Adult-onset leukoencephalopathy provides a diagnostic challenge that often results in a lengthy and expensive diagnostic process, including frequent misdiagnosis as multiple sclerosis or cerebral microangiopathy. This situation is especially true for leukoencephalopathies, in which biochemical markers, such as lysosomal enzyme activity in white blood cells for metachromatic leukodystrophy and Krabbe disease or abnormal fatty acids in X-linked adrenoleukodystrophy/adrenomyeloneuropathy and cerebrotendinous xanthomatosis, are missing. In such cases, standard diagnostic algorithms fail and brain biopsy is often the ultima ratio tool to resolve the issue. However, biopsy results frequently remain descriptive. Prominent examples of such a constellation were, until recently, hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy. Although the 2 conditions were initially described as distinct neuropathologic entities, careful comparison revealed substantial overlap and generated the concept of a common clinicopathologic entity of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).¹ Patients with ALSP share a serious brain disorder leading to a rapidly progressive cognitive decline and neuropsychiatric manifestation with depressive, apathic, or psychotic elements in combination with a complex movement disorder with pyramidal, extrapyramidal, and cerebellar features. Characteristic neuroimaging findings include a patchy or confluent leukoencephalopathy affecting the periventricular and deep white matter preferentially of the frontal and parietal lobes as well as the corpus callosum, which is frequently mistaken as lesions from multiple sclerosis.^2,3