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

Author

Van Egroo, Maxime, van Someren, Eus J.W., Grinberg, Lea T., Bennett, David A., and Jacobs, Heidi I.L.

Subjects
LOCUS coeruleus, ALZHEIMER'S disease, AUTOPSY, COGNITION disorders, HYPOPIGMENTATION, CEREBRAL amyloid angiopathy
Abstract

Objective: While 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. Methods: This 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. Results: Among 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). Interpretation: These 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;95:653–664 [ABSTRACT FROM AUTHOR]

Published
2024
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55. Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease

Author

Prokopiou, Prokopis C., primary, Engels-Domínguez, Nina, additional, Schultz, Aaron P, additional, Sepulcre, Jorge, additional, Koops, Elouise A., additional, Papp, Kathryn V, additional, Marshall, Gad A., additional, Normandin, Marc D., additional, El Fakhri, Georges, additional, Rentz, Dorene, additional, Sperling, Reisa A., additional, Johnson, Keith A, additional, and Jacobs, Heidi I.L., additional

Published
2023
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62. Cognitive‐behavioral associations of amygdala subregional tau pathology in cognitively unimpaired Presenilin‐1 E280A mutation carriers

Author

Langella, Stephanie, primary, Sanchez, Justin S, additional, Martinez, Jairo E., additional, Rubinstein, Zoe B., additional, Baena, Ana Y., additional, Vila‐Castelar, Clara, additional, Ramirez‐Gomez, Liliana A., additional, Aduen, Paula, additional, Jacobs, Heidi I.L., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Lopera, Francisco, additional, Gatchel, Jennifer R, additional, and Quiroz, Yakeel T., additional

Published
2022
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63. Plasma ptau231 predicts locus coeruleus integrity earlier in life than other Alzheimer’s disease plasma markers: a 7T MRI study across the adult lifespan

Author

Jacobs, Heidi I.L., primary, Riphagen, Joost M., additional, Ashton, Nicholas J., additional, Janelidze, Shorena, additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Yang, Hyun‐Sik, additional, Blennow, Kaj, additional, Hansson, Oskar, additional, Zetterberg, Henrik, additional, and Van Egroo, Maxime, additional

Published
2022
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64. Longitudinal hippocampal atrophy is associated with cognitive decline independently of amyloid and tau in neocortex

Author

Hanseeuw, Bernard, primary, Jacobs, Heidi I.L., additional, Schultz, Aaron P, additional, Buckley, Rachel F., additional, Properzi, Michael J, additional, Becker, Alex, additional, Farrell, Michelle E., additional, Sanchez, Justin S, additional, Papp, Kathryn V., additional, Yang, Hyun‐Sik, additional, Chhatwal, Jasmeer P., additional, Price, Julie C, additional, Fakhri, Georges El, additional, Rentz, Dorene M., additional, Sperling, Reisa A., additional, and Johnson, Keith A., additional

Published
2022
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65. Lower novelty‐related locus coeruleus function is associated with entorhinal tau‐mediated memory decline in older individuals.

Author

Prokopiou, Prokopis C., primary, Engels, Nina, additional, Schneider, Christoph, additional, Schultz, Aaron P., additional, Sepulcre, Jorge, additional, Riphagen, Joost M., additional, Koops, Elouise A., additional, Papp, Kathryn V., additional, Fakhri, Georges El, additional, Rentz, Dorene M., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, and Jacobs, Heidi I.L., additional

Published
2022
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66. Developing early vulnerable area aggregates for PET detection of beta‐amyloid based on young and middle‐aged adults from the Framingham Heart Study

Author

Thibault, Emma G., primary, Farrell, Michelle E., additional, Beiser, Alexa S, additional, Becker, Alex, additional, Satizabal, Claudia L, additional, Jacobs, Heidi I.L., additional, DeCarli, Charles S., additional, Hanseeuw, Bernard, additional, Killiany, Ronald J, additional, Sperling, Reisa A., additional, Seshadri, Sudha, additional, and Johnson, Keith A., additional

Published
2022
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67. Associations Between Mild Behavioral Impairment (MBI‐C) Affective Domains and Alzheimer’s Disease Neuroimaging Biomarkers in Older Adults

Author

Mayblyum, Danielle V., primary, Quiroz, Yakeel T., additional, Langella, Stephanie, additional, Udeogu, Onyinye J., additional, Jacobs, Heidi I.L., additional, Rubinstein, Zoe B., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Blacker, Deborah, additional, Marshall, Gad A, additional, and Gatchel, Jennifer R, additional

