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Kalimo, Hannu
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Publications (10 of 43) Show all publications
Hägerstrand, D., Smits, A., Eriksson, A., Sigurdardottir, S., Olofsson, T., Hartman, M., . . . Östman, A. (2008). Gene expression analyses of grade II gliomas and identification of rPTPbeta/ as a candidate oligodendroglioma marker. Neuro-Oncology, 10(1), 2-9
Open this publication in new window or tab >>Gene expression analyses of grade II gliomas and identification of rPTPbeta/ as a candidate oligodendroglioma marker
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2008 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 10, no 1, p. 2-9Article in journal (Refereed) Published
Abstract [en]

Grade 11 gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes-astrocytomas, oligodendrogliomas, and oligoastrocytomas-constitute true biological entities is largely unresolved. Furthermore, morphological classification is often ambiguous and would be facilitated by specific subtype markers. In this study, 23 grade II gliomas were expression-profiled and subjected to hierarchical clustering. All six oligodendrogliomas were grouped together in one of two major clusters; a significant correlation was thus observed between gene expression and histopathological subtype. Supervised analyses were performed to identify genes differentiating oligodendrogliomas from other grade II tumors. In a leave-one-out test using 10 features for classification, 20 out of 23 tumors were correctly classified. Among the most differentially expressed genes was rPT beta/zeta. The expression of the rPTP beta/zeta protein in oligodendrogliomas and astrocytomas was further validated by immunohistochemistry in an independent set of tumors. All 11 oligodendrogliomas of this set displayed strong staining. In contrast, neoplastic astrocytes were mostly negative for rPTP beta/zeta staining. In summary, this study demonstrates a correlation between gene expression pattern and histological subtype in grade 11 gliomas. Furthermore, the results from the immunohistochemical analyses of rPTP beta/zeta expression should prompt further evaluation of this protein as a novel oligodendroglioma marker.

Keywords
grade II glioma, histological marker, microarray, oligodendroglioma, rPTP beta/zeta
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-15549 (URN)10.1215/15228517-2007-041 (DOI)000252971200002 ()
Available from: 2008-02-19 Created: 2008-02-19 Last updated: 2017-12-08Bibliographically approved
Qu, M., Olofsson, T., Sigurdardottir, S., You, C., Kalimo, H., Nistér, M., . . . Ren, Z.-P. (2007). Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas. Acta Neuropathologica, 113(2), 129-136
Open this publication in new window or tab >>Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas
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2007 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 113, no 2, p. 129-136Article in journal (Refereed) Published
Abstract [en]

Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.

Keywords
Oligoastrocytomas, Microdissection, LOH 1p, LOH 19q, TP53 mutation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-23628 (URN)10.1007/s00401-006-0142-0 (DOI)000243690100003 ()17031656 (PubMedID)
Available from: 2007-01-31 Created: 2007-01-31 Last updated: 2017-12-07Bibliographically approved
Low, W. C., Junna, M., Börjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., . . . Kalaria, R. N. (2007). Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL. Brain, 130(Part 2), 357-367
Open this publication in new window or tab >>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
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2007 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, no Part 2, p. 357-367Article in journal (Refereed) Published
Abstract [en]

Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.

Keywords
Adult, Brain/blood supply/ultrastructure, CADASIL/*genetics, Chromosome Mapping/methods, DNA Mutational Analysis/methods, Dementia; Multi-Infarct/*genetics/metabolism/pathology, Female, Humans, Intracranial Arteriosclerosis/genetics/pathology, Magnetic Resonance Imaging, Male, Microcirculation/metabolism, Middle Aged, Mutation, Pedigree, Polymerase Chain Reaction/methods, Receptors; Notch/*genetics/metabolism, Skin/ultrastructure
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10696 (URN)10.1093/brain/awl360 (DOI)000243810500012 ()17235124 (PubMedID)
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2017-12-11Bibliographically approved
Stenborg, A., Kalimo, H., Viitanen, M., Terént, A. & Lind, L. (2007). Impaired Endothelial Function of Forearm Resistance Arteries in CADASIL Patients. Stroke, 38(10), 2692-2697
Open this publication in new window or tab >>Impaired Endothelial Function of Forearm Resistance Arteries in CADASIL Patients
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2007 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 38, no 10, p. 2692-2697Article in journal (Refereed) Published
Abstract [en]

