Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL.

BACKGROUND AND PURPOSE: Leptomeningeal artery abnormalities in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) have not been extensively characterized. We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry. METHODS: Frontal and temporal cortex of 6 genetically proven CADASIL brains (average age, 66 years), 6 controls without symptoms of cerebrovascular disease, and 6 very old brains (average age, 89 years) were examined for leptomeningeal artery intimal, medial, and adventitial thickness; inner diameter; and sclerotic index and for smooth muscle markers. RESULTS: The intima of CADASIL arteries was thickened 5-fold compared with controls and the very aged (P<0.0001). Medial thickness was lower in CADASIL compared with controls and the very old (P<0.01). The adventitia was not significantly increased in CADASIL compared with age-matched controls. Arterial diameters were not smaller in CADASIL compared with controls. Sclerotic index was significantly increased in CADASIL compared with other groups (P<0.00001). Intimal cells in CADASIL expressed smooth muscle actin, S100A4, and vimentin but not desmin. CONCLUSIONS: Principle changes of leptomeningeal arteries in CADASIL include intimal thickening and medial thinning, but not luminal narrowing. Smooth muscle-like cells participate in neointimal thickening of CADASIL arteries.

ABO blood antigens define human cerebral endothelial diversity.

Cerebral endothelial cells participate in the blood-brain barrier and regulate activity-dependent changes in brain blood flow. It has been assumed that all cerebral endothelial cells are similar, but genetic studies in mice suggest that there are heterogeneous populations of endothelial cells in rodent brain. In this study, we tested for molecular heterogeneity of endothelial cells in the human brain. Human brains (five A and five O blood type patients) from autopsies were analyzed by immunohistochemistry and immunofluorescence using antibodies against von Willebrand factor (vWF) and A and H blood group antigens. vWF and ABO antigens were confined to the endothelium. Although all endothelial cells expressed vWF, capillary endothelial cells from A blood type brains showed a heterogeneous expression of A and H antigens, with individual cells expressing either one or both antigens. There were no differences between the gray and the white matter in the percentage of A-reactive or H-reactive capillaries. We conclude that ABO antigen expression in the human brain is modulated at the level of the individual endothelial cell. Future studies are warranted to determine whether differences in capillary permeability and cerebral autoregulation vary over short distances within the brain.

Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression.

BACKGROUND AND PURPOSE: CADASIL (cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy) is a genetic disorder hallmarked by ischemic stroke and vascular dementia. Characteristic pathological changes in the vasculature include thickening of small arteries and accumulation of heterogeneous material within the vessel wall. We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression. METHODS: Brain sections obtained at autopsy from six North American CADASIL patients were examined using immunohistochemistry for vWF and IgG. Rat aortic smooth muscle cells (A7R5 cells) were tested for binding to infrared-tag labeled vWF. Finally, A7R5 cells were exposed to vWF, and expression of mature smooth muscle marker genes was analyzed by quantitative reverse transcriptase PCR. RESULTS: vWF is expressed in the penetrating arterial walls in all CADASIL samples. IgG, a marker of serum extravasation, was present only in a minority of arterial walls. vWF binds to smooth muscle cells in vitro, and low concentrations of vWF rapidly activate c-fos, EGR, TSP1, and c-myc while specifically inhibiting RNA encoding smooth muscle actin, calponin, and SM22. CONCLUSIONS: These data demonstrate that vWF, likely produced by the endothelium, permeates the vessel wall of CADASIL brains. Exposure of smooth muscle cells to vWF results in reduction of specific RNAs required for normal vascular homeostasis. This is the first report of accumulation of a protein within CADASIL vessels that inhibits vascular gene expression and implicates a role for vWF beyond hemostasis.

Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of types I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of types I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of types I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Types I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for types I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, types I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best characterized genetic cause of vascular dementia and stroke and has been extensively reported in European and Asian populations. OBJECTIVE: To report the pathological and genetic analysis of CADASIL in an African American man with a 15-base pair NOTCH3 duplication. DESIGN: Case report. SETTING: University hospital. PATIENT: A 78-year-old man with dementia, recurrent strokes, a family history of similar neurological disease, and white matter abnormalities seen on brain magnetic resonance imaging. MAIN OUTCOME MEASURES: Brain pathology and genetic analysis of NOTCH3. RESULTS: The patient's brain showed widespread arteriopathy in large and small arteries. Using electron microscopy, granular osmiophilic material typical of CADASIL was identified abutting the plasma membrane of smooth muscle cells. Brain extracts contained elevated NOTCH3 protein levels. Sequencing of the NOTCH3 gene revealed a novel 15-base pair heterozygous duplication in exon 7, which is predicted to direct expression of a protein that contains 5 extra amino acids, including a cysteine residue. CONCLUSIONS: To our knowledge, this is the first reported pathological and genetic analysis of an African American patient with CADASIL. The mutation in NOTCH3 is the longest duplication within this gene yet reported.

Paraspinal malignant ossifying fibromyxoid tumor with spinal involvement.

Ossifying fibromyxoid tumors (OFT), first described in 1989 by Enzinger et al., are rare lesions; malignant OFT (MOFT) are even rarer. We report a large recurrent paraspinal MOFT invading the spine and causing epidural compression in a 70-year-old male, despite prior debulking and radiotherapy. Paraspinal involvement of these tumors has been reported only twice before. We describe its imaging, pathology, and also review the pertinent literature.

Radiation-induced meningeal osteosarcoma of tentorium cerebelli with intradural spinal metastases.

BACKGROUND: Primary meningeal osteosarcomas and radiation-induced extraosseous tumors are extremely rare. We encountered a patient with a radiation-induced meningeal osteosarcoma with metastatic spread. CASE DESCRIPTION: A 54-year-old man presented with a 2-week history of nausea, vomiting, and ataxia. CT and MRI studies revealed an extra-axial, dural-based mass in the posterior fossa arising from the tentorium cerebelli. The patient underwent complete resection of the tumor with adjuvant chemotherapy. Histopathologic analysis revealed chondroblastic osteosarcoma. Tumor recurrence was observed 9 months after initial diagnosis, and adjuvant radiation therapy was administered. The intracranial disease stabilized; however, multiple cervico-thoracic spinal metastases were discovered 15 months after initial diagnosis. The patient expired 16 months after initial diagnosis. CONCLUSION: Meningeal osteosarcomas are rare lesions that can metastasize and should be considered in the differential diagnosis for dural-based lesions, especially in the case of previous radiation therapy.

Autopsy findings in eight patients with fatal H1N1 influenza.

A novel H1N1 influenza A virus emerged in April 2009, and rapidly reached pandemic proportions. We report a retrospective observational case study of pathologic findings in 8 patients with fatal novel H1N1 infection at the University of Michigan Health Systems (Ann Arbor) compared with 8 age-, sex-, body mass index-, and treatment-matched control subjects. Diffuse alveolar damage (DAD) in acute and organizing phases affected all patients with influenza and was accompanied by acute bronchopneumonia in 6 patients. Organizing DAD with established fibrosis was present in 1 patient with preexisting granulomatous lung disease. Only 50% of control subjects had DAD. Peripheral pulmonary vascular thrombosis occurred in 5 of 8 patients with influenza and 3 of 8 control subjects. Cytophagocytosis was seen in all influenza-related cases. The autopsy findings in our patients with novel H1N1 influenza resemble other influenza virus infections with the exception of prominent thrombosis and hemophagocytosis. The possibility of hemophagocytic syndrome should be investigated in severely ill patients with H1N1 infection.