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Figure 3: (a) Eleven year old MCMA girl with abundant ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglia. Approximately 50% of the perivascular cells are Iba-1+ (Iba-1 antibody with DAB + brown product). (b) Eleven year old MCMA girl with brainstem perivascular accumulation of HLA-DR positive cells (HLA-DR antibody and DAB + brown product). (c) Frontal cortex in a MCMA 24 y old male with perivascular partially degranulated tryptase positive cells (Tryptase Ab with DAB + brown product). (d) Olfactory bulb blood vessel in a 14 year old MCMA boy. Notice a vacuolated endothelial cell and a polymorphonuclear leucocyte (PMN) attached to the vessel wall. Two glomeruli are adjacent to the damaged vessel. H&E. (e) Olfactory bulb blood vessel in a 14-year-old MCMA male APOE 3/3. Endothelial cells in the delicate vessel exhibit abundant lipofuscin, a highly oxidized and covalently cross-linked aggregate of proteins associated with aging. H&E. (f) Frontal cortex white matter from a MCMA 33 year old healthy subject with a cluster of blood vessels displaying perivascular numerous macrophages with lisosomal bodies and lipofuscin. The larger vessel displays abundant cell debris within the wall. One micron toluidine blue section. (g) Fourteen year old MCMA girl prefrontal white matter with an abnormal blood vessel displaying perivascular macrophages with lisosomal bodies and lipofuscin, abundant cell debri within the wall, apoptotic nuclei and focal enlargement of the Virchow-Robin space. One micron toluidine blue section. (h) Vascular lesions are also seen in young MCMA dogs. This 19 month dog exhibits a frontal white matter arteriole with hyperplastic endothelial cells partially reducing the lumen. One micron toluidine blue section. (i) The prefrontal cortex exhibits extensive vascular white matter damage, illustrated in this 13 y old MCMA girl. The arteriole shows extensive perivascular accumulation of macrophages with abundant lisosomal bodies. A striking enlargement of the Virchow-Robin space is seen with focal white matter damage. One micron toluidine blue section. (j) Seventeen year old MCMA teen brainstem blood vessel with extensive leaking expanding the Virchow-Robin space. (k) Same child as (j), the breakdown of the neurovascular unit also affects smaller blood vessels. (l) Electron micrograph of an olfactory bulb arteriole in a 17 y old MCMA boy. There is marked focal thickening of the vessel wall, numerous perivascular macrophages with lisosomal bodies and lipofuscin and vacuolization of endothelial cells. (m) Nanosized particles are seen in endothelial cells in many brain regions. This electron micrograph from a 17 y old MCMA male shows an arteriole in the olfactory bulb with two sharply defined particles in the endothelial cell cytoplasm and its basement membrane. The particles are 16 to 20 nanometers. EM ×50,000.