It is suggested that in early-stage PD, nbM microstructural changes may account for unique variance in executive dysfunction in PD, independent of the effects of LC degeneration, and with a stronger association in PD than controls.
Abstract
Background: Degeneration in the cholinergic nucleus basalis of Meynert (nbM) is thought to contribute to early cognitive deficits in Parkinson's disease (PD). However, it is unknown whether this relationship is confounded by the parallel degeneration of the substantia nigra (SN) and the locus coeruleus (LC), and whether this relationship is unique to PD. Methods: We conducted a cross-sectional analysis in 112 PD patients (disease duration <10 years) and 46 controls who underwent standard neuropsychological testing, diffusion-weighted and neuromelanin magnetic resonance imaging. Mean diffusivity (MD) of the nbM and neuromelanin signal of the SN and LC were used as proxy measures of neurodegeneration. Results: nbM MD did not differ between PD patients and controls ({beta}=0.05, 95% CI [-0.27, 0.37], p=.771), a finding that was replicated using other MRI metrics. Higher nbM MD in PD patients was associated with worse executive function ({beta}=-0.22, 95% CI [-0.39, -0.05], pFDR=.027), controlling for degeneration in the SN and LC. An association with attention did not survive multiple comparisons correction ({beta}=-0.22, 95% CI [-0.41, -0.02], pFDR=.112), and there was no association with memory ({beta}=0.08, 95% CI [-0.15, 0.30], pFDR=.572). When considering both groups jointly, the relationship between increased nbM MD and worse executive function was stronger in PD than controls ({beta}nbM*Group=-0.30, 95% CI [-0.54, -0.06], pFDR=.036). Conclusion: Our findings suggest that in early-stage PD, nbM microstructural changes may account for unique variance in executive dysfunction in PD, independent of the effects of LC degeneration, and with a stronger association in PD than controls.
Abstract Background The locus coeruleus (LC), the brain’s principal noradrenergic nucleus, is implicated early in Alzheimer’s disease (AD) pathophysiology. Growing evidence from animal models, human post-mortem studies, and in vivo neuroimaging suggests that LC structural and functional alterations may reflect AD-related neurodegeneration and could serve as a biomarker across the AD continuum. We aimed to systematically evaluate LC-related evidence in AD and to quantify group differences using meta-analysis restricted to LC neuroimaging outcomes. Aims & Objectives This systematic review aims to evaluate whether LC structural and functional changes can serve as a biomarker for AD, including diagnostic differentiation among AD, mild cognitive impairment (MCI), and healthy controls (HC). Method We systematically reviewed the literature in accordance with PRISMA guidelines. Eligible studies included: (1) animal studies evaluating LC-related AD pathology; (2) human post-mortem studies assessing LC degeneration and AD pathology; and (3) human neuroimaging studies examining LC structural and/or functional alterations in AD, MCI, and HC. Observational designs (cross-sectional, cohort, longitudinal) and randomized controlled trials involving LC-related interventions were eligible. Meta-analysis was conducted only for neuroimaging studies reporting quantitative LC measures (neuromelanin-sensitive MRI signal/contrast, LC volume, diffusion metrics, resting-state functional connectivity, PET-related indices), pooling standardized effect sizes under a random-effects model. Two reviewers independently screened records, extracted data, and resolved discrepancies by consensus. Risk of bias was assessed using appropriate tools based on study design. Results A total of 239 studies were included (animal: 88; post-mortem: 83; neuroimaging: 68). The neuroimaging meta-analysis comprised 24 studies. Across animal and post-mortem studies, convergent evidence supports LC vulnerability in AD, including LC-related pathological burden and degeneration with accompanying noradrenergic alterations. In neuroimaging meta-analysis, LC measures were substantially reduced in AD compared with HC (pooled SMD = −1.21; high heterogeneity), with the largest and most consistent effects observed for neuromelanin-sensitive MRI contrast/signal indices. In contrast, the pooled difference between MCI and HC was not significant overall (SMD = −0.08; very high heterogeneity), although some structural metrics (e.g., LC length and, to a lesser extent, volume) suggested potential early-stage change in subset analyses. Publication bias tests indicated possible small-study effects in AD–HC comparisons, while bias signals were not evident for MCI–HC. Discussion & Conclusions LC integrity measured by neuroimaging, particularly neuromelanin-sensitive MRI, shows strong promise as a biomarker for AD, supported by complementary animal and post-mortem evidence. However, substantial methodological heterogeneity and potential small-study effects underscore the need for standardized LC acquisition/segmentation and larger, longitudinal cohorts to establish robust diagnostic and prognostic utility.
