Locus Coeruleus Signal Research Articles

Locus Coeruleus Is Associated with Higher Openness to Experience and IQ: Implications for the Noradrenergic System for Novelty Seeking in Daily Life.

Novelty exposure and the upregulation of the noradrenergic (NA) system have been suggested as crucial for developing cognitive reserve and resilience against neurodegeneration. Openness to experience (OE), a personality trait associated with interest in novel experiences, may play a key role in facilitating this process. High-OE individuals tend to be more curious and encounter a wider range of novel stimuli throughout their lifespan. To investigate the relationship between OE and the main core of the NA system, the locus coeruleus (LC), as well as its potential mediation of IQ-a measure of cognitive reserve-MRI structural analyses were conducted on 135 healthy young adults. Compared with other neuromodulators' seeds, such as dorsal and median raphe-5-HT, ventral tegmental area-DA-, and nucleus basalis of Meynert-Ach-, the results indicated that higher LC signal intensity correlated with greater OE and IQ. Furthermore, mediation analyses revealed that only the LC played a mediating role between OE and IQ. These findings shed light on the neurobiology of personality and emphasize the importance of LC-NA system integrity in a novelty-seeking behavior. They provide a psychobiological explanation for how OE expression can contribute to the maintenance of the NA system, enhancing cognitive reserve and resilience against neurodegeneration.

Greater physical fitness ( ) in healthy older adults associated with increased integrity of the locus coeruleus-noradrenergic system.

Physical activity (PA) is a key component for brain health and Reserve, and it is among the main dementia protective factors. However, the neurobiological mechanisms underpinning Reserve are not fully understood. In this regard, a noradrenergic (NA) theory of cognitive reserve (Robertson, 2013) has proposed that the upregulation of NA system might be a key factor for building reserve and resilience to neurodegeneration because of the neuroprotective role of NA across the brain. PA elicits an enhanced catecholamine response, in particular for NA. By increasing physical commitment, a greater amount of NA is synthetised in response to higher oxygen demand. More physically trained individuals show greater capabilities to carry oxygen resulting in greater - a measure of oxygen uptake and physical fitness (PF). We hypothesized that greater would be related to greater Locus Coeruleus (LC) MRI signal intensity. In a sample of 41 healthy subjects, we performed Voxel-Based Morphometry analyses, then repeated for the other neuromodulators as a control procedure (Serotonin, Dopamine and Acetylcholine). As hypothesized, greater related to greater LC signal intensity, and weaker associations emerged for the other neuromodulators. This newly established link between and LC-NA system offers further understanding of the neurobiology underpinning Reserve in relationship to PA. While this study supports Robertson's theory proposing the upregulation of the NA system as a possible key factor building Reserve, it also provides ground for increasing LC-NA system resilience to neurodegeneration via enhancement.

Evidence for Locus Coeruleus–Norepinephrine System Abnormality in Military Posttraumatic Stress Disorder Revealed by Neuromelanin-Sensitive Magnetic Resonance Imaging

BackgroundThe complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)–norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder. MethodsStudy participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32). Clinical measures included the Clinician-Administered PTSD Scale for DSM-5, and neuroimaging measures included a neuromelanin-sensitive magnetic resonance imaging scan to measure the LC signal. Robust linear regression analyses related the LC signal to clinical measures. ResultsCompared with control participants, the LC signal was significantly elevated in the PTSD group (t62 = 2.64, p = .010), and this group difference was most pronounced in the caudal LC (t56 = 2.70, Cohen’s d = 0.72). The caudal LC signal was also positively correlated with the severity of Clinician-Administered PTSD Scale for DSM-5 hyperarousal symptoms in the PTSD group (t26 = 2.16, p = .040). ConclusionsThese findings are consistent with a growing body of evidence indicative of elevated LC-norepinephrine system function in PTSD. Furthermore, they indicate the promise of neuromelanin-sensitive magnetic resonance imaging as a noninvasive method to probe the LC-norepinephrine system that has the potential to support subtyping and treatment of PTSD or other neuropsychiatric conditions.

Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum

AbstractBackgroundNoradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.MethodThis study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.ResultConsistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p<0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p<0.0001; MMSE score: t(254) = 4.30, p<0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (<27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).ConclusionWhile cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.

Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum

AbstractBackgroundNoradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.MethodThis study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.ResultConsistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p<0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p<0.0001; MMSE score: t(254) = 4.30, p<0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (<27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).ConclusionWhile cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.

In vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in frontotemporal degeneration and corticobasal syndrome.

AbstractBackgroundNeuropathological studies have shown alterations in both locus coeruleus (LC) and basal forebrain in frontotemporal degeneration (FTD) and corticobasal syndrome (CBS) particularly in progressive supranuclear palsy (PSP). We aimed to investigate in vivo the LC and nucleus basalis of Meynert (NBM) integrity in patients with FTD and CBS.MethodWe compared the LC signal intensity (LC‐I), which reflects the LC integrity, and the NBM volume on 3T MRI in i) FTD patients (n = 17) ii) CBS patients (n = 8;) iii) prodromal/mild AD (n = 34) and iv) amyloid‐negative controls (n = 15). PiB‐PET and/or AD CSF biomarkers were negative in all FTD and CBS patients, and positive in all AD patients. All subjects underwent a complete neuropsychological assessment and 3T brain MRI performed on the same scan. The four groups were age‐matched. The MMSE score did not differ significantly between the 3 groups of patients.ResultCompared to controls, LC‐I and NBM volume were significantly decreased in FTD (p = 0.05 and 0.00015, respectively) and AD patients (p = 0.0005 and 0.002, respectively). LC‐I and NBM volume were also decreased in CBS in comparison with controls but the difference was not statistically significant. In addition, we found no statistically significant difference in LC‐I and NBM volume between the three groups of patients. We observed no correlation between LC‐I or NBM volume and amyloid load, either when considering the whole group of patients or AD and FTD/CBS patients separately.ConclusionOur results are in line with neuropathological data and suggest that both cholinergic and noradrenergic systems are altered in AD and FTD. Post mortem data have suggested that, in FTD, both structures were more impaired in tau than in TDP‐43 proteinopathy, which cannot be explored in our study. In CBS, our results are less clear‐cut, probably due to the small sample size. Taken together, our data support the pathophysiological model in which both LC and NBM play a critical role not only in AD but also in other diseases and proteinopathies like FTD.

Evaluation of locus coeruleus changes during aging by post‐mortem brain MRI contrast

AbstractBackgroundNeuropathological studies have pointed to the importance of neurodegeneration in the locus coeruleus (LC) as a possible early biomarker of Alzheimer’s Disease (AD). The aim of this study is to explore a non‐invasive MRI technique to evaluate normal and pathological changes in the LC during aging.MethodsSubjects were recruited from our Capital’s Death Verification Service. After obtaining written consent from family members, 24 individuals (55‐94 yrs) were submitted for post‐mortem brain in situ MRI with a 7T scanner. Post‐mortem interval ranged from 7 to 20 hours and body temperature varied from 14.8°C to 26°C. MRI protocol included acquisition of multi‐echo gradient‐echo axial images with 2 mm thickness and 0.4 mm in‐plane resolution. LC signal intensity was evaluated from a single gradient‐echo image presenting the brightest signal for the LC. In the same slice normalized values for the left and right LC were quantified (LNV and RNV) by selecting a ROI on the brightest spot of the LC (one‐pixel sized) and dividing it by the signal intensity measured in the left and right pons, respectively (ROI of approx. 50mm2) (Figure1). Subject’s Clinical Dementia Rating (CDR) was obtained by interviewing a close family member. A two‐tailed paired t‐test was performed between the RNV and the LNV, and dependence with age was analyzed by Pearson correlation.ResultsCDR was 0 (n = 17); 0,5 (n = 2); 1 (n = 1), 2 (n = 1), and 3 (n = 3). LNV was higher than RNV (t(23) = 3.9; p< 0.001 (Figure2). The mean of LNV and RNV (MNV) was higher in individuals with CDR = 0 than in subjects with CDR >0, but subjects with CDR>0 were also significantly elder, and there was a significant effect of age on the MNV (r = ‐ 0,49, p = 0,015), Figure 3.ConclusionMRI LC contrast was able to depict LC changes as a function of age, whereby subjects with symptons seemed to present lower LC intensity. The left LC was consistently brighter than the right LC endorsing results observed in other studies (Betts et al.2019 https://doi.org/10.1016/j.dadm.2019.02.001). Future histopathological analysis will help to elucidate the origin for this signal difference.

