Fully automated segmentation of the locus coeruleus: application to assess the effects of age, sex and education DOI Creative Commons
Robin de Florès,

T. K. Blanchard,

Emilie Foyard

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Abstract Background Locus coeruleus (LC) imaging using neuromelanin-sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD) and Parkinson’s (PD). Although semi or fully automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on single template built in standardized space and/or depend number of voxels be accounted that defined priori. Thus, algorithms make it impossible perform direct volumetric analyses do not properly account inter-individual anatomical variability. To fill this gap, our aim was develop new multi-atlas automated segmentation method the Automatic Segmentation Hippocampal Subfields (ASHS) software. A second investigate effects age, sex education intensity volume. Method We used cross-sectional data from 101 cognitively unimpaired older adults (mean age: 73.8±6.6 years; mean education: 13.2±3.0 58 women, 43 men) Age-Well randomized controlled trial whom high-resolution NM-MRI (T1-w with magnetization transfer; 0.3×0.3×0.75mm 3 ) standard T1-w (1×1x1mm were available. The manually segmented 30 randomly selected participants NM-MRI, MRI, bilateral segmentations fed into ASHS training pipeline generate atlas (ASHS-LC). ASHS-LC applied 71 remaining subjects segment we assessed both i) (normalized pons) ii) volume total intracranial volume). Result Five-fold cross-validation experiments revealed high accuracy relative manual (Dice coefficient 0,83±0,04). ICCs demonstrated excellent reliability (ICC = 0.99), whereas lower 0.43). significantly higher women than men (Cohen’s d 0.94, p < 0.001) while no associations age (β -0.0002, 0.98) 0.11, 0.37) found. In contrast, different between 0.10, p= 0.55) but negatively associated -0.25, 0.04) -0.27, 0.04). Lastly, statistically correlated, neither (atlas set: β 0.05, 0.78) nor 0.57; analysis -0.07, 0.55). Conclusion Overall, allows automatically accurately offers opportunity measure terms This importance since two metrics may offer complementary insights integrity, as evidenced differing influences demographic factors

Language: Английский

Cognitive, functional, and neuropsychiatric correlates of regional tau pathology in autopsy-confirmed chronic traumatic encephalopathy DOI Creative Commons
Michael L. Alosco, Micaela White, Carter Bell

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 6, 2024

Abstract Background Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors autopsy-confirmed CTE, we investigated the association of p-tau density and location cognitive, functional, neuropsychiatric symptoms. Methods 364 autopsy confirmed semi-quantitative severity (range: 0–3) was assessed in 10 cortical subcortical regions. We summed ratings across regions to form global composite 0–30). Informants completed standardized scales cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation BRI; Barratt Impulsiveness BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), apathy (Apathy Evaluation AES). Ordinary least squares regression models examined associations between regional (separate for each region) scale, adjusting age at death, racial identity, education level, history hypertension, obstructive sleep apnea, substance use treatment. Ridge that incorporated all same model which showed independent effects. Results sample predominantly American football players (333; 91.2%); 140 (38.5%) had low 224 (61.5%) high CTE. Global higher (i.e., worse) scores on cognitive functional scales: MI ( $$\beta$$ β = 0.02, 95%CI 0.01–0.04), CDS FAQ 0.03, 0.01–0.04). After false-discovery rate correction, frontal, inferior parietal, superior temporal cortex, amygdala s 0.17–0.29, ps < 0.01) 0.21–0.26, 0.01); frontal parietal cortex 0.21–0.29, 0.05); BRI 0.21, p 0.01). Regions effects other included (CDS, MI, FAQ, BRI), (CDS) (FAQ). P-tau explained 13–49% variance 6–14% scales. Conclusion Accumulation aggregates, especially certain symptoms

Language: Английский

Citations

18
Anything but small: Microarousals stand at the crossroad between noradrenaline signaling and key sleep functions DOI Creative Commons
Anita Lüthi, Maiken Nedergaard

