State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer’s disease: Challenges and opportunities

Engels, Nina; Koops, Elouise A.; Prokopiou, Prokopis C.; Egroo, Maxime Van; Schneider, Christoph; Riphagen, Joost M.; Singhal, Tarun; Jacobs, Heidi I.L.

doi:10.1016/j.neubiorev.2022.104998

Cited by 17 publications

(13 citation statements)

References 257 publications

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“…Our previous work demonstrated a strong correlation between LC integrity and tau deposition in both autopsy and in vivo data 9 , suggesting a contribution of tau-related processes. The current findings are consistent with this, though neuromelanin, water, lipids 53 , 54 and other macromolecular elements are likely also playing a role. Neuropathology–imaging correlations are needed to disentangle the contribution of tau and other potential biological sources to the MRI signal.…”

Section: Discussionsupporting

confidence: 90%

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Bueichekú,

Diez,

Kim

et al. 2024

Nat Aging

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Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer’s disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC’s selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC–medial temporal lobe–limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC’s selective vulnerability to Alzheimer’s disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

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Section: Discussionsupporting

confidence: 90%

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Bueichekú,

Diez,

Kim

et al. 2024

Nat Aging

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“…Given the previously reported link between AD pathophysiological measures and actigraphy-derived 24-hour rest-activity patterns 6,57 or LC integrity 18,58 in asymptomatic individuals, collecting in vivo data related to ongoing AD pathophysiological processes would allow to evaluate their role in the highlighted associations already in the preclinical stage of the disease. Likewise, given the nature of the study sample, it mainly comprises very old individuals and additional studies in younger populations are therefore still required to examine earlier associations (eg, during midlife) between rest-activity patterns and LC integrity, for example by leveraging MRIderived investigation of LC structure and function in vivo, 59 in the context of initial AD-related processes.…”

Section: Discussionmentioning

confidence: 99%

Associations of 24‐Hour Rest‐Activity Rhythm Fragmentation, Cognitive Decline, and Postmortem Locus Coeruleus Hypopigmentation in Alzheimer's Disease

Van Egroo,

van Someren,

Grinberg

et al. 2024

Annals of Neurology

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ObjectiveWhile studies suggested that locus coeruleus (LC) neurodegeneration contributes to sleep–wake dysregulation in Alzheimer's disease (AD), the association between LC integrity and circadian rest‐activity patterns remains unknown. Here, we investigated the relationships between 24‐hour rest‐activity rhythms, cognitive trajectories, and autopsy‐derived LC integrity in older adults with and without cortical AD neuropathology.MethodsThis retrospective study leveraged multi‐modal data from participants of the longitudinal clinical‐pathological Rush Memory and Aging Project. Indices of 24‐hour rest‐activity rhythm fragmentation (intradaily variability) and stability (interdaily stability) were extracted from annual actigraphic recordings, and cognitive trajectories were computed from annual cognitive evaluations. At autopsy, LC neurodegeneration was determined by the presence of hypopigmentation, and cortical AD neuropathology was assessed. Contributions of comorbid pathologies (Lewy bodies, cerebrovascular pathology) were evaluated.ResultsAmong the 388 cases included in the study sample (age at death = 92.1 ± 5.9 years; 273 women), 98 (25.3%) displayed LC hypopigmentation, and 251 (64.7%) exhibited cortical AD neuropathology. Logistic regression models showed that higher rest‐activity rhythm fragmentation, measured up to ~7.1 years before death, was associated with increased risk to display LC neurodegeneration at autopsy (odds ratio [OR] = 1.46, 95% confidence interval [CI95%]: 1.16–1.84, pBONF = 0.004), particularly in individuals with cortical AD neuropathology (OR = 1.56, CI95%: 1.15–2.15, pBONF = 0.03) and independently of comorbid pathologies. In addition, longitudinal increases in rest‐activity rhythm fragmentation partially mediated the association between LC neurodegeneration and cognitive decline (estimate = ‐0.011, CI95%: ‐0.023–‐0.002, pBONF = 0.03).InterpretationThese findings highlight the LC as a neurobiological correlate of sleep–wake dysregulation in AD, and further underscore the clinical relevance of monitoring rest‐activity patterns for improved detection of at‐risk individuals. ANN NEUROL 2024

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“…However, a dichotomous functional division model of the LC might be oversimplistic, and technical difficulties concerning imaging of the LC (such as low spatial resolution of functional imaging techniques, inconvenient anatomical location, or noise from adjacent cerebrospinal fluid spaces; Engels-Domínguez et al, 2023 ) could hide a more complex underlying functional organization. Additionally, multiple overlapping axes of functional organization might be present that can confound current traditional cluster-based models that seek to divide the LC into subregions ( Haak and Beckmann, 2020 ; Poe et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions

Veréb

Mijalkov

Canal-Garcia

et al. 2023

eLife

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The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging and whether it is associated with cognition and mood. Here we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years old (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology.

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State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer’s disease: Challenges and opportunities

Cited by 17 publications

References 257 publications

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Associations of 24‐Hour Rest‐Activity Rhythm Fragmentation, Cognitive Decline, and Postmortem Locus Coeruleus Hypopigmentation in Alzheimer's Disease

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions

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