Preliminary validation of the Stress and Adversity Inventory for Adults (Adult STRAIN) in Dutch and its associations with in‐vivo locus coeruleus integrity

AbstractBackgroundThe Stress and Adversity Inventory (STRAIN) systematically assesses lifetime stressor exposure, but its validity has yet to be established in The Netherlands. This work aims to validate the Dutch translation of STRAIN and its association with key biological correlates: cortisol measures and the locus coeruleus (LC), a brainstem nucleus involved in stress responses and accumulating phosphorylated tau early in adulthood.MethodsEighty‐seven cognitively unimpaired Dutch participants (31‐81 years; ∼45% female; Table 1) completed stress‐ and affective‐related questionnaires, cognitive testing, salivary and plasma cortisol measurements, and 7T‐MRI. The STRAIN was administered after translation into Dutch. LC MRI signal intensity was extracted from an MT‐TFL sequence by normalizing LC signal against the pontine tegmentum (reference region) and creating a sample‐specific LC template. Pearson correlation models assessed associations between STRAIN summary scores (total stressor count and severity), and stress‐related (MIA‐Anxiety, PSS, DASS‐Stress, NEO PI‐R‐Neuroticism), affective (DASS‐Anxiety‐Depression, HDRS), cognitive (WLTDR, LDST, STR3), stress‐related biological (salivary‐, plasma cortisol), and LC measures (Table 1). HDRS models employed Spearman correlations. Age and sex were included as covariates, additionally including education for cognitive measures. Analyses were FDR‐corrected and conducted based on complete cases.ResultsOverall, the sample had relatively low lifetime stressor counts (M = 14.08; Figure 1A). When assessing concurrent validity, the STRAIN was positively associated with other stress measures (r = .21,.36; pFDR <.05; Figure 1B,C). Models including cortisol revealed that less stressor exposure and severity were associated with higher cortisol levels (r = ‐.22,‐.23; pFDR <.05). Affective and cognitive measures were investigated for discriminant validity. STRAIN was not associated with DASS, but was positively associated with HDRS (r = .17,.28; pFDR <.05). Generally, greater stressor exposure was related to poorer cognitive performance (r = .13,‐.19; pFDR <.05), except for a positive association between WLTDR and stressor severity (r = .18; pFDR <.05). No significant associations were found with LC MRI signal intensity (Figure 1B).ConclusionThis study demonstrates preliminary good concurrent and discriminative validity for the Dutch STRAIN translation, even among individuals with low‐to‐moderate self‐reported stress levels. We found no direct associations between LC integrity and lifetime stressors. Future research will investigate associations with other STRAIN domains and potential moderating effects of Alzheimer’s Disease‐related biomarkers on the relationship between cumulative stressor exposure and LC integrity.

Neurogenic orthostatic hypotension in Parkinson’s disease: is there a role for locus coeruleus magnetic resonance imaging?

