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Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal damage in SVD are unknown. Neurofilaments are axonal structural proteins. Neurofilament-light (NfL) is an emerging biomarker for neurological disease. Here, we examined the high molecular weight form neurofilament-heavy (NfH) and quantified a characteristic pattern of peri-arterial (vasculocentric) NfH labeling. Subcortical frontal and parietal white matter from young adult controls, aged controls, and older people with SVD or severe Alzheimer disease (n = 52) was immunohistochemically labeled for hyperphosphorylated NfH (pNfH). The extent of pNfH immunolabeling and the degree of vasculocentric axonal pNfH were quantified. Axonal pNfH immunolabeling was sparse in young adults but a common finding in older persons (controls, SVD, or AD). Axonal pNfH was often markedly concentrated around small penetrating arteries. This vasculocentric feature was more common in older people with SVD than in those with severe AD (p = 0.004). We conclude that axonal pNfH is a feature of subcortical white matter in aged brains. Vasculocentric axonal pNfH is a novel parenchymal lesion that is co-located with SVD arteriopathy and could be a consequence of vessel pathology.

Cerebral small vessel disease in deep penetrating arteries is a major cause of lacunar infarcts, white matter lesions and vascular cognitive impairment. Local cerebral blood flow in these small vessels is controlled by endothelial-derived nitric oxide, which exerts a primary vasodilator stimulus on vascular myocytes, via cytoplasmic cyclic GMP. Here, we investigated whether the cGMP-degrading enzyme phosphodiesterase-5 (PDE5) is present in small penetrating arteries in the deep subcortical white matter of older people. Frontal cortical tissue blocks were examined from donated brains of older people (n = 42, 24 male: 18 female, median age 81, range: 59-100 years). PDE5, detected by immunohistochemical labeling, was graded as absent, sparse, or abundant in vascular cells within small arteries in subcortical white matter (vessel outer diameter: 20-100 µm). PDE5 labeling within arterial myocytes was detected in all cases. Degree of PDE5 expression (absent, sparse, or abundant) was not associated with age or with neuropathological diagnosis of small vessel disease. In conclusion, PDE5 is present in vascular myocytes within small penetrating arteries in older people. This is a potential molecular target for pharmacological interventions.