of the endplate and affecting the functioning of AChRs.
American Journal Of Pathology 10/2009; 175(4):1536-44. · 4.89 Impact Factor
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ABSTRACT: To explore the ability of whole-body 7.0-T magnetic resonance (MR) imaging to depict differences in aspects of the cerebral cortex of postmortem human brain specimens with cerebral amyloid beta deposition in connection with Alzheimer disease (AD), Down syndrome, or sporadic or hereditary cerebral amyloid angiopathy (CAA) and control brain specimens lacking such deposition.
This study was approved by the local institutional review board. In all cases, informed consent was obtained to perform autopsy and to use the tissues for research purposes. T2- and T2*-weighted MR imaging was performed in formalin-fixed samples of brain tissue from six subjects with AD changes, seven with CAA, and five subjects without immunohistochemical evidence of cerebral amyloid beta deposition. All MR images were visually assessed for hypointense foci in and inhomogeneity of the cortex. Sensitivity, specificity, and kappa values of these MR imaging features in the detection of histologic changes were calculated.
High-spatial-resolution 0.3 x 0.3 x 0.3-mm three-dimensional T2*-weighted images revealed hypointense foci, inhomogeneity of the cortex, or both in all specimens with brain amyloid beta deposition. These MR imaging features were observed in none of the control specimens.
The finding of postmortem susceptibility-weighted changes in the cerebral cortex of patients with cerebral amyloidosis with a human 7.0-T MR imaging system opens up the possibility of obtaining in vivo radiologic evidence of cerebral amyloid beta deposition.
Radiology 09/2009; 253(3):788-96. · 5.73 Impact Factor
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Acta Neuropathologica 04/2008; 115(3):369-70. · 9.32 Impact Factor
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Brain 02/2008; 131(Pt 1):e88. · 9.46 Impact Factor
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ABSTRACT: The hypothalamic hypocretin (orexin) system plays a central role in the regulation of various functions, including sleep/wake regulation and metabolism. There is a growing interest in hypocretin function in Parkinson's disease (PD), given the high prevalence of non-motor symptoms such as sleep disturbances in this disorder. However, studies measuring CSF hypocretin levels have yielded contradictory results. In PD patients and matched controls, we (i) estimated the number of hypocretin neurons in post-mortem hypothalami using immunocytochemistry and an image analysis system (ii) quantified hypocretin levels in post-mortem ventricular CSF and (iii) prefrontal cortex using a radioimmunoassay. Furthermore, presence of Lewy bodies was verified in the hypothalamic hypocretin cell area. Data are presented as median (25th-75th percentile). We showed a significant decrease between PD patients and controls in (i) the number of hypocretin neurons (PD: 20 276 (13 821-31 229); controls: 36 842 (32 546-50 938); P = 0.016); (ii) the hypocretin-1 concentration in post-mortem ventricular CSF (PD: 365.5 pg/ml (328.0-448.3); controls: 483.5 (433.5-512.3); P = 0.012) and (iii) the hypocretin-1 concentrations in prefrontal cortex (PD: 389.6 pg/g (249.2-652.2); controls: 676.6 (467.5-883.9); P = 0.043). Hypocretin neurotransmission is affected in PD. The hypocretin-1 concentration in the prefrontal cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% reduced. The total number of hypocretin neurons was almost half compared to controls.
Brain 07/2007; 130(Pt 6):1577-85. · 9.46 Impact Factor
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ABSTRACT: Ewing sarcoma/peripheral primitive neuro-ectodermal tumor (PNET) is a round-cell sarcoma that may show varying degrees of neuro-ectodermal differentiation. These tumors are identified by a characteristic round-cell morphology and immunohistochemical profile, as well as by specific translocations involving the EWS gene on chromosome 22 and the 3' portion of the E26 transformation-specific family of transcription factors. These translocations result in fusion proteins that act as aberrant transcription factors. The majority of Ewing sarcoma cases are characterized by a balanced t(11;22). Specific chromosomal abnormalities often correlate with distinct morphologic or phenotypic subtypes of tumors and play an important role in prognosis. Here we describe the molecular cytogenetic investigation of a case of Ewing sarcoma in the proximal humerus of a 39-year-old male using COBRA (combined binary ratio labelling) fluorescent in situ hybridization karyotyping, array comparative genomic hybridization, and EWS-gene specific fluorescence in situ hybridization. Multiple chromosomal aberrations were identified, including a der(22)r(20;22), resulting in an amplification of the proximal region of the EWS gene. This is the first time that both translocation and amplification involving the EWS gene and an unidentified gene are described. This case adds to the spectrum of both morphology and genetic rearrangements in Ewing sarcoma, and shows the importance of combined molecular cytogenetic approaches in identifying uncommon rearrangements in sarcomas.
Cancer Genetics and Cytogenetics 02/2007; 172(1):12-22. · 1.39 Impact Factor
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ABSTRACT: To assess the development of beta-amyloid (Abeta) plaques in the brain with age in the transgenic mouse model of Alzheimer's disease (AD) pathology by in vivo magnetic resonance microimaging (microMRI).