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and degenerates early in Parkinson’s disease (PD). The objective of this study is to test whether degeneration of the LC is associated with orthostatic hypotension (OH) in PD. A total of 22 cognitively intact PD patients and 52 age-matched healthy volunteers underwent 3 T magnetic resonance (MRI) with neuromelanin-sensitive T1-weighted sequences (LC-MRI). For each subject, a template space-based LC-MRI was used to calculate LC signal intensity (LC contrast ratio—LCCR) and the estimated number of voxels (LCVOX) belonging to LC. Then, we compared the LC-MRI parameters in PD patients with OH (PDOH+) versus without OH (PDOH−) (matched for sex, age, and disease duration) using one-way analysis of variance followed by multiple comparison tests. We also tested for correlations between subject’s LC-MRI features and orthostatic drop in systolic blood pressure (SBP). PDOH− and PDOH+ did not differ significantly (p > 0.05) based on demographics and clinical characteristics, except for blood pressure measurements and SCOPA-AUT cardiovascular domain (p < 0.05). LCCR and LCVOX measures were significantly lower in PD compared to HC, while no differences were observed between PDOH− and PDOH+. Additionally, no correlation was found between the LC-MRI parameters and the orthostatic drop in SBP or the clinical severity of autonomic symptoms (p > 0.05). Conversely, RBD symptom severity negatively correlated with several LC-MRI parameters. Our results failed to indicate a link between the LC-MRI features and the presence of OH in PD but confirmed a marked alteration of LC signal in PD patients.

49 Locus Coeruleus MR Signal Interacts with CSF p-tau/AB42 to Predict Attention, Executive Function, and Verbal Memory

Objective:The locus coeruleus (LC) plays a key role in cognitive processes such as attention, executive function, and memory. The LC has been identified as an early site of tau accumulation in Alzheimer’s disease (AD). LC neurons are thought to survive, albeit with limited functionality, until later stages of the disease, though how exactly this limited functionality impacts cognition through the course of AD is still poorly understood. We investigated the interactive effects of an imaging biomarker of the LC and AD-related cerebrospinal fluid (CSF) biomarkers on attention, executive function, and memory.Participants and Methods:We recruited 67 older adults from the San Diego community (mean age=74.52 years; 38 cognitively normal, 23 with mild cognitive impairment, and 6 with probable AD). Participants had LC-sensitive magnetic resonance imaging (MRI) used to obtain a measure of LC signal relative to surrounding tissue, with lower LC signal possibly indicating limited functionality. Participants also underwent a lumbar puncture to obtain CSF measurements of amyloid-beta 42 (Ab42) and phosphorylated tau (p-tau). We calculated the p-tau/Ab42 ratio, which is positively correlated with AD progression. Finally, participants were administered a comprehensive neuropsychological battery, and cognitive composites were created for attention (Digit Symbol, Digit Span Forward, Trails A), executive function (Digit Span Backward, Trails B, Color-Word Inhibition Switching), and two measures of verbal memory [learning (CVLT List A 1-5, Logical Memory Immediate Recall) and delay (CVLT Long Free Recall, Logical Memory Delayed Recall)]. Four multiple linear regressions modeled the relationship between each composite with age, gender, education, p-tau/Ab42, average LC contrast, and interactions between average LC contrast and p-tau/Ab42. For models that were statistically significant, additional regressions were assessed to determine which segment of the LC (caudal, middle, rostral) contributed to the relationship.Results:Our model predicted attention (p=.001, R2=.298) with main effects of average LC signal, p-tau/Ab42, and LC by p-tau/Ab42 interaction. Follow-up regressions revealed that each LC segment contributes to this relationship. Our model predicted executive function (p=.006, R2=.262) with a main effect of average LC signal and LC by p-tau/Ab42 interaction. Follow-up regressions revealed that this relationship was limited to the caudal and middle LC. Our models predicted both verbal learning (p&lt;.001, R2=.512) and delayed memory (p&lt;.001, R2=.364); both with main effects of gender and education. Follow-up regressions revealed that the rostral LC signal interacts with p-tau/Ab42 to predict both verbal learning and delayed memory. For all interactions, those with low p-tau/Ab42 exhibited a positive relationship between LC signal and cognition, whereas those with higher p-tau/Ab42 showed a negative relationship.Conclusions:MR-assessed LC signal relates to attention, executive function, and verbal learning and memory in a manner that depends on CSF levels of p-tau and Ab42. The relationship between LC signal and cognition is positive at low levels and negative at higher levels of p-tau/Ab42. If lower LC signal indicates reduced integrity, these findings imply that MR-assessed LC signal may be a more meaningful marker of AD progression in earlier stages of the disease. Alternatively, this measure may capture a different underlying mechanism depending on tau and amyloid biomarker status.

