Pathology

Pathological findings on autopsy of CADASIL patients include multiple small, deep infarcts in WM, deep gray matter in the brainstem, and a diffuse myelin loss in the hemispheric WM (Fig. 1C). The cortex, cerebellum, and other tissues seem well preserved. Histological sections show a widespread angiopathy first described in small-and medium-sized brain arteries.[3] Finally, lesions occur throughout the systemic blood vasculature including capillaries and veins.[5]

This angiopathy is characterized by a slight to marked thickening of the wall depending on the localization, destruction of VSMCs, and wall accumulation of eosino-philic smudgy material, which is periodic acid Schiffpositive (PAS+) but negative in Congo red staining, ruling out the diagnosis of amyloid angiopathy.[3,5,6] The ultrastructural CADASIL hallmark is a granular osmiophilic material (GOM) without filament-like profiles[5,6] surround ing VSMCs and often lodging within VSMC infoldings (Fig. 1D-F). So far, the GOM nature is not known. An important breakthrough in understanding CADASIL vascular wall changes is the finding that the Notch3 protein expression is restricted to VSMCs[7] and that its extracellular domain (NECD) accumulates within CADASIL patients' vessel walls, in close vicinity to GOMs and can be visualized immunohistochemically.[7] Given the uncertain specificity and sensitivity of this technique,[8] GOMs observed in skin biopsies continue to remain a diagnostic tool.[3,5,6] Moreover, it appears to be detectable early, before age 20 years in skin vessels.[3] Nevertheless, we did not find

Fig. 2 Schematic representation of vascular changes in CADASIL patients and transgenic mice. (A) Normal vessel wall. (B) First modifications observed within the vessel wall of young CADASIL patients (8 years old) and of young mice before 10 months. (C and D) Evolution of VSMC alterations with a dramatic separation of the different vessel wall cells and the presence of GOM (arrow) observed on and after 20 years in humans and 14 months in transgenic mice. E, endothelium; SES, subendothelial space; EL, elastic lamina; dpl, dense plaque; db, dense core; ICS, intercellular space.

Fig. 2 Schematic representation of vascular changes in CADASIL patients and transgenic mice. (A) Normal vessel wall. (B) First modifications observed within the vessel wall of young CADASIL patients (8 years old) and of young mice before 10 months. (C and D) Evolution of VSMC alterations with a dramatic separation of the different vessel wall cells and the presence of GOM (arrow) observed on and after 20 years in humans and 14 months in transgenic mice. E, endothelium; SES, subendothelial space; EL, elastic lamina; dpl, dense plaque; db, dense core; ICS, intercellular space.

GOM in very young patients (8 years old), whereas VSMC alterations were already present, suggesting that VSMCs are the target of Notch3 mutations. In a study of 50 CADASIL cases, Brulin et al.[9] confirmed that skin VSMC alterations begin early; since age of 20 years, VSMCs are already isolated, irregular-shaped, and surrounded with an increased extracellular matrix, which seems to just replace the VSMC destruction (Figs. 1D and 2B and C). VSMC destructions increase with the patient's age. Finally, vessel wall VSMCs are barely recognizable at 60 years (Fig. 2D) Interestingly, no real stenosis (lumen diameter decreasing) is found compared with 20 younger controls even though vessel walls are thickened. These findings are also observed in brain tissues from five CADASIL cases.[9]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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