Y. Zhou, M. Ali, R. Hou· International Journal of Neu...· 0 citations
Background The brainstem nucleus locus coeruleus (LC) is a rod-shaped, cylindrical, deeply pigmented neuromelanin (NM)-rich cluster of noradrenergic cells placed bilaterally in the dorsolateral tegmentum of the pons. The main neurotransmitter synthesised by these neurons is norepinephrine (NE), which polymerises to NM. Collectively, it regulates a plethora of activities, including vigilance, synaptic plasticity, memory processing, pain, stress responses, selective attention, cognition, sleep, emotion, capillary wall permeability and cerebral blood flow, thereby holding a ‘master key’ to several processes. Despite being small in dimensions, it is of enormous significance in diverse functions. Degeneration of the LC occurs early and progressively in both Alzheimer’s disease (AD) and Parkinson’s disease (PD), with diverse impacts, and is linked to neuropsychiatric entities such as depression, anxiety, cognitive impairment, schizophrenia and rapid eye movement sleep disorders, thereby raising considerable interest in normal physiology as well as in disease. Summary This review is to better understand the neuroanatomical connections of human LC (master regulator of the central nervous system), pigmentation, cellular types, neurotransmitters/co-transmitters, and its role in ageing and neurodegenerative diseases. Recent and relevant classical research and review articles were referred to from PubMed to prepare a short review of the structure of LC, its projections, NM pigment and neuroprotection. We further examined the details of its cell types, neurotransmitters, co-transmitter functions and its effects in ageing, AD and PD, with emphasis on human studies. Key Message LC is a vital region that offers neuroprotection, assists in the maintenance of cognitive reserve and enhances resilience and neuronal survival, despite the presence of AD and PD pathology for several decades. Further, it synthesises NE and co-transmitters that regulate attention, sleep–wake cycle, mood, cognition and so on. Maintaining its integrity and function promises potential scope to promote its health with normal ageing and improve clinical strategies in patients with neurodegeneration.
Ahana Bhattacharya, Ravi Manjithaya, Y. Chickabasaviah et al.· Annals of Neurosciences· 0 citations
Different diagnostic group-specific patterns in the olfaction-brain structure relationship are highlighted, with implications for understanding early pathological aging and neurodegeneration.
P. P. Giriprakash, J. Caldwell, R. L. Doty et al.· Journal of Neurological Scie...· 0 citations
The cholinergic basal forebrain and subcortical gray matter have previously been implicated in Parkinson’s disease (PD), but the relationship between the symptomology of PD, including cognitive impairment, and specific patterns of damage remains unclear. Additionally, understanding the impact of fitness, including motor skills, on brain structure remains a knowledge gap. In this study, we examine a longitudinal cohort of PD patients using advanced microstructural analysis derived from diffusion MRI, alongside volumetric and connectivity components. These imaging metrics are compared to comprehensive cognitive and motor skill fitness metrics. Although the volumetric components well characterize change across the longitudinal timescale, the microstructural analysis was related to a number of composite cognitive scores, including attention, executive function, cognition, language, and the level of motor skill fitness. We further assess the connectivity of the cholinergic basal forebrain, particularly the nucleus basalis of Meynert in area 4 (CH4), and find that connectivity between CH4 and the thalamus is associated with motor skill fitness. The pattern of microstructural results suggests that increased cellularity may support reduced cognitive decline in individuals with PD and greater motor skill fitness.
B. Newman, R. Foreman, E. Donahue et al.· Frontiers in Neurology· 0 citations
Background Glymphatic dysfunction is thought to underlie neurodegenerative dementia; however, its interplay with dopaminergic degeneration and concurrent amyloid-β (Aβ) pathology in Parkinson's disease (PD) remains unresolved. This study aimed to evaluate MRI-based glymphatic metrics (the diffusion tensor image analysis along the perivascular space [DTI-ALPS] index and choroid plexus volume [CPV]) and their associations with dopaminergic degeneration, Aβ burden, and cognitive impairment (CI) in PD. Methods 79 PD patients (48 with CI (PD-CI), and 31 cognitive normal (PD-N)) and 28 age-, gender-matched normal controls (NC) were included. Dopaminergic degeneration was measured by dopamine transporter (DAT) availability using 11C-CFT-PET in PD. Additionally, 46 out of 79 PD patients conducted 18F-Florbetapir-PET for quantifying global Aβ burden (Centiloid values) and regional Aβ burden (voxel-wise regression analysis). Results PD-CI showed a significantly reduced DTI-ALPS index (1.31 ± 0.12 vs. 1.40 ± 0.12, p = 0.014; and 1.41 ± 0.12, p = 0.004) and enlarged CPV (1.43 ± 0.31 vs. 1.07 ± 0.18; and 1.14 ± 0.24; p < 0.001 respectively) compared to NC and PD-N. Both the DTI-ALPS index and CPV were significantly correlated with age and caudate DAT availability (CAU_DAT), but not correlated with DAT availability in anterior / posterior putamen, Centiloid values or regional Aβ burden. Further mediation analyses indicated that CAU_DAT mediated the associations between glymphatic metrics and CI after adjustment for covariates, as assessed by the DTI-ALPS index (p = 0.026) and CPV (p = 0.042). Conclusions The caudate dopaminergic degeneration corelates with MRI-based glymphatic metrics and cognitive deterioration in PD.
Xinyi Xie, Ruolian Dai, Mei Xin et al.· NeuroImage: Clinical· 0 citations
Clinical significant apathy in PD prior to STN-DBS is associated with reduced white matter integrity in the left internal capsule involving the broader left-sided vmPFC projection system, which may contribute to future optimization of apathy management with STN-DBS.
Jip de Bruin, B. Kopell, H. Mayberg et al.· Brain Stimulation· 0 citations
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