Figure - available from: Annals of Clinical and Translational Neurology
This content is subject to copyright. Terms and conditions apply.
Imaging of locus coeruleus with 3T MRI and Box plot of the locus coeruleus signal intensity across groups. (A) Axial neuromelanin‐sensitive T1‐weighted images of the locus coeruleus/subcoeruleus (a) in a 64‐year‐old control and (b) in a 61‐year‐old patient with prodromal typical Alzheimer’s disease, MMSE = 27/30. The locus coeruleus area (arrows) is visible as an area of increased signal intensity. (B) Box plot of the locus coeruleus intensity in controls compared to the whole AD group (typical and atypical AD) or typical and atypical AD subgroups. (C) Box plot of the locus coeruleus intensity in controls compared to prodromal and mild demented AD subgroups. Signal intensity: normalized signal intensity in the locus coeruleus area. Plots indicate median, the boxes indicate the upper and lower quartiles. Whiskers are defined as the lowest (highest) values still within the 1.5 interquartile range from the box. AD = Alzheimer’s disease.
Source publication
Neuropathological studies showed early locus coeruleus (LC) neuronal loss associated with tauopathy in Alzheimer’s Disease (AD). We used the LC signal intensity (LC‐I) on 3T MRI to assess the LC integrity in AD (n = 37) and controls (n = 17). The LC‐I was decreased in AD regardless of typical (amnesic) and atypical presentation (logopenic aphasia/v...
Similar publications
DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish cl...
Citations
... The analysis was performed using a previously described automated method [38][39][40]. Three regions (serving as bounding boxes) were manually defined on the International Consortium for Brain Mapping template and were resampled onto the individual turbo spin echo T1-weighted images. ...
... We found lowered NBM volume and a slightly less marked alteration in LC-I, independently of the clinical phenotype in these patients. In early amnestic-AD patients, our results are in accordance with both neuropathological and MRI data showing early involvement of the NBM [46,47] and of the LC [40,48], both structures being affected by tau pathology at an early stage of the disease [14][15][16]. Recent studies also showed associations between LC-I and early tau accumulation in the entorhinal cortex [49], and between NBM volume and neurodegeneration in the entorhinal and perirhinal cortices [50], which argues in favour of an early involvement of these subcortical structures in AD pathogenesis, particularly as a potential starting point for the spread of proteinopathies. ...
Background
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer’s disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
Methods
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
Results
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
Conclusions
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
... In atypical forms of AD or non-amnestic MCI subjects, drawing similar assumption would have been more challenging. To the best of our knowledge, only one LC-MRI study has been performed up to now in patients with atypical AD (Olivieri et al. 2019). Even though those authors found that the LC degeneration occurs to a similar extent both in typical and atypical AD (Olivieri et al. 2019), the specific reasons for which AD pathology might affect the LC projections to either frontotemporal or occipitoparietal cortices rather than the limbic ones have not been elucidated yet. ...
... To the best of our knowledge, only one LC-MRI study has been performed up to now in patients with atypical AD (Olivieri et al. 2019). Even though those authors found that the LC degeneration occurs to a similar extent both in typical and atypical AD (Olivieri et al. 2019), the specific reasons for which AD pathology might affect the LC projections to either frontotemporal or occipitoparietal cortices rather than the limbic ones have not been elucidated yet. ...
The noradrenergic nucleus Locus Coeruleus (LC) is precociously involved in Alzheimer’s Disease (AD) pathology, and its degeneration progresses during the course of the disease. Using Magnetic Resonance Imaging (MRI), researchers showed also in vivo in patients the disruption of LC, which can be observed both in Mild Cognitively Impaired individuals and AD demented patients. In this study, we report the results of a follow-up neuroradiological assessment, in which we evaluated the LC degeneration overtime in a group of cognitively impaired patients, submitted to MRI both at baseline and at the end of a 2.5-year follow-up. We found that a progressive LC disruption can be observed also in vivo, involving the entire nucleus and associated with clinical diagnosis. Our findings parallel neuropathological ones, which showed a continuous increase of neuronal death and volumetric atrophy within the LC with the progression of Braak’s stages for neurofibrillary pathology. This supports the reliability of MRI as a tool for exploring the integrity of the central noradrenergic system in neurodegenerative disorders.
