Frontal and periventricular brain white matter lesions and cortical deafferentation of cholinergic and other neuromodulatory axonal projections.

White matter fiber bundles form a spatial pattern defined by anatomical and functional architecture. Structural lesions in the white matter may cause clinical symptoms because of disruption of fiber tracts. The clinical significance will depend on the anatomic location of such lesions and whether the functional integrity of specific fiber bundles is affected. Unlike more acute lesions of stroke or multiple sclerosis that may cause sudden sensorimotor deficits, white matter lesions of aging manifest with more subtle and gradual symptoms that are often cognitive in nature. Such cognitive symptoms have been explained by strategically located white matter lesions in the deep forebrain that may disrupt cholinergic projection fibers at their proximal origin. Recent in vivo imaging studies provide supportive evidence that periventricular white matter lesions are associated with cortical cholinergic deafferentation in elderly with leukoaraiosis. White matter lesions at the frontal horns, so-called "capping," are in close proximity to cholinergic axons that originate in the basal forebrain. Therefore, these lesions may result in more significant cortical deafferentation because of the more proximal axonal disruption. A unique anatomic feature common to all cortical projections from subcortical neuromodulator systems (that not only include the cholinergic but also the monoaminergic systems, such as dopamine, serotonin, and norepinephrine) is that the proximal axons largely pass through the deep forebrain before fanning out to the cortex. It is thus plausible that deep frontal white matter lesions may result in not only cholinergic but also variable monoaminergic cortical deafferentation.