Characterization of an automated method to segment the human locus coeruleus.

Following the development of magnetic resonance imaging (MRI) methods to assay the integrity of catecholamine nuclei, including the locus coeruleus (LC), there has been an effort to develop automated methods that can accurately segment this small structure in an automated manner to promote its widespread use and overcome limitations of manual segmentation. Here we characterize an automated LC segmentation approach (referred to as the funnel-tip [FT] method) in healthy individuals and individuals with LC degeneration in the context of Alzheimer's disease (AD, confirmed with tau-PET imaging using [18F]MK6240). The first sample included n = 190 individuals across the AD spectrum from cognitively normal to moderate AD. LC signal assayed with FT segmentation showed excellent agreement with manual segmentation (intraclass correlation coefficient [ICC] = 0.91). Compared to other methods, the FT method showed numerically higher correlation to AD status (defined by presence of tau: Cohen's d = 0.64) and AD severity (Braak stage: Pearson R = -.35, cognitive function: R = .25). In a separate sample of n = 12 control participants, the FT method showed excellent scan-rescan reliability (ICC = 0.82). In another sample of n = 30 control participants, we found that the structure of the LC defined by FT segmentation approximated its expected shape as a contiguous line: <5% of LC voxels strayed >1 voxel (0.69 mm) from this line. The FT LC segmentation shows high agreement with manual segmentation and captures LC degeneration in AD. This practical method may facilitate larger research studies of the human LC-norepinephrine system and has potential to support future use of neuromelanin-sensitive MRI as a clinical biomarker.

Evidence of Sympathetic Overactivity in Subjects with REM Behavior Disorder at Risk for Parkinson’s Disease (P6-13.002)

<h3>Objective:</h3> To evaluate sympathetic nervous system (SNS) activity in subjects with REM sleep behavior disorder (RBD) at risk of Parkinson’s disease, using imaging and autonomic functions markers. <h3>Background:</h3> While the nature of RBD is not completely understood, there is evidence that enhancement of noradrenergic activity may play a causative role, as suggested by evidence of persistent tonic discharge of locus coeruleus (LC) and RBD-triggering action of selective norepinephrine reuptake inhibitors. <h3>Design/Methods:</h3> Subjects &gt;50 years old with RBD with at least one pre-motor PD symptom (hyposmia, constipation, depression) were tested with a battery of autonomic evaluations including SCOPA-AUT questionnaire, cardiac MIBG scintigraphy, Heart Rate Variability (HRV) and neuromelanin sensitive MRI (NSMRI) of LC and substantia nigra (SN). Analyzed variables included: 1) for MIBG, late heart/mediastinum (H/M) ratio and washout ratio (WR); 2) for HRV, time and frequency domain measures; 3) for NSMRI, contrast-to-noise ratio (CNR) between LC and pons and between substantia nigra (SN) and cerebral peduncles. Results were compared with available normative ranges. <h3>Results:</h3> 14 subjects (11M, age 66.2±8.2) were enrolled. Average total SCOPA-AUT score was increased (12.1±6.7 vs 8.8±5.4), with gastrointestinal (2.4±2.1 vs 1.4±1.6), urinary (5.4±2.7 vs 3.9±2.4) and cardiovascular (0.86±1.10 vs 0.3±0.6) scores above normal ranges. MIBG late H/M ratio was reduced (1.45±0.31) with increased WR (33.0±14.8). HRV results showed enhanced sympathetic and low parasympathetic activity both in time (SDNN 106.8±73.2ms; RMSSD 21.9±10.9ms; PNN50% 6.7±8.4%) and frequency domain (LF/HF 3.4±1.8). NMSMRI showed high LC CNR (right 3.26±1.9 vs 2.08±0.5; left 2.95±0.9 vs 2.79±0.5). SN CNR was high (Medial 6.24±1.9 vs 4.57±0.8; Central 6.26±1.6 vs 3.43±0.6; Lateral 3.44±2.1 vs 3.05±0.5) and MDS-UPDRS motor scores were low (2.9±3.3). <h3>Conclusions:</h3> RBD subjects at risk for PD show abnormal autonomic scores, which appears to be driven by SNS overactivity, as suggested by increased MIBG WR, elevated LF/HF HRV ratios and increased LC and SN NSMRI signal. <b>Disclosure:</b> Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbott. Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Boston Scientific. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Supernus. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroDerm. Dr. Tagliati has received publishing royalties from a publication relating to health care. Dr. Gregorio has nothing to disclose. Dr. Maghzi has nothing to disclose. Gloria Obialisi has nothing to disclose. Dr. Hogg has nothing to disclose. Dr. Malatt has nothing to disclose. Dr. Tan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Allergan. Dr. Artal has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. Dr. Artal has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Private Parties. The institution of Dr. Artal has received research support from Jazz Pharma. The institution of Dr. Artal has received research support from Axsome. The institution of Dr. Artal has received research support from Suven. Dr. Shehata has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Brian Renner has nothing to disclose. The institution of Dr. Sati has received research support from National Multiple Sclerosis Society. The institution of Dr. Sati has received research support from National Institutes of Health. Dr. Sati has received publishing royalties from a publication relating to health care.