Live transgenic mice (Tg2576) and nontransgenic littermates (control) were studied at regular intervals between the ages of 12 and 18 months. Plaques were visualized using a T(2)-weighted rapid acquisition with relaxation enhancement (RARE) sequence. Changes in T(2) relaxation times were followed using a multislice multiecho (MSME) sequence. Plaque load and numerical density in MR images were calculated using SCIL image software.
Abeta plaques were clearly detected with the T(2)-weighted RARE sequence in the hippocampal and cortical regions of the brain of Tg2576 mice but not in control mice. Following the plaque development in the same animals with age showed that plaque area, number, and size increased markedly, while T(2) relaxation time showed a decreasing trend with age.
These results demonstrate that microMRI is a viable method for following the development of Abeta plaques in vivo, and suggest that this method may be feasible for assessing the effect of therapeutic interventions over time in the same animals.
Journal of Magnetic Resonance Imaging 10/2006; 24(3):530-6. · 2.70 Impact Factor
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ABSTRACT: Parvovirus B19 infection in gestation has been associated with severe fetal complications such as anaemia, hydrops and fetal demise. Fetal infection in the first trimester poses the greatest risk for these complications, but infection during the third trimester is more common than previously appreciated and can be associated with severe complications, i.e. fetal death, in the absence of hydrops or classical clinical symptoms. Parvovirus B19 infection has been associated with vasculitis and pathological changes in the central nervous system, which may cause stroke. We report a newborn infant with a rare combination of a recent central nervous system infection with parvovirus B19 and a factor V Leiden mutation, who developed fetal stroke. Conclusion: Factor V Leiden mutation leads to activated protein C resistance and increases the risk of thromboembolism. Thromboembolism occurs rarely in newborns with activated protein C resistance, but can be precipitated by dehydration, asphyxia and infection. Although parvovirus B19 infection of the central nervous system may be a precipitant in neonatal and/or fetal stroke, it can also cause stroke independent of a thrombophilic mutation. In this case, both causative factors may have coincided.
Acta Paediatrica 08/2006; 95(7):863-7. · 2.07 Impact Factor
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ABSTRACT: Most human patients with narcolepsy have no detectable hypocretin-1 in their cerebrospinal fluid. The cause of this hypocretin deficiency is unknown, but the prevailing hypothesis states that an autoimmune-mediated mechanism is responsible. We screened for the presence of autoantibodies against neurons in the lateral hypothalamus in 76 patients and 63 controls, using immunohistochemistry. Autoantibodies were present in two patients, but also in two controls. However, one of the patients had a clearly different staining pattern and nerve endings of immunolabeled cells were found to project onto hypocretin-producing neurons, suggesting a possible pathophysiological role. Humoral immune mechanisms appear not to play a role in the pathogenesis of narcolepsy, at least not in the clinically overt stage of the disease.
Journal of Neuroimmunology 06/2006; 174(1-2):187-91. · 2.96 Impact Factor
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ABSTRACT: We review the clinical, radiologic, and neuropathologic features of the hereditary and sporadic forms of cerebral amyloid angiopathy (CAA) associated with vascular deposition of the beta-amyloid peptide. Amino acid substitutions at 4 sites in the beta-amyloid precursor protein, all situated within the beta-amyloid peptide sequence itself, have been shown to cause heritable forms of CAA. The vascular diseases caused by these mutations are associated primarily with cerebral hemorrhages, white matter lesions, and cognitive impairment, and only variable extents of the plaque and neurofibrillary pathologies characteristic of Alzheimer disease. Sporadic CAA typically presents 20 or more years later than hereditary CAA, but is otherwise characterized by a comparable constellation of recurrent cerebral hemorrhages, white matter lesions, and cognitive impairment. The clinical, radiologic and pathologic similarities between hereditary and sporadic CAA suggest that important lessons for this common age-related process can be learned from the mechanisms by which mutation makes beta-amyloid tropic or toxic to vessels.
Brain Pathology 02/2006; 16(1):30-9. · 3.99 Impact Factor
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Umesh A Badrising,
Marion L C Maat-Schieman,
Johannes C van Houwelingen,
Peter A van Doorn, Sjoerd G van Duinen,
Baziel G M van Engelen,
Carin G Faber,
Jessica E Hoogendijk,
Aeiko E de Jager,
Peter J Koehler,
Marianne de Visser,
Jan J G M Verschuuren,
Axel R Wintzen
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ABSTRACT: The clinical features of inclusion body myositis (IBM) were of minor importance in the design of consensus diagnostic criteria, mainly because of controversial views on the specificity of signs and symptoms, although some authors reported "typical" signs. To re-assess the clinical spectrum of IBM, a single investigator using a standard protocol studied a cohort of 64 patients cross-sectionally. Symptom onset was before the age of 50 years in 20% of cases. Only a few patients (14 %) started with weakness other than that of quadriceps, finger flexor or pharyngeal muscles. The sequence of power loss was erratic, but onset of symptoms with quadriceps weakness predicted an earlier onset of dysphagia in older patients (> or = 56 years) compared with younger ones (< 56 years) (p = 0.02). Despite widespread weakness patients had favourable scores on three commonly used function scales and they kept their employment. Complete wheel-chair dependency was rare (3 %). A dominant characteristic was the anatomical distribution of afflicted muscles: ventral extremity muscle groups were more affected than dorsal muscle groups and girdle muscles were least affected, the latter preserving postural stability. Ankylosis, especially in extension of the fingers,was frequently present. Together with the sparing of intrinsic hand muscles it was helpful in the preservation of many skillful movements. IBM has a unique distribution of muscle weakness. Ankylotic contractures are common. We feel that their joint impact on daily functioning is characteristic for the disease.
