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.

Figure 1

Flow chart of study participants. DAT PET, dopamine transporter positron emission tomography; MRI, magnetic resonance imaging; NPH, normal pressure hydrocephalus; PNFA, progressive nonfluent aphasia; QC, quality control.

Figure 2

Voxel‐wise analyses for the associations between DAT uptakes and WMHs. Univariable analyses for voxel‐wise DAT uptake using BF volume and PWMH‐A as a predictor (A). Multivariable analysis for voxel‐wise DAT uptake using BF volume and PWMH‐A as predictors (B). Univariable analyses for voxel‐wise WMHs using BF volume and DAT‐AC as a predictor (C). Multivariable analyses for voxel‐wise WMHs using BF volume and DAT‐AC as predictors (D). All analyses were performed after controlling for age, sex, education, intracranial volume, hypertension, diabetes mellitus, dyslipidemia, microbleeds, and lacunes. Negative correlations between WMH and DAT were tested. Effect sizes (r score) were indicated by color intensities within statistically significant regions identified by multiple comparisons correction (false discovery rate [FDR] corrected, p < 0.05). AC, anterior caudate; BF, basal forebrain; DAT, dopamine transporter uptake; WMH, white matter hyperintensities; PWMH‐A, anterior periventricular WMH.