Background and Purpose-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy, which mainly involves the brain causing stroke and dementia. Mice expressing the mutated protein display early dysfunction in vasoreactivity in resistance arteries, but studies of patients have been inconclusive so far. Methods-We examined peripheral endothelium-dependent vasodilatation in 10 CADASIL-patients and 20 controls using 3 methods: venous occlusion plethysmography of forearm blood flow with intraarterial acetylcholine and sodium nitroprusside infusions for evaluation of resistance arteries, ultrasound with flow mediated vasodilatation (FMD) of the brachial artery for evaluation of a conduit artery, and the pulse wave method with measurements before and after terbutaline for evaluation of systemic endothelium-dependent vasodilation. Results-The CADASIL patients displayed reductions in both basal (P=0.034) and stimulated blood flow (P=0.023 for the highest dose of acetylcholine) and an impaired endothelium-dependent vasodilation when investigated in forearm resistance arteries (P=0.019). The FMD and the pulse wave method did not show any reduction in endothelium-dependent vasodilation in the patients. Conclusions-Endothelium-dependent vasodilation was impaired in resistance arteries, but not in a conduit artery, in the forearm of CADASIL patients.

Keywords
CADASIL syndrome, endothelium, vasodilation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96701 (URN)10.1161/STROKEAHA.107.490029 (DOI)000249694900014 ()17761910 (PubMedID)
Available from: 2008-02-08 Created: 2008-02-08 Last updated: 2017-12-14Bibliographically approved
Aaltonen, M., Soukka, H., Halkola, L., Jalonen, J., Kalimo, H., Holopainen, I. E. & Kääpä, P. O. (2007). Inhaled nitric oxide treatment inhibits neuronal injury after meconium aspiration in piglets. Early Human Development, 83(2), 77-85
Open this publication in new window or tab >>Inhaled nitric oxide treatment inhibits neuronal injury after meconium aspiration in piglets
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2007 (English)In: Early Human Development, ISSN 0378-3782, E-ISSN 1872-6232, Vol. 83, no 2, p. 77-85Article in journal (Refereed) Published
Abstract [en]

Background: Meconium aspiration-induced hypertensive lung injury is frequently associated with neuronal damage. Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary hypertension, but its effects on the brain are poorly known. Aims: The aim of this study was to determine the effects of iNO treatment on the neuronal tissue after meconium aspiration. Study design: 71 anesthetized, catheterized and ventilated newborn piglets were studied for 6 h. Thirty-five piglets were instilled with a bolus of human meconium intratracheally and 36 piglets with saline instillation served as controls. Nineteen meconium piglets and 17 control piglets were continuously treated with 20 ppm of iNO, started at 30 min after the insult. The extent of neuronal injury was analysed histologically, and the levels of brain tissue lipid peroxidation products, reduced glutathione (GSH), myeloperoxidase activity and oxidized DNA were analysed as indicators of oxidative stress. Results: iNO treatment diminished the pulmonary hypertensive response caused by meconium aspiration, but did not change systemic or carotid hemodynamics. NO administration was associated with reduced neuronal injury and diminished amount of oxidized DNA in the hippocampus of the meconium piglets. Further, iNO treatment was associated with decreased level of GSH in the cortex, but no change in lipid peroxidation production or myeloperoxidase activity was detected in any of the studied brain areas. Conclusions: Our results suggest that iNO treatment may inhibit DNA oxidation and neuronal injury in the hippocampus, associated with newborn meconium aspiration.

Keywords
Administration; Inhalation, Analysis of Variance, Animals, Asphyxia Neonatorum/*drug therapy/etiology, Blood Pressure, Cardiac Output, Case-Control Studies, Chromatography; High Pressure Liquid, Deoxyguanosine/analogs & derivatives/metabolism, Glutathione/metabolism, Heart Rate, Humans, Infant; Newborn, Interneurons/*pathology, Lipid Peroxidation/physiology, Meconium Aspiration Syndrome/*physiopathology, Nitric Oxide/administration & dosage/*therapeutic use, Oxidative Stress/*physiology, Peroxidase/metabolism, Spectrophotometry; Ultraviolet, Sus scrofa, Thiobarbituric Acid Reactive Substances/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10695 (URN)10.1016/j.earlhumdev.2006.05.003 (DOI)16793227 (PubMedID)
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2017-12-11Bibliographically approved
Bandusela, V., Ochala, J., Lamberg, K., Kalimo, H. & Larsson, L. (2007). Muscle paralysis and myosin loss in a patient with cancer cachexia. Acta myologica, 26(3), 136-144
Open this publication in new window or tab >>Muscle paralysis and myosin loss in a patient with cancer cachexia
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2007 (English)In: Acta myologica, ISSN 1128-2460, Vol. 26, no 3, p. 136-144Article in journal (Refereed) Published
Abstract [en]