Journal of Neurology 01/2006; 252(12):1448-54. · 3.47 Impact Factor
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Blandine Franke-Fayard,
Chris J Janse,
Margarida Cunha-Rodrigues,
Jai Ramesar,
Philippe Büscher,
Ivo Que,
Clemens Löwik,
Peter J Voshol,
Marion A M den Boer, Sjoerd G van Duinen,
Maria Febbraio,
Maria M Mota,
Andrew P Waters
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ABSTRACT: Sequestration of malaria-parasite-infected erythrocytes in the microvasculature of organs is thought to be a significant cause of pathology. Cerebral malaria (CM) is a major complication of Plasmodium falciparum infections, and PfEMP1-mediated sequestration of infected red blood cells has been considered to be the major feature leading to CM-related pathology. We report a system for the real-time in vivo imaging of sequestration using transgenic luciferase-expressing parasites of the rodent malaria parasite Plasmodium berghei. These studies revealed that: (i) as expected, lung tissue is a major site, but, unexpectedly, adipose tissue contributes significantly to sequestration, and (ii) the class II scavenger-receptor CD36 to which PfEMP1 can bind is also the major receptor for P. berghei sequestration, indicating a role for alternative parasite ligands, because orthologues of PfEMP1 are absent from rodent malaria parasites, and, importantly, (iii) cerebral complications still develop in the absence of CD36-mediated sequestration, dissociating parasite sequestration from CM-associated pathology. Real-time in vivo imaging of parasitic processes may be used to evaluate the molecular basis of pathology and develop strategies to prevent pathology.
Proceedings of the National Academy of Sciences 09/2005; 102(32):11468-73. · 9.68 Impact Factor
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ABSTRACT: To evaluate the efficacy of radiotherapy in patients with glioblastoma multiforme (GBM) with a limited prognosis and in patients older than 70 years.
Retrospective analysis of 202 patients with GBM treated between 1990 and 2000 in a single institution. Patients (including patients >or=70 years) were assigned to RPA groups and their survival was compared with RTOG data.
Median survival was 8.0 months for the total group and 13.9, 10.6, 3.8, 2.1 months for RPA group III (n=17), IV (n=87), V (n=60) and VI (n=38), respectively. Median survival for patients >or=70 years was 3.6 vs. 8.1 months for 50--70 years and 11.0 months for <50. In each separate RPA group, patients >or=70 years had a similar survival compared to patients of 50--70 years. Irradiated patients (66%) survived significantly longer than non-irradiated patients: 10.6 vs. 1.9 months (P<0.0001). In RPA group V the median survival for irradiated patients was 9.4 vs. 2.1 months for non-irradiated patients. In a multivariate analysis, RT remained the only prognostic factor for survival (HR 8.9, P<0.001).
Prognosis for patients above 70 years of age is not different from younger patients, when analyzed for separate RPA groups. For patients with a poor prognosis (i.e. RPA group V), radiotherapy improves survival significantly.
Radiotherapy and Oncology 05/2005; 75(2):210-6. · 5.58 Impact Factor
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Martin C Herzig,
David T Winkler,
Patrick Burgermeister,
Michelle Pfeifer,
Esther Kohler,
Stephen D Schmidt,
Simone Danner,
Dorothee Abramowski,
Christine Stürchler-Pierrat,
Kurt Bürki, Sjoerd G van Duinen,
Marion L C Maat-Schieman,
Matthias Staufenbiel,
Paul M Mathews,
Mathias Jucker
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ABSTRACT: The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.
Nature Neuroscience 10/2004; 7(9):954-60. · 15.53 Impact Factor
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ABSTRACT: Although the amyloid beta protein (Abeta) E693Q mutation enhances Abeta fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal Abeta deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of Abeta by glial cells may play a role in this regard, this immunohistochemical study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double staining with glial markers and end-specific antibodies to Abetax-42 (Abeta42) and Abetax-40 (Abeta40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic Abeta42(+)40(-) granules were scattered among non-fibrillar (Congo red-negative) Abeta deposits, i.e., clouds, fine diffuse plaques, and Abeta42(+)40(-) dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) Abeta deposition, i.e., Abeta42(+)40(+) dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of Abeta granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal Abeta deposits may be liable to glial clearance. Abeta sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble Abeta oligomers in HCHWA-D brain.
Acta Neuropathologica 06/2004; 107(5):389-98. · 9.32 Impact Factor