Published
2022
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69. Using 7T MRI to Evaluate COVID‐19 and Brain

Author

Hosseini, Akram A., primary, Bowtell, Richard, additional, Mougin, Olivier, additional, Penny, Gowland, additional, Katshu, Mohammad Zia, additional, Mukaetova‐Ladinska, Elizabeta, additional, Ibrahim, Tamer, additional, Girard, Timothy D., additional, Vahidy, Farhaan S., additional, Jacobs, Heidi I.L., additional, Snyder, Heather M., additional, de Erausquin, Gabriel A., additional, and Seshadri, Sudha, additional

Published
2022
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71. Vascular health is associated with locus coeruleus‐related entorhinal tau deposition

Author

Riphagen, Joost M., primary, Chhatwal, Jasmeer P., additional, Becker, Alex, additional, Kwong, Kenneth, additional, Engels, Nina, additional, Yau, Wai‐Ying Wendy, additional, Prokopiou, Prokopis C., additional, Schneider, Christoph, additional, Koops, Elouise A., additional, Rentz, Dorene M., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, and Jacobs, Heidi I.L., additional

Published
2022
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73. Lower in‐vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology

Author

Engels, Nina, primary, Hsieh, Stephanie, additional, Schneider, Christoph, additional, Prokopiou, Prokopis C., additional, Schultz, Aaron P., additional, Riphagen, Joost M., additional, Koops, Elouise A., additional, Hanseeuw, Bernard, additional, Rentz, Dorene M., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, and Jacobs, Heidi I.L., additional

Published
2022
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79. Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study

Author

Buckley, Rachel F., primary, O'Donnell, Adrienne, additional, McGrath, Emer R., additional, Jacobs, Heidi I.L., additional, Lois, Cristina, additional, Satizabal, Claudia L., additional, Ghosh, Saptaparni, additional, Rubinstein, Zoe B., additional, Murabito, Joanne M., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Seshadri, Sudha, additional, and Beiser, Alexandra S., additional

Published
2022
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80. Locus coeruleus microstructural integrity is linked to plasma GFAP concentration and Aβ42/40 ratio in cognitively unimpaired individuals: a 7T MRI study.

Author

Patsyuk, Yuliya, Van Egroo, Maxime, van Hooren, Roy W.E., Ashton, Nicholas J., Blennow, Kaj, Zetterberg, Henrik, Poser, Benedikt A, and Jacobs, Heidi I.L.

Abstract

Background: Recent autopsy and in vivo MRI studies supported structural integrity of the brainstem locus coeruleus (LC) as a potential indicator of initial AD‐related pathological processes. Importantly, in the earliest stages of the disease, these changes to the neuronal density of the LC are associated with changes to the somatic morphology and dendritic atrophy. Here, we aimed to examine whether LC microstructural integrity, assessed in vivo with advanced diffusion‐weighted magnetic resonance imaging (dMRI), is related to plasma AD biomarkers in a sample of cognitively unimpaired individuals. Method: Fifty‐seven cognitively unimpaired participants (mean age = 59.3±14.7y; 28 females) (Table 1) underwent a dMRI scanning session using a multi‐shell, high angular resolution acquisition protocol in a 7T scanner. LC microstructure was evaluated by applying the Neurite Orientation Dispersion and Density Imaging (NODDI) biophysical model on the dMRI data, yielding two metrics of microstructural integrity: Neurite Density Index (NDI) and Orientation Dispersion Index (ODI). Additionally, blood samples were analyzed to assess AD plasma biomarkers, including Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau phosphorylated at threonine 181 (pTau181) or threonine 231 (pTau231). Result: Higher age was associated with lower LC ODI (t = ‐2.77, p = 0.008) but not LC NDI values (t = 0.44, p = 0.658). Multiple linear regressions adjusted for age, sex, and estimated Total Intracranial Volume (eTIV) showed that lower NDI in the LC was associated with higher plasma GFAP levels (t = ‐2.08, p =.04, Figure 1). In addition, we found a negative association between ODI within the LC and Aβ42/40 (t = ‐2.79, p =.007, Figure 2). No significant relationships were found between LC NDI/ODI values and plasma NfL or pTau biomarkers. Conclusion: Consistent with animal studies, these findings suggest that microstructural changes in the LC are associated with astroglial activation in the earliest stages of the disease. Associations with Aβ42/40 were unexpected but might reflect loss of white matter compartments or changes in lipid density. In future analyses, we will further examine the biological interpretation of the NODDI metrics in subcortical regions, in particular in the context of AD‐related processes. [ABSTRACT FROM AUTHOR]

