White matter hyperintensities and cholinergic degeneration as Lewy body disease

Abstract

Objective: Although basal forebrain (BF) cholinergic degeneration and white matter hyperintensities (WMHs) are important in neurodegeneration in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), their relationships with dopaminergic degeneration and clinical manifestations remain unclear.

Methods: A total of 407 patients with cognitive impairment meeting the diagnostic criteria for AD, DLB, or both (AD+DLB) were assessed. All participants underwent 3T MRI, dopamine transporter (DAT) positron emission tomography, neuropsychological tests, and assessments for parkinsonism, cognitive fluctuation, visual hallucination, and rapid eye movement sleep behavior disorder (RBD). General linear and logistic regression models were used to investigate the relationships among BF volume, DAT uptake in the anterior caudate (DAT-AC), WMH volumes in anterior, posterior, periventricular, and deep regions, and clinical manifestations.

Results: DAT-AC was positively associated with BF volume and negatively associated with anterior periventricular WMH volume, but not with deep WMHs. Both deep and periventricular WMHs volumes were associated with hypertension and the number of microbleeds and lacunae. Lower BF volume and DAT-AC were independently associated with increased risk of cognitive fluctuation and visual hallucination, whereas lower DAT-AC was additionally associated with increased risk of RBD and greater parkinsonian severity. Both lower BF volume and DAT-AC were independently associated with widespread cognitive impairment, whereas higher anterior periventricular WMH volume was associated with executive dysfunction.

Interpretation: BF cholinergic degeneration and anterior periventricular WMHs are closely associated with dopaminergic degeneration. Anterior periventricular WMHs may represent axonal alterations caused by the interplay between Lewy body-related degeneration and vascular pathologies.