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Continuous sleep restores the brain and body, whereas fragmented harms cognition health. Microarousals (MAs), brief (3- to 15-s-long) wake intrusions into sleep, are clinical markers for various disorders. Recent rodent studies show that MAs during healthy non-rapid eye movement (NREM) driven by infraslow fluctuations of noradrenaline (NA) in coordination with electrophysiological rhythms, vasomotor activity, cerebral blood volume, glymphatic flow. hence part dynamics, raising questions about their biological roles. We propose bolster NREM sleep's benefits associated NA fluctuations, according an inverted U-shaped curve. Weakened noradrenergic as may occur neurodegenerative diseases or aids, reduce MAs, exacerbated caused stress fragment collapse signaling. suggest crucial restorative plasticity-promoting functions advance our insight normal pathological arousal dynamics from sleep.

Language: Английский

Citations

5
Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART DOI Creative Commons
Alexander J. Ehrenberg, Michael A. Kelberman, Kathy Liu

et al.

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(5), P. 2182 - 2196

Published: Jan. 15, 2023

Abstract The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau‐associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction cortical lesions. Accumulating evidence supports role behavioral neuropsychiatric manifestations featured AD. Experimental studies even suggest that AD‐associated drives brain neuroinflammatory status contributes to progression, including exacerbation Given important pathophysiologic etiologic roles involve AD stages, there is an urgent need expand our understanding mechanisms underlying vulnerability more precisely detail clinical progression changes Here, Professional Interest Area International Society Advance Research Treatment highlights knowledge gaps about within provides recommendations priorities specific research, biomarker development, modeling, intervention. Highlights Neuromodulatory degenerate pathological stages. pathophysiology exacerbated by degeneration. symptoms dementia. Biomarkers integrity would be value‐creating dementia care. present strategic prospects disease‐modifying therapies.

Language: Английский

Citations

34
Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing DOI Creative Commons
Isabella F. Orlando, James M. Shine, Trevor W. Robbins

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105167 - 105167

Published: April 11, 2023

Noradrenergic and cholinergic systems are among the most vulnerable brain in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's Lewy body dementia, progressive supranuclear palsy. As these fail, they contribute directly to many characteristic cognitive psychiatric symptoms. However, their contribution symptoms is not sufficiently understood, pharmacological interventions targeting noradrenergic have met with mixed success. Part challenge complex neurobiology systems, operating across multiple timescales, non-linear changes adult lifespan disease course. We address challenges a detailed review outlining roles cognition behaviour, how influence disease. By bridging levels analysis, we highlight opportunities for improving drug therapies pursuing personalised medicine strategies.

Language: Английский

Citations

33
The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance DOI Creative Commons
Martin J. Dahl, Shelby L. Bachman, Shubir Dutt

et al.

Nature Aging, Journal Year: 2023, Volume and Issue: 3(9), P. 1128 - 1143

Published: Aug. 31, 2023

Abstract Changes in dopaminergic neuromodulation play a key role adult memory decline. Recent research has also implicated noradrenaline shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles age-related cognitive changes. Here, combining longitudinal MRI of the substantia nigra–ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) younger ( n = 69) older 251) adults, we found that integrity are differentially associated with performance. While LC was related to better episodic across several tasks, SN-VTA linked working Longitudinally, age more negative change integrity. Notably, changes reliably predicted future These differential associations nuclei decline potential clinical utility, given their degeneration age-associated diseases.

Language: Английский

Citations

32
Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease DOI Creative Commons
Michael A. Kelberman, Jacki M. Rorabaugh,

Claire R. Anderson

et al.