Published
2023
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82. Associations Between Brainstem Volume and Alzheimer’s Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study

Author

Jacobs, Heidi I.L., primary, O’Donnell, Adrienne, additional, Satizabal, Claudia L., additional, Lois, Cristina, additional, Kojis, Daniel, additional, Hanseeuw, Bernard J., additional, Thibault, Emma, additional, Sanchez, Justin S., additional, Buckley, Rachel F., additional, Yang, Qiong, additional, DeCarli, Charles, additional, Killiany, Ron, additional, Sargurupremraj, Muralidharan, additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Beiser, Alexa S., additional, and Seshadri, Sudha, additional

Published
2022
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83. Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults

Author

Farrell, Michelle E., primary, Papp, Kathryn V., additional, Buckley, Rachel F., additional, Jacobs, Heidi I.L., additional, Schultz, Aaron P., additional, Properzi, Michael J., additional, Vannini, Patrizia, additional, Hanseeuw, Bernard J., additional, Rentz, Dorene M., additional, Johnson, Keith A., additional, and Sperling, Reisa A., additional

Published
2022
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85. Waning locus coeruleus integrity precedes cortical tau accrual in preclinical autosomal dominant Alzheimer's disease

Author

Jacobs, Heidi I.L., primary, Becker, John Alex, additional, Kwong, Kenneth, additional, Munera, Diana, additional, Ramirez‐Gomez, Liliana, additional, Engels‐Domínguez, Nina, additional, Sanchez, Justin S, additional, Vila‐Castelar, Clara, additional, Baena, Ana, additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Lopera, Francisco, additional, and Quiroz, Yakeel T., additional

Published
2022
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86. Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals

Author

Jacobs, Heidi I.L., primary, Schoemaker, Dorothee, additional, Torrico-Teave, Hei, additional, Zuluaga, Yesica, additional, Velilla-Jimenez, Lina, additional, Ospina-Villegas, Carolina, additional, Lopera, Francisco, additional, Arboleda-Velasquez, Joseph F., additional, and Quiroz, Yakeel T., additional

Published
2022
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88. Extraneous neuroimaging factors do not contribute to sex differences in flortaucipir signal: Analysis of skull binding and partial volume effects

Author

Scott, Matthew R., primary, Edwards, Natalie C, additional, Properzi, Michael J, additional, Jacobs, Heidi I.L., additional, Price, Julie C, additional, Manning, Lyssa K, additional, Mayblyum, Danielle V., additional, Rubinstein, Zoe B., additional, Rentz, Dorene M., additional, Johnson, Keith A., additional, Sperling, Reisa A., additional, Schultz, Aaron P., additional, and Buckley, Rachel F., additional

Published
2021
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89. Brainstem volume is negatively associated with amyloid deposition in the Framingham Heart Study

Author

Jacobs, Heidi I.L., primary, O’Donnell, Adrienne, additional, Satizabal, Claudia L., additional, Hanseeuw, Bernard, additional, Thibault, Emma G., additional, Koijs, Daniel, additional, Sanchez, Justin S., additional, Buckley, Rachel F., additional, Yang, Qiong, additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Beiser, Alexa S., additional, and Seshadri, Sudha, additional

Published
2021
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90. Amygdala tau pathology in preclinical autosomal dominant Alzheimer’s disease

Author

Sanchez, Justin S., primary, Martinez, Jairo E., additional, Rubinstein, Zoe B., additional, Baena, Ana Y., additional, Vila‐Castelar, Clara, additional, Fox‐Fuller, Joshua T., additional, Gatchel, Jennifer R., additional, Ramirez‐Gomez, Liliana A., additional, Aduen, Paula, additional, Guzman‐Velez, Edmarie, additional, Pluim, Celina F., additional, Jacobs, Heidi I.L., additional, Sperling, Reisa A., additional, Johnson, Keith A., additional, Lopera, Francisco, additional, and Quiroz, Yakeel T., additional

Published
2021
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91. Locus coeruleus integrity as a proxy of initial tau burden: in vivo versus ex vivo observations