... Several authors aimed to dissect the association between LC degeneration and AD pathological hallmarks, i.e., tau and amyloid pathology [55••, 59, 63••, 64••, 66]. The first papers addressing this aspect found none or only a limited association between the LC signal and amyloid pathology, assessed either through CSF analysis [59] or amyloid PET [60]. However, in 2021, Jacobs and colleagues published a very interesting study, in which they explored the integrity of LC by MRI in a cohort of both cognitively intact and impaired elderlies, whose AD pathology had been assessed through amyloid and tau PET scans [55••]. ...
... However, in all the LC-MRI studies in which there was a concomitant cognitive assessment, a consistent correlation emerged between LC integrity and memory performance, spanning both verbal and visuospatial memory [60] 3 T HC 17 AD 37 (21 typical, 17 atypical) LC signal is significantly lower in AD patients than in HC, both considering typical and atypical AD, either in the prodromal or mild dementia phase. LC signal directly correlates with episodic memory performances 2021 Hou et al. [61] 3 T HC 24 AD 24 LC signal is significantly lower in AD when compared to HC and correlates with global cognitive scores 2021 Elman et al. [71] 3 T HC 373 aMCI 36 naMCI 22 A lower LC signal increases the risk of the aMCI diagnosis. ...
Performing a thorough review of magnetic resonance imaging (MRI) studies assessing locus coeruleus (LC) integrity in ageing and Alzheimer’s disease (AD), and contextualizing them with current preclinical and neuropathological literature.
MRI successfully detected LC alterations in ageing and AD, identifying degenerative phenomena involving this nucleus even in the prodromal stages of the disorder. The degree of LC disruption was also associated with the severity of AD cortical pathology, cognitive and behavioral impairment, and the risk of clinical progression.
Locus coeruleus-MRI has proved to be a useful tool to assess the integrity of the central noradrenergic system in vivo in humans. It allowed to test in patients preclinical and experimental hypothesis, thus confirming the specific and marked involvement of the LC in AD and its key pathogenetic role. Locus coeruleus-MRI–related data might represent the theoretical basis on which to start developing noradrenergic drugs to target AD.
... The loss of LC neurons in AD occurs at early stages (Betts et al., 2019a(Betts et al., , 2019bBraak and Braak, 1991), is most pronounced in the rostral and middle LC portion (Beardmore et al., 2021;Betts et al., 2019a;Theofilas et al., 2017;Tomlinson et al., 1981) and appears to correlate with disease duration (Zarow et al., 2003) and disease severity Olivieri et al., 2019). In fact, a post-mortem analysis showed a decrease in LC volume by circa 8% for every Braak stage (Theofilas et al., 2017). ...
... In fact, a post-mortem analysis showed a decrease in LC volume by circa 8% for every Braak stage (Theofilas et al., 2017). Reduced LC volume during AD is also supported by in vivo studies showing reduced LC MRI contrast in AD compared to healthy controls (Betts et al., 2019a;Cassidy et al., 2022;Li et al., 2022;Olivieri et al., 2019). ...
The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic firing, it modulates cognition and autonomic functions and is involved in the brain's immune response. The extent of degeneration to the LC in healthy ageing remains unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD). Despite their differences in progression at later disease stages, the early involvement of the LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant to other neurodegenerative diseases.
... LC integrity is severely impaired in AD demented patients and significant disruption can be found already in the MCI stage. In addition, the degree of LC disruption is associated with the severity of cognitive impairment, and not only considering memory performances Betts et al., 2019a;Galgani et al., 2023;Hou et al., 2021;Jacobs et al., 2021;Olivieri et al., 2019;Takahashi et al., 2015;Van Egroo et al., 2023). ...
... They also showed greater involvement of right occipital and parietal regions, particularly the posterior cingulate. 21 The lack of correlation between locus coeruleus signal intensity and cognition in the atypical AD group may be explained by the more heterogeneous cognitive profiles observed in this group, characterised by lvPPA and focal visuospatial deficits. ...
Introduction: Neuropsychological symptoms and cortical atrophy patterns show similarities between typical Alzheimer’s Disease (AD) and its variants. Thus, correct diagnosis is difficult, leading to errors in the therapeutic process. Indeed, the challenge in cognitive neuroscience focuses on identifying key features of cognitive-linguistic profiles and improving the knowledge of neural correlates for accurate differential diagnosis between the heterogeneous profiles of typical and atypical AD.
Aim: This systematic review aims to describe different AD profiles, considering their neuropsychological symptoms and neural correlates.