Cancer cachexia has a significant negative effect on quality of life, survival and the response to treatment. Recent in vitro and experimental animal studies have shown that myosin may be the primary target of the muscle wasting associated with cancer cachexia. In this study, we have extended these analyses to detailed studies of regulation of myofibrillar protein synthesis at the gene level, myofibrillar protein expression and regulation of muscle contraction at the muscle cell level in a 63-year old man with a newly diagnosed small cell lung cancer and a rapidly progressing lower extremity muscle wasting and paralysis. A significant preferential loss of the motor protein myosin together with a downregulation of protein synthesis at the transcriptional level was observed in the patient with cancer cachexia. This had a significant negative impact on muscle fiber size as well as maximum force normalized to muscle fiber cross-sectional area (specific tension).

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16638 (URN)18646562 (PubMedID)
Available from: 2008-06-10 Created: 2008-06-10 Last updated: 2012-12-05Bibliographically approved
Ihalainen, S., Soliymani, R., Iivanainen, E., Mykkänen, K., Sainio, A., Pöyhönen, M., . . . Baumann, M. (2007). Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient. Molecular medicine (Cambridge, Mass. Print), 13(5-6), 305-314
Open this publication in new window or tab >>Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient
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2007 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 13, no 5-6, p. 305-314Article in journal (Refereed) Published
Abstract [en]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in NOTCH3 gene, a majority of which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor like repeats in the extracellular domain of Notch3 receptor (N3ECD). Disease is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we have characterized the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs by proteomic analysis. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs and cellular stress. Based on the results the misfolding of Notch3 seems to cause endoplasmic reticulum stress and activation of unfolded protein response leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signalling system of VSMC contraction. The accumulation of the N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.

Keywords
CADASIL/*pathology, Cells; Cultured, Collagen/metabolism, Electrophoresis; Gel; Two-Dimensional, Gels, Gene Expression Profiling, Humans, Infant; Newborn, Muscle Contraction, Muscle; Smooth; Vascular/*chemistry/*pathology, Myocytes; Smooth Muscle/*chemistry/*pathology, Proteins/metabolism, Proteome/*analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16695 (URN)10.2119/2006-00069.Ihalainen (DOI)000248312600009 ()17622327 (PubMedID)
Available from: 2008-06-03 Created: 2008-06-03 Last updated: 2017-12-08Bibliographically approved
Venojärvi, M., Kvist, M., Jozsa, L., Kalimo, H., Hänninen, O. & Atalay, M. (2007). Skeletal Muscle HSP Expression in Response to Immobilization and Remobilization. International Journal of Sports Medicine, 28(4), 281-286
Open this publication in new window or tab >>Skeletal Muscle HSP Expression in Response to Immobilization and Remobilization
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2007 (English)In: International Journal of Sports Medicine, ISSN 0172-4622, E-ISSN 1439-3964, Vol. 28, no 4, p. 281-286Article in journal (Refereed) Published
Abstract [en]

Heat shock proteins play an important regulatory role in the cellular defence. Oxidative stress is one of the factors inducing heat shock protein expression. This study tested the effects of 4 weeks of immobilization and subsequent remobilization on heat shock protein expression and oxidative stress in the lateral gastrocnemius and plantaris muscles of the rat. Active mobilization or free mobilization protocols were used for remobilization. In active mobilization, strenuous uphill treadmill running, twice a day, was started immediately after the immobilization and lasted for six days. Rats in the free mobilization group moved freely in their cages immediately after the immobilization. Expression of heat shock proteins was upregulated during the recovery from immobilization, especially in the lateral gastrocnemius muscle in the active mobilization group. However, markers of oxidative stress, such as protein carbonyls and 4-hydroxynonenal protein adducts, or activities of the antioxidant enzymes glutathione peroxidase and glutathione reductase, did not change after the immobilization and subsequent recovery. In summary, following immobilization, both intensive and spontaneous exercise upregulated the heat shock protein expressions in the lateral gastrocnemius muscle and partly in the plantaris muscle, which may contribute to the recovery from immobilization atrophy.

