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Brain, May 26 2025, awaf196 | https://doi.org/10.1093/brain/awaf196
Cholinergic basal forebrain degeneration in isolated REM sleep behaviour disorder
Ryul Kim,1 Bora Jin,1 Heejung Kim,2 Kyung Ah Woo,1 Eun Jin Yoon,2 Seoyeon Kim,1 Jung Hwan Shin,3 Hyunwoo Nam,1 Yu Kyeong Kim,2 Beomseok Jeon3 and Jee-Young Lee1
1 Department of Neurology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
2 Department of Nuclear Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
3 Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
Correspondence to: Jee-Young Lee, MD, PhD
1 Department of Neurology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
2 Department of Nuclear Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
3 Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
Correspondence to: Jee-Young Lee, MD, PhD
Abstract
Although growing evidence suggests that cholinergic basal forebrain degeneration is linked to cognitive impairment and axial motor symptoms in Lewy body disorders (LBDs), the cholinergic contribution to their prodromal phase remains largely unknown. Herein, we aimed to address three important yet unresolved questions focusing on prodromal LBDs: (1) to examine whether and where basal forebrain degeneration begins; (2) to determine how such alterations are related to other brain morphometric changes and monoaminergic deficits; and (3) to investigate the extent to which basal forebrain atrophy contributes to the clinical picture.
We included 93 patients with polysomnography-confirmed isolated REM sleep behavior 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-FP-CIT 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 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 LBDs.
We included 93 patients with polysomnography-confirmed isolated REM sleep behavior 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-FP-CIT 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 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 LBDs.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-27)
- 국내 연구진
- 의약학 > 신경의학
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