The enigma of depression in corticobasal degeneration, a frequent but poorly understood co-morbidity.

Depression is one of the most frequent neuropsychiatric symptoms in corticobasal degeneration (CBD), a rare, sporadic, and late-onset progressive neurodegenerative disorder of unknown etiology. It is clinically characterized by a levodopa-poorly responsible akinetic-rigid syndrome, apraxia, limb dystonia, cognitive, mood, behavioral, and language disorders. This 4-repeat (4R) tauopathy is morphologically featured by asymmetric frontoparietal atrophy, neuronal loss, and gliosis in cortex and subcortex including substantia nigra, ballooned/achromatic neurons with filamentous 4R tau aggregates in cortex and striatum, widespread thread-like structures, pathognomonic "astroglial plaques", "tufted astrocytes", and numerous "coiled bodies" (in astrocytes and oligodendroglia) in cerebral white matter. CBD is non-specific, as pathologically proven cases include several clinical phenotypes. Pubmed and Google Scholar were systematically analyzed until October 2023, with focus on the prevalence, clinical manifestation, neuroimaging data, and treatment options of depression in CBD. Its prevalence is about 30-40% which is more frequent than in most other atypical parkinsonian syndromes. Depression usually does not correlate with motor and other clinical parameters, suggesting different pathophysiological mechanisms. Asymmetric atrophy and hypometabolism of frontoparietal cortical areas are associated with disruption of fronto-subcortical circuits, nigrostriatal dopaminergic, and cholinergic deficiency. Since no specific neuroimaging, neuropathological, or biomarker studies of depression in CBD are available, its pathobiological mechanisms and pathogenesis are poorly understood. Antidepressive therapy may be useful, but is often poorly tolerated. Depression in CBD, like in other parkinsonian syndromes, may be related to multi-regional patterns of cerebral disturbances and complex pathogenic mechanisms that deserve further elucidation as a basis for early diagnosis and adequate treatment to improve the quality of life in this fatal disease.