Different patterns of Locus Coeruleus MRI alteration in Alzheimer's and Dementia with Lewy bodies.

the integrity of Locus Coeruleus can be evaluated in vivo using specific Magnetic Resonance Imaging sequences. While this nucleus has been shown to be degenerated both in post-mortem and in vivo studies in Alzheimer's Disease, for other neurodegenerative dementias such as Dementia with Lewy Bodies this has only been shown ex-vivo. to evaluate the integrity of the Locus Coeruleus through Magnetic Resonance Imaging in patients suffering from Dementia with Lewy Bodies and explore the possible differences with the Locus Coeruleus alterations occurring in Alzheimer's Dementia. eleven patients with Dementia with Lewy Bodies and 35 with Alzheimer's Dementia were recruited and underwent Locus Coeruleus Magnetic Resonance Imaging, along with 52 cognitively intact, age-matched controls. Images were analyzed applying an already developed template-based approach; Locus Coeruleus signal was expressed through the Locus Coeruleus Contrast Ratio parameter, and a locoregional analysis was performed. both groups of patients showed significantly lower values of Locus Coeruleus Contrast Ratio when compared to controls. A different pattern of spatial involvement was found; patients affected by Dementia with Lewy bodies showed global and bilateral involvement of the Locus Coeruleus, whereas the alterations in Alzheimer's Dementia patients were more likely to be localized in the rostral part of the left nucleus. Magnetic Resonance Imaging successfully detects widespread Locus Coeruleus degeneration in patients suffering from Dementia with Lewy Bodies. Further studies, in larger cohorts and in earlier stages of the disease, are needed to better disclose the potential diagnostic and prognostic role of this neuroradiological tool.

Normative Values of Neuromelanin-Sensitive MRI Signal in Older Adults Obtained Using a Turbo Spin Echo Sequence.