Neurobiology of Aging, Journal Year: 2023, Volume and Issue: 125, P. 98 - 108

Published: Feb. 1, 2023

Language: Английский

Citations

27
Updates and future perspectives on neuropsychiatric symptoms in Alzheimer's disease DOI Creative Commons
Myuri Ruthirakuhan, Dylan X. Guan, Moyra E. Mortby

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract Neuropsychiatric symptoms (NPS) are common throughout the Alzheimer's disease (AD) continuum and profoundly affect patients, caregivers, health‐care systems. This review synthesizes key research presented in 2022 2023 Association International Society to Advance Research Treatment Syndromes–Professional Interest Area (NPS‐PIA) Year‐In‐Reviews, emphasizing six critical areas: (1) diversity disparities, (2) diagnostic frameworks, (3) neurobiology of NPS, (4) NPS as a marker, (5) impact COVID‐19, (6) interventions. accelerates AD progression, increases functional decline, diminishes quality life, heightens caregiver burden institutionalization rates. Current treatments primarily rely on psychotropics, which offer limited efficacy raise safety concerns. aims inform clinicians researchers about recent advancements while identifying gaps for future studies improve outcomes individuals with AD. Highlights disease–related neuropsychiatric has rapidly increased, indicating heightened interest. Key areas include: diversity, diagnostics, markers, COVID‐19 impact, treatments. A road map studies, based research, is provided. includes considerations study applicability validity.

Language: Английский

Citations

1
Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau DOI Creative Commons
Maxime Van Egroo, Joost M. Riphagen, Nicholas J. Ashton

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(6), P. 2412 - 2422

Published: April 5, 2023

Abstract Autopsy data indicate that the locus coeruleus (LC) is one of first sites in brain to accumulate hyperphosphorylated tau pathology, with rostral part possibly being more vulnerable earlier stages disease. Taking advantage recent developments ultra-high field (7 T) imaging, we investigated whether imaging measures LC also reveal a specific anatomic correlation using novel plasma biomarkers different species tau, how early adulthood these associations can be detected and if are associated worse cognitive performance. To validate correlations, tested rostro-caudal gradient pathology at autopsy from Rush Memory Aging Project (MAP). We found higher phosphorylated particular ptau 231 , correlated negatively dorso-rostral integrity, whereas correlations for neurodegenerative markers (neurofilament light, total tau) were scattered throughout including middle caudal sections. In contrast, Aβ 42/40 ratio, amyloidosis, did not correlate integrity. These findings observed when entire or hippocampus. Furthermore, MAP data, than tangle density LC, independent disease stage. The vivo LC-phosphorylated became significant midlife, earliest effect starting about age 55. Finally, interactions between lower integrity concentrations predicted Together, demonstrate vulnerability dedicated magnetic resonance measures, highlighting promise as an marker AD-related processes.

Language: Английский

Citations

22
Declining locus coeruleus–dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer’s disease DOI Creative Commons
Martin J. Dahl, Agnieszka Kulesza, Markus Werkle‐Bergner

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 153, P. 105358 - 105358

Published: Aug. 17, 2023

Language: Английский

Citations

22
Neuromelanin-sensitive MRI as a promising biomarker of catecholamine function DOI
Paula Trujillo, Megan Aumann, Daniel O. Claassen

et al.

Brain, Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 5, 2023

Abstract Disruptions to dopamine and noradrenergic neurotransmission are noted in several neurodegenerative psychiatric disorders. Neuromelanin-sensitive (NM)-MRI offers a non-invasive approach visualize quantify the structural functional integrity of substantia nigra locus coeruleus. This method may aid diagnosis quantification longitudinal changes disease could provide stratification tool for predicting treatment success pharmacological interventions targeting dopaminergic systems. Given growing clinical interest NM-MRI, understanding contrast mechanisms that generate this signal is crucial appropriate interpretation NM-MRI outcomes continued development quantitative MRI biomarkers assess severity progression. To date, most studies associate measurements content neuromelanin pigment and/or density neuromelanin-containing neurons, while recent suggest main source not presence but high-water neurons. In review, we consider biological physical basis discuss wide range interpretations NM-MRI. We describe different acquisition image processing approaches how these methods be improved standardized facilitate large-scale multisite translation into use. review potential applications neurological disorders promise as biomarker disease, finally, current limitations need addressed before technique can utilized translated practice offer suggestions future research.

Language: Английский

Citations

20