Methods: The present study followed the PRISMA guidelines and included studies from the PubMed, ScienceDirect, Scopus, and Web of Science databases, published between 2011 and 2021.
Results: Thirty-one articles were included in this systematic review for critical analysis. Results suggest significant declines in episodic and working memory and executive function. Likewise, in all groups, verbal fluency and visuospatial/visuoconstructive skills declined. However, these symptoms overlap between typical AD, logopenic variant primary progressive aphasia, posterior cortical atrophy, behavioural/dysexecutive or frontal variant AD, and corticobasal syndrome. On the other hand, the neural correlate showed a pattern of atrophy in frontal, temporal, parietal, and occipital areas, even compromising the cuneus and precuneus.
Conclusion: Spontaneous language and semantic and phonological verbal fluency could be an important biomarker for differential diagnosis between typical AD and its atypical variants. Likewise, clinical assessment should consider using advanced neuroimaging techniques to establish early associations between brain dysfunction and neuropsychological performance, with particular attention to brain areas such as the cuneus and precuneus.
... To date, different attempts have been made to gain insight into the functionality and microstructure of the human LC. The anatomical region itself can be depicted in MRI by applying neuromelanin-sensitive sequences [12,13] to generate measures of LC structural integrity (for reviews see [14,15]) which have been shown to correlate with proposed psychological capacities of the LC and the mentioned diseases [16][17][18]. Recently, functional MRI studies have assessed the general interplay between the LC with other brain regions [19][20][21][22], disturbances in LC functional connections and structural integrity in aging [23,24] and associations with antidepressant medication [25]. ...
The locus coeruleus (LC) in the brainstem as the main regulator of brain noradrenaline gains increasing attention because of its involvement in neurologic and psychiatric diseases and its relevance in general to brain function. In this study, we created a structural connectome of the LC nerve fibers based on in vivo MRI tractography to gain an understanding into LC connectivity and its impact on LC-related psychological measures. We combined our structural results with ultra-high field resting-state functional MRI to learn about the relationship between in vivo LC structural and functional connections. Importantly, we reveal that LC brain fibers are strongly associated with psychological measures of anxiety and alertness indicating that LC-noradrenergic connectivity may have an important role on brain function. Lastly, since we analyzed all our data in subject-specific space, we point out the potential of structural LC connectivity to reveal individual characteristics of LC-noradrenergic function on the single-subject level.
... patients, it is conceivable that a direct viral implication can clearly accentuate the vascular pathology, but this is not a necessary prerequisite for the loss of vascular tonus [22,44]. Furthermore, a loss of cholinergic neurons, which in fact is frequently found in many central nervous system pathologies, such as for example Alzheimer's disease, can also lead to a long-lasting loss of vascular tonicity in these patients [50,51]. ...
Background:
In the CNS, a multitude of changes have been described associated with SARS-CoV-2 infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic-ischemic changes, microthrombosis, infarcts or hemorrhages.
Objective:
We sought here to assess the vascular basement membranes (vBM) and surrounding perivascular astrocytes for any morphological changes in the acute respiratory syndrome (COVID-19) patients.
Methods:
We analyzed the light microscopy morphology of the vBM and the perivascular astrocytes from brains of 14 patients with confirmed SARS-CoV-2 infection, and compared it to 4 control patients utilizing fluorescent immunohistochemistry for collagen IV and astrocytes (GFAP), endothelia (CD31), Tight Junction 1 (TJ1) adhesion protein, as well as the aquaporin 4 (AQP4) water channel. On 2D and 3D deconvoluted images from the cortex and white matter, we calculated vessel densities, diameters, degree of gliosis, collagen IV/GFAP and GFAP/AQP4 colocalizations, as well as the fractal dimension (FD) of astrocytes and vMB viewed in tangential planes.
Results:
FD analysis of the GFAP-stained astrocytes revealed lower branching complexities, and decreased GFAP-collagen IV colocalization for COVID-19 patients. Interesting, vBM showed significantly increased irregularities (FD values) compared to controls. Vessel diameters were increased in COVID-19 cases, especially for the white matter, TJ1 protein decreased its colocalization with the endothelia, and AQP4 reduced its co-expression in astrocytes.
Conclusions:
Our data of the irregularity of the basement membranes, loss of endothelial tight junction, reduction of the astrocyte end-feets, and decrease of AQP4, suggest subtle morphological changes of BBB in COVID-19 brains that could be linked with indirect inflammatory signaling or hypoxia/hypercapnia.