The integrity and function of catecholamine neurotransmitter systems can be assessed using neuromelanin-sensitive MRI (NM-MRI). The relevance of this method to neurodegenerative and psychiatric disorders is becoming increasingly evident, and it has potential as a clinical biomarker. To support future application of NM-MRI as a clinical biomarker by defining the normative range of NM-MRI signal and volume metrics in cognitively normal older adults. Prospective. A total of 152 cognitively normal older adults aged 53-86 years old, including 41 participants who had follow-up NM-MRI data collected 9-16months later. A 3.0 T; NM-MRI turbo spin echo and T1-weighted magnetization-prepared rapid acquisition with gradient echo sequences. NM-MRI images were processed to yield summary measures of volume and signal (contrast-to-noise ratio, CNR) for the substantia nigra (SN) and locus coeruleus (LC) using a recently developed software employing a fully automated algorithm. Change in these metrics over time was also assessed. Mean and standard deviation of NM-MRI metrics were calculated; change over time was tested for significance using 1-sample t-tests. P values < 0.05 were considered statistically significant. At baseline SN signal (CNR) was 10.02% (left) and 10.28% (right) and LC signal was 24.71% (left) and 20.42% (right). Baseline SN volume was 576 mm3 (left) and 540 mm3 (right) and LC volume was 6.31 mm3 (left) and 6.30 mm3 (right). The only NM-MRI metric showing significant change was a decrease in left SN volume (t40 =-2.57, P=0.014). We report normative values for NM-MRI signal and volume in the SN and LC of cognitively normal older adults and explore their change over time. These values may help future efforts to use NM-MRI as a clinical biomarker by facilitating identification of patients with extreme NM-MRI values. 1.

Examining the Locus Coeruleus Norepinephrine System With Neuromelanin-Sensitive MRI: Applications in Psychiatric and Neurodegenerative Illness

Neuromelanin-sensitive MRI (NM-MRI) yields a high signal contrast in the principal catecholaminergic nuclei of the brain, the substantia nigra and the locus coeruleus (LC). Loss of LC signal contrast has been studied as a proxy of noradrenergic cell death in neurodegenerative conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). LC signal contrast may also reflect norepinephrine system function and be altered in some psychiatric disorders.

Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer's disease.

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer's disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [18F]MK6240 and [18F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [18F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t186 = -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

Locus Coeruleus magnetic resonance imaging in cognitively intact elderly subjects

The locus coeruleus is the main noradrenergic nucleus of the brain and is often affected in neurodegenerative diseases. Recently, magnetic resonance imaging with specific T1-weighted sequences for neuromelanin has been used to evaluate locus coeruleus integrity in patients with these conditions. In some of these studies, abnormalities in locus coeruleus signal have also been found in healthy controls and related to ageing. However, this would be at variance with recent post-mortem studies showing that the nucleus is not affected during normal ageing. The present study aimed at evaluating locus coeruleus features in a well-defined cohort of cognitively healthy subjects who remained cognitively intact on a one-year follow-up. An ad-hoc semiautomatic analysis of locus coeruleus magnetic resonance was applied. Sixty-two cognitively intact subjects aged 60–80 years, without significant comorbidities, underwent 3 T magnetic resonance with specific sequences for locus coeruleus. A semi-automatic tool was used to estimate the number of voxels belonging to locus coeruleus and its intensity was obtained for each subject. Each subject underwent extensive neuropsychological testing at baseline and 12 months after magnetic resonance scan. Based on neuropsychological testing 53 subjects were cognitively normal at baseline and follow up. No significant age-related differences in locus coeruleus parameters were found in this cohort. In line with recent post-mortem studies, our in vivo study confirms that locus coeruleus magnetic resonance features are not statistically significantly affected by age between 60 and 80 years, the age range usually evaluated in studies on neurodegenerative diseases. A significant alteration of locus coeruleus features in a cognitively intact elderly subject might be an early sign of pathology.

Lower Locus Coeruleus MRI intensity in patients with late-life major depression.

BackgroundThe locus coeruleus (LC) is the major noradrenergic source in the central nervous system. Structural alterations in the LC contribute to the pathophysiology of different neuropsychiatric disorders, which may increase to a variable extent the likelihood of developing neurodegenerative conditions. The characterization of such alterations may therefore help to predict progression to neurodegenerative disorders. Despite the LC cannot be visualized with conventional magnetic resonance imaging (MRI), specific MRI sequences have been developed to infer its structural integrity.MethodsWe quantified LC signal Contrast Ratios (LCCRs) in late-life major depressive disorder (MDD) (n = 37, 9 with comorbid aMCI), amnestic Mild Cognitive Impairment (aMCI) (n = 21, without comorbid MDD), and healthy controls (HCs) (n = 31), and also assessed the putative modulatory effects of comorbidities and other clinical variables.ResultsLCCRs were lower in MDD compared to aMCI and HCs. While no effects of aMCI comorbidity were observed, lower LCCRs were specifically observed in patients taking serotonin/norepinephrine reuptake inhibitors (SNRIs).ConclusionOur results do not support the hypothesis that lower LCCRs characterize the different clinical groups that may eventually develop a neurodegenerative disorder. Conversely, our results were specifically observed in patients with late-life MDD taking SNRIs. Further research with larger samples is warranted to ascertain whether medication or particular clinical features of patients taking SNRIs are associated with changes in LC neurons.

