Neurology International · May 26, 2026

White Matter Hyperintensities and Clinical Phenotype in Late-Onset Psychiatric Disorders: A Multidimensional Clinical-Neuroimaging Study

By Silva T, Nunes C, Ribeiro A et al.

BACKGROUND: White matter hyperintensities (WMHs) have been implicated in late-onset psychiatric disorders, but their contribution to this clinical phenotype remains insufficiently understood. METHODS: We conducted a cross-sectional transdiagnostic study of 90 consecutively admitted acute patients with schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD) meeting the predefined inclusion criteria. Patients with a late onset were compared to earlier onset (EO) psychiatric patients. Late onset was defined as the median age of the disorder onset of the sample (≥40 years). Multidimensional clinical, cognitive, psychomotor, metabolic, and neuroimaging data were evaluated (WHM burden and cerebral atrophy), and a cognitive-psychopathologic composite index was derived. Correlations and sensitivity analysis were performed. A multivariable linear regression was performed to assess the independent effects of age, vascular risk factors, and WMH severity on cognitive performance and psychiatric symptoms. RESULTS: In patients with LO psychiatric disorders, greater WMH burden was significantly associated with poorer global cognition and specific cognitive domains, lower delusional symptoms severity, and greater suicidal thoughts/behavior intensity. These associations were markedly weaker or not present in EO patients. The regression model explained 36.5% of the variance in the cognitive-psychopathologic composite index. After adjusting for age and cumulative risk factors, Fazekas was the only significant independent predictor (β = -0.495, p = 0.001). CONCLUSIONS: WMH burden was associated with differences in clinical characteristics in LO psychiatric disorders, including cognitive and neuropsychiatric symptoms. Our findings support a possible vascular-neuropsychiatric interaction in LO phenotypes.

doi.org/10.3390/neurolint18060105Open accessPubMed 42347114Populations