... This semi-automated method segments in each participants' native space, via an (automated) intensity-threshold-free cluster search within an (manually-drawn) overinclusive mask. Several recent papers have also opted to segment in native space (Jacobs et al., 2021;Olivieri et al., 2019;Giorgi et al., 2022a, b;García-Lorenzo et al., 2013), which obviates the distortion that can be introduced via registration to a template, which can be especially threatening to small structures. However, our overinclusive mask showed high overlap with the recently published "metaMask" template (Dahl et al., 2022), which averages six previously published LC masks (Betts et al., 2017;Dahl et al., 2019;Keren et al., 2009;Tona et al., 2017;Ye et al., 2021) (see Inline Supplementary Fig. 1). ...
Late-life depression (LLD) is a risk factor for age-dependent cognitive deterioration. Norepinephrine-related degeneration in the locus coeruleus (LC) may explain this link. To examine the LC norepinephrine system in vivo, we acquired neuromelanin-sensitive MRI (NM-MRI) in a sample of 48 participants, including 25 with LLD (18 women, age 68.08±5.41) and 23 never-depressed comparison participants (ND, 12 women, age 70±8.02), matched on age and cognitive status. We employed a semi-automated procedure to segment the LC into three bilateral sections along its rostro-caudal extent, and calculated relative contrast as a proxy of integrity. Then, we examined associations between integrity and LLD diagnosis, age, and cognition, as measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Delis-Kaplan Executive Function System (D-KEFS). We did not identify an effect of LLD diagnosis nor age on LC integrity, but exploratory canonical correlation analysis across the combined participant sample revealed a strong (Rc=.853) and significant multivariate relationship between integrity and cognition (Wilks’ λ=0.03, F(84, 162.44)=1.66, p=<.01). The first and only significant variate explained 72.83% model variance, and linked better attention and delayed memory performance, faster processing speed, and lower verbal fluency performance with higher integrity in the right rostral but lower integrity in the left caudal LC. Our results complement prior evidence of LC involvement in cognition in healthy older adults, and extend this association to individuals with LLD.
... Specific T 1 -weighted sequences, enhancing the LC signal in the pons, seem to be the most reliable [14] and show LC signal reduction in patients with Alzheimer's disease dementia (ADD) compared with cognitively healthy individuals [15][16][17]. Conversely, MRI evidence of LC degeneration in MCI is limited to a few studies, performed with different methodologies and cross-sectional design [15,18,19]. ...
... We found a reduction in LC CR in ADD patients compared with HC in line with recent studies [16][17][18]. The main and novel finding of our study, however, is that a marked reduction of left LC CR , specifically in its rostral subregion, reaching values resembling the ones of the ADD group, was also seen at baseline in the MCI subjects who ) and caudal (f, h) subregions of the right LC. ...
Background:
Human neuropathological studies indicate that the pontine nucleus Locus Coeruleus (LC) undergoes significant and early degeneration in Alzheimer's Disease. This line of evidence alongside experimental data suggests that the LC functional/structural decay may represent a critical factor for Alzheimer's Disease pathophysiological and clinical progression. In the present prospective study, we used Magnetic Resonance Imaging with LC-sensitive sequence (LC-MRI) to investigate in vivo the LC involvement in Alzheimer's Disease progression, and whether specific LC-MRI features at baseline are associated with the prognosis and cognitive performances in amnestic Mild Cognitive Impairment.
Methods:
LC-MRI parameters were measured at baseline through a template-based method on 3.0Tesla MR-images in 34 patients with Alzheimer's Disease dementia, 73 with amnestic Mild Cognitive Impairment, and 53 cognitively intact individuals. Exhaustive neurological and neuropsychological assessment was performed at baseline and 2.5-year follow-up.
Results:
In subjects with Mild Cognitive Impairment who converted to dementia (N=32), the LC-intensity and number of LC-related voxels were significantly lower than in cognitively intact individuals, resembling those observed in demented patients. Such a reduction was not detected in the Mild Cognitive Impairment individuals who remained stable at follow-up. In Mild Cognitive Impairment subjects converting to dementia, LC-MRI parameters reduction was maximal in the rostral part of the left nucleus. Structural equation modeling analysis showed that LC-MRI parameters positively correlate with cognitive performances.
Conclusions:
Our findings highlight a potential role of LC-MRI for predicting clinical progression in Mild Cognitive Impairment and support the key role of LC degeneration in the Alzheimer clinical continuum.