A case-control study of the locus coeruleus degeneration in Alzheimer's disease

The locus coeruleus (LC) is the major source of noradrenaline, which plays a key role in cognition. We aimed to detect the extent of the LC signal attenuation in Alzheimer's disease (AD) patients using a neuromelanin (NM)-sensitive MRI and how it may correlate with inflammatory and autonomic measures. An individually matched case-control study design was employed. 24 patients with AD and 24 age and gender matched controls with no cognitive impairment were recruited. The primary outcome measure was the LC signal intensity indicated by the LC contrast ratio (CR) and measured by the NM-sensitive MRI. Secondary outcome measures included neuropsychometric tests of cognitive state, peripheral inflammatory and autonomic measures. Conditional logistic regression analysis revealed a significant 22% LC-CR reduction in the AD group compared with the control group. However, there was no statistical significance from inflammatory or autonomic measures. This is the largest individually-matched case-control study to visualise the LC degeneration in AD patients. The study revealed significant LC degeneration which holds promise to stratify patients who may benefit from treatment targeting noradrenergic dysfunction.

In vivo assessment of the noradrenergic nucleus locus coeruleus in Alzheimer’s disease and other types of dementia

AbstractBackgroundThe Locus Coeruleus (LC) is the main noradrenergic nucleus of the brain. Pathological analysis in humans have shown that LC is degenerated in Alzheimer’s disease (AD), and that its impairment might start years before the occurrence of cognitive impairment. Several experimental studies in animal models even suggested a pathogenetic role of an early LC degeneration in AD pathogenesis. LC neuromelanin‐containing neurons can be assessed by using MRI scan, in T1‐weighted sequences. In this study, we assessed in vivo the integrity of LC by 3T MRI in patients with dementia due to AD (ADD) and in MCI subjects, comparing them with patients with Fronto‐temporal dementia (FTD), with patients with Lewy Body Dementia (LBD)/ Parkinson’s Disease Dementia (PDD) and with healthy controls (HC).Method234 subjects (HC=60; MCI=80; ADD=40; FTD=18; LBD/PDD=36) were submitted to a 3 Tesla brain MRI (Signa‐GEH), including neuromelanin (NM)‐sensitive FSE T1‐weighted sequences for LC study. The sequences were then evaluated using a semi‐automatic software by blinded operators. An indirect measures of LC volume, based on the number of Voxels selected, is expressed by the parameter VOX. All subjects underwent detailed clinical and neuropsychological assessment.ResultVOX was significantly lower in ADD compared to HC, while no differences were observed between HC and FTD. The lowest values of were observed in LBD/PDD and Early Onset AD (EOAD) patients. MCI subjects showed an LC signal lower than HC, although not statistically significant. Patients with confirmed AD pathology presented lower values of VOX than HC, and their cognitive performances correlated with the degree of LC signal reduction.ConclusionWe observed in vivo a marked alteration of LC signal in AD patients, compared to healthy controls, in line with the hypothesis of LC involvement in AD pathogenesis; the severe alteration found in EOAD, further supports this association. As expected from neuropathological and NM‐MRI studies, also PDD/LBD showed LC alterations, while FTD did not. In MCI a trend was observed, even if not significant: a longitudinal study is required to evaluate potential association with ADD conversion rate. Funding sponsor: Ministero della Salute PE‐2013‐02359574 (P.I.: FSG).