Subcortical U-fibers, also known as short association fibers, represent connections between adjacent gyri of the brain, located within the cortex or immediately deep to it in the very outer parts of the subcortical white matter ¹. 

They are among the last parts of the brain to myelinate, as late as the third or fourth decade and have very slow myelin turnover. The exception are the perirolandic and occipital poles, which myelinate earliest in infancy ⁴. It is hypothesized this may be due to the evolutionary importance of the functions of movement and sight.

Whether or not they are involved in diseases that primarily affect the white matter depends on the underlying relationship of the pathology to myelin metabolism and oligodendroglial cells.

In diseases in which the abnormality is one of myelin metabolism/turnover as these fibers have very slow metabolism, they tend to be affected last. Note: often the word 'spared' is used, which is correct in so far as at the time one is imaging these patients there is little involvement of these fibers, however, this should not be taken to mean that they cannot be involved; in fact, in many instances they are involved eventually. 

In contrast, diseases in which the damage is direct to oligodendroglial cells, then no such relative sparing will be evident. 

As if this wasn't potentially confusing enough, superimposed on these metabolic differences between subcortical U-fibers and deeper white matter, is that merely by their location, subcortical U-fibers are relatively protected from chronic small vessel ischemic change ⁵. As the hemispheric white matter receives dual blood supply, superficially from penetrating arteries that pass through the cortex as well as deeper vessels that ascend from the perforators, it stands to reason that the white matter closest to either source of blood should be least affected. Indeed this is what is observed, with chronic small vessel ischemic change relatively sparing both the periventricular and subcortical white matter ⁵. It is important to note that this does not apply to large vessel occlusion which will involve the cortex as well as the underlying subcortical white matter. 

Examples of early and late subcortical involvement include ^3,4: 

• subcortical U-fibers usually initially spared
  • chronic small vessel ischemic white matter lesions
    • including Binswanger disease
  • CADASIL ⁶
  • HIV encephalopathy
  • many toxic leukoencephalopathies
    • heroin smoking: chasing the dragon
    • radiation/chemotherapy
  • many leukodystrophies
    • X-linked adrenoleukodystrophy
    • metachromatic leukodystrophy
    • globoid cell leukodystrophy (Krabbe disease)
  • many inborn errors of metabolism
    • phenylketonuria
    • maple syrup urine disease
    • Lowe syndrome
    • hypohomocysteinemia
• subcortical U-fibers involved relatively early/indiscriminately
  • multiple sclerosis (juxtacortical lesions)
  • progressive multifocal leukoencephalopathy (PML)
  • acute disseminated encephalomyelitis (ADEM)
  • Alexander disease
  • Canavan disease
  • van der Knaap disease 
  • galactosemia
  • Salla disease
  • Pelizaeus-Merzbacher disease

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History and etymology

U-fibers are so-called due to their similarity to that letter of the alphabet.