Keywords
Mobilization, oxidative stress, heat shock proteins
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10694 (URN)10.1055/s-2006-924350 (DOI)17024631 (PubMedID)
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2017-12-11Bibliographically approved
Järvelä, S., Bragge, H., Paunu, N., Järvelä, T., Paljärvi, L., Kalimo, H., . . . Haapasalo, H. (2006). Antioxidant enzymes in oligodendroglial brain tumors: association with proliferation, apoptotic activity and survival. Journal of Neuro-Oncology, 77(2), 131-40
Open this publication in new window or tab >>Antioxidant enzymes in oligodendroglial brain tumors: association with proliferation, apoptotic activity and survival
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2006 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 77, no 2, p. 131-40Article in journal (Refereed) Published
Abstract [en]

Purpose of the study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in oligodendroglial tumors. The expression of antioxidant enzymes and related proteins (AOEs), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR) and gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), was studied in 85 oligodendroglial tumors. The material included 71 primary (43 grade II and 28 grade III) and 14 recurrent (6 grade II and 8 grade III) tumors. Fifty-seven cases were pure oligodendrogliomas and 28 were mixed oligoastrocytomas. Immunoreactivity for MnSOD was found in 89%, Trx in 29%, TrxR in 76%, GLCL-C in 70% and GLCL-R in 68% of cases. Increased Trx expression was associated with higher tumor grade, cell proliferation and apoptosis (P=0.006, P=0.001 and P=0.003, Mann-Whitney test). Pure oligodendrogliomas showed more intense staining than oligoastrocytomas, especially for MnSOD (P=0.002, Mann-Whitney test). In the total series Trx was associated with poor prognosis in univariate survival analysis (P=0.0343, log-rank test) and furthermore in Cox multivariate analysis (P=0.009) along with age (P=0.002). The results suggest that the expression of Trx has a correlation to patient outcome and that there may be some association between AOEs, like MnSOD and Trx, and clinicopathological features of oligodendrogliomas.

Keywords
Antioxidants/*metabolism, Apoptosis/physiology, Brain Neoplasms/*metabolism/mortality, Cell Proliferation, Glutamate-Cysteine Ligase/biosynthesis, Humans, Oligodendroglioma/*metabolism/mortality, Prognosis, Superoxide Dismutase/biosynthesis, Survival Analysis, Thioredoxin/biosynthesis, Thioredoxin Reductase (NADPH)/biosynthesis, Tumor Markers; Biological/*analysis, Tumor Suppressor Protein p53/biosynthesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10689 (URN)10.1007/s11060-005-9030-z (DOI)16292483 (PubMedID)
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2017-12-11Bibliographically approved
Miao, Q., Paloneva, T., Tuisku, S., Roine, S., Poyhonen, M., Viitanen, M. & Kalimo, H. (2006). Arterioles of the lenticular nucleus in CADASIL. Stroke, 37(9), 2242-2247
Open this publication in new window or tab >>Arterioles of the lenticular nucleus in CADASIL
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2006 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 37, no 9, p. 2242-2247Article in journal (Refereed) Published
Abstract [en]

Background and Purpose-In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the arteriopathy leads to recurrent infarcts in cerebral white matter (WM) and deep gray matter (GM), whereas cortex is spared. To assess the pathogenesis of deep GM infarcts, we analyzed structural changes in arterioles of the lenticular nucleus (LN) in 6 CADASIL patients.

Methods-Five elderly and one 32-year-old deceased CADASIL patients were studied. Seven elderly and 4 young deceased persons without cerebrovascular diseases served as controls. In addition to immunohistochemical analysis the external and luminal diameters of arterioles in the LN, cerebral cortex and WM were measured. The thickness of arteriolar wall and sclerotic index were calculated.

Results-In CADASIL patients, LN arterioles were immunoreactive for the extracellular domain of Notch3 and collagen 1, whereas a-smooth muscle actin staining was irregular or negative. No major leakage of plasma fibrinogen or fibronectin was observed. Although in patients the walls of LN arterioles were significantly thicker than in controls, definite stenosis was not observed. Arteriolar lumina in the LN were not only significantly larger than in the WM, where most lacunar infarcts in CADASIL occur, but also larger than in cortical GM, where infarcts virtually never exist.

Conclusions-Fibrotic thickening of the arteriolar walls without consequent stenosis occurs in the LN of CADASIL patients. The pathogenesis of lacunar infarcts in the WM and LN seem to be different, stenosis in the former and probably hemodynamic disturbances in the latter.

Keywords
CADASIL, cerebral arteries, fibrosis, lenticular nucleus, stenosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10691 (URN)10.1161/01.STR.0000236838.84150.c2 (DOI)000241715900022 ()16873707 (PubMedID)
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2017-12-11Bibliographically approved
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