Cholinergic basal forebrain degeneration in isolated REM sleep behaviour disorder

Abstract

Although growing evidence suggests that cholinergic basal forebrain degeneration is linked to cognitive impairment and axial motor symptoms in Lewy body disorders, the cholinergic contribution to their prodromal phase remains largely unknown. Herein, we aimed to address three important yet unresolved problems focusing on prodromal Lewy body disorders: (i) to examine whether and where basal forebrain degeneration begins; (ii) to determine how such alterations are related to other brain morphometric changes and monoaminergic deficits; and (iii) to investigate the extent to which basal forebrain atrophy contributes to the clinical picture. We included 93 patients with polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD), 33 with de novo Parkinson's disease (PD) with a premorbid history of RBD (dnPDRBD) and 36 healthy controls. Participants underwent baseline assessments including volumetric MRI, 18F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane PET scan, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale and neuropsychological evaluations. Regional volumes of cholinergic nuclei 1, 2 and 3 (Ch1-3) and cholinergic nucleus 4 (Ch4) were extracted using probabilistic maps, and voxel-based and surface-based morphometric analyses were applied to identify basal forebrain atrophy-associated cortical and subcortical regions. Subgroups of patients with iRBD underwent repeated motor and cognitive assessments (38 and 34 patients for 2 and 4 years, respectively). Among the basal forebrain complex, Ch4 volumes, but not Ch1-3 volumes, were significantly reduced in patients with iRBD. This reduction was positively correlated with limbic regions, including the amygdala and cingulate cortex, and, to a lesser extent, with the neocortical regions, particularly the frontal and temporal cortices. With respect to clinical symptoms, both Ch1-3 and Ch4 volume reductions were modestly associated with severe axial motor symptoms. Additionally, Ch1-3 volume reduction was associated with higher incidence of dementia and faster progression of memory impairment, whereas Ch4 volume reduction was associated with faster progression of limb bradykinesia. Using a multimodal imaging approach, we found that iRBD patients who later converted to PD showed predominant monoaminergic deficits but variable cholinergic involvement, and these patterns were similar to those observed in the dnPDRBD group. Conversely, iRBD patients who later converted to dementia with Lewy bodies showed predominant cholinergic deficits but variable monoaminergic involvement. This comprehensive analysis provides important implications for understanding how cholinergic basal forebrain degeneration is associated with brain morphometric changes, clinical outcomes and monoaminergic degeneration during the prodromal phase of Lewy body disorders.

Keywords: Lewy body; REM sleep; basal forebrain; cholinergic; prodromal.

Figure 1

Basal forebrain volumes and striatal and extrastriatal monoaminergic innervation integrity. (A and B) The distribution of each outcome is shown by traditional box-and-whisker plots and density plots. The boxes represent the interquartile ranges of each variable, with the horizontal line in each box representing the median and whiskers showing the minimum and maximum values (excluding outliers that are >1.5 times the values represented at each end of the box). *P < 0.05, **P < 0.01 and ***P < 0.001. (C) Correlation coefficient matrix heat map using z-scores. The numbers in the squares represent Spearman’s rank-correlation coefficients. The colour is arranged in gradation from green to red in accordance with the magnitude of correlation from positive to negative. *P < 0.05. AP = anterior putamen; Amg = amygdala; Caud = Caudate nucleus; Ch1–3 = cholinergic nuclei 1, 2 and 3; Ch4 = cholinergic nucleus 4; dnPDRBD = de novo Parkinson’s disease with a premorbid history of REM sleep behaviour disorder; GP = globus pallidus; HC = healthy controls; ns = not significant; NAc = nucleus accumbens; PP = posterior putamen; SN = substantia nigra; STN = subthalamic nucleus; SUVR = specific uptake value ratio; TIV = total intracranial volume.

Figure 2

Voxel-based and surface-based analyses of grey matter clusters associated with Ch4 volumes in patients with iRBD. Warm colours represent positive correlations (A–D). Family-wise error rate correction was applied to control multiple comparisons at the voxel level (A) and surface vertex level (C). Ch4 = cholinergic nucleus 4; iRBD = isolated REM sleep behaviour disorder; SBM = surface-based morphometry; VBM = voxel-based morphometry.

Figure 3

Association of basal forebrain volumes with baseline motor and cognitive outcomes in patients with iRBD. (A) Correlation coefficient matrix heat map. The numbers in the squares represent Spearman’s rank-correlation coefficients. The colour is arranged in gradation from green to red in accordance with the magnitude of correlation from positive to negative. *P < 0.05. (B) Comparison of basal forebrain volume z-scores based on the presence of MCI. AT = action tremor; Ch1–3 = cholinergic nuclei 1, 2 and 3; Ch4 = cholinergic nucleus 4; COWAT-P = Controlled Oral Word Association Test-phonemic; COWAT-S = Controlled Oral Word Association Test-semantic; CWST = Colour–Word Stroop Test; DST-FB = Digit Span Test Forward–Backward; iRBD = isolated REM sleep behaviour disorder; K-BNT = Korean version of the Boston Naming Test; MCI = mild cognitive impairment; MDSUPDRS3 = Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Part 3; PIGD = postural instability and gait difficulties; RCFT = Rey–Osterrieth Complex Figure Test; RT = resting tremor; SVLT-DR = Seoul Verbal Learning Test-delayed recall; SVLT-IR = Seoul Verbal Learning Test-immediate recall; SVLT-Rec = Seoul Verbal Learning Test-recognition; TMT = Trail-Making Test.

Figure 4

Kaplan–Meier curves in groups with reduced basal forebrain volumes (z-scores < 0) and normal volumes (z-scores ≥ 0). (A) Development of dementia. (B) Development of LBD. Ch1–3 = cholinergic nuclei 1, 2 and 3; Ch4 = cholinergic nucleus 4; LBD = Lewy body disorder.

Figure 5

Cholinergic and monoaminergic degeneration patterns in patients with iRBD and patients with dnPDRBD. Scatter plots showing the relationship between Ch4 volume z-scores and posterior putamen SUVR z-scores in iRBD patients and dnPDRBD patients (A) and in disease converters among the iRBD patients (B). Isolated cholinergic deficits indicate Ch4 volume z-score < 0 with posterior putamen SUVR z score ≥ 0, isolated monoaminergic deficits indicate Ch4 volume z-score ≥ 0 with posterior putamen SUVR z score < 0, and both deficits indicate Ch4 volume z-score < 0 with posterior putamen SUVR z-score < 0. Ch4 = cholinergic nucleus 4; DLB = dementia with Lewy bodies; dnPDRBD = de novo Parkinson’s disease with a premorbid history of REM sleep behaviour disorder; iRBD = isolated REM sleep behaviour disorder; PD = Parkinson’s disease; SUVR = specific uptake value ratio.