Author

Jacobs, Heidi I.L., primary, Becker, Alex, additional, Kwong, Kenneth, additional, Engels, Nina, additional, Prokopiou, Prokopis C., additional, Papp, Kate V., additional, Properzi, Michael J, additional, Hampton, Olivia L., additional, Sanchez, Justin S., additional, Rentz, Dorene M., additional, Fakhri, Georges El, additional, Normandin, Marc D., additional, Bennett, David A., additional, Sperling, Reisa A., additional, and Johnson, Keith A., additional

Published
2021
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92. Longitudinal associations between amyloid and tau‐PET: Impact for prevention trials

Author

Hanseeuw, Bernard, primary, Jacobs, Heidi I.L., additional, Becker, Alex, additional, Buckley, Rachel F., additional, Properzi, Michael J., additional, Farrell, Michelle E., additional, Schultz, Aaron P., additional, Sanchez, Justin S., additional, Chhatwal, Jasmeer P., additional, Price, Julie C., additional, Sperling, Reisa A., additional, and Johnson, Keith A., additional

Published
2021
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93. Regional beta‐amyloid and tau deposition: Results from the Framingham Heart Study

Author

Thibault, Emma G., primary, Farrell, Michelle E., additional, Beiser, Alexa S., additional, Sanchez, Justin S., additional, Satizabal, Claudia L., additional, Mayblyum, Danielle V., additional, O’Donnell, Adrienne, additional, Rubinstein, Zoe B., additional, Jacobs, Heidi I.L., additional, DeCarli, Charles S., additional, Hanseeuw, Bernard, additional, Killiany, Ronald J., additional, Sperling, Reisa A., additional, Seshadri, Sudha, additional, and Johnson, Keith A., additional

Published
2021
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95. Sequential early cognitive changes sensitive to rising beta‐amyloid and tau pathology in preclinical AD

Author

Farrell, Michelle E., primary, Papp, Kate V., additional, Buckley, Rachel F., additional, Jacobs, Heidi I.L., additional, Schultz, Aaron P, additional, Properzi, Michael J, additional, Vannini, Patrizia, additional, Hanseeuw, Bernard, additional, Rentz, Dorene M., additional, Johnson, Keith A., additional, and Sperling, Reisa A., additional

Published
2021
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96. Self‐reported history of estrogen hormone therapy differentiates rates of amyloid accumulation (PiB‐PET) relative to males: Findings from the Harvard Aging Brain Study

Author

Rubinstein, Zoe B., primary, Buckley, Rachel F., additional, Scott, Matthew R., additional, Manning, Lyssa K., additional, Mayblyum, Danielle V., additional, Thibault, Emma G., additional, Jacobs, Heidi I.L., additional, Farrell, Michelle E., additional, Properzi, Michael J., additional, Rabin, Jennifer S., additional, Chhatwal, Jasmeer P., additional, Lois, Cristina, additional, Rentz, Dorene, additional, Price, Julie C., additional, Schultz, Aaron P., additional, Sperling, Reisa A., additional, and Johnson, Keith A., additional

Published
2021
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97. Evidence for engagement of the nucleus of the solitary tract in processing intestinal chemonociceptive input irrespective of conscious pain response in healthy humans

Author

Beckers, Abraham B., primary, van Oudenhove, Lukas, additional, Weerts, Zsa Zsa R.M., additional, Jacobs, Heidi I.L., additional, Priovoulos, Nikos, additional, Poser, Benedikt A., additional, Ivanov, Dimo, additional, Gholamrezaei, Ali, additional, Aziz, Qasim, additional, Elsenbruch, Sigrid, additional, Masclee, Ad A.M., additional, and Keszthelyi, Daniel, additional

Published
2021
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99. Waning locus coeruleus integrity precedes cortical tau accrual in preclinical autosomal dominant Alzheimer's disease.

Author

Jacobs, Heidi I.L., Becker, John Alex, Kwong, Kenneth, Munera, Diana, Ramirez‐Gomez, Liliana, Engels‐Domínguez, Nina, Sanchez, Justin S, Vila‐Castelar, Clara, Baena, Ana, Sperling, Reisa A., Johnson, Keith A., Lopera, Francisco, and Quiroz, Yakeel T.

Abstract

Introduction: Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored. Methods: We associated LC integrity (3T‐MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word‐List‐Learning) among 27 carriers and 27 non‐carriers of the presenilin‐1 (PSEN1) E280A mutation. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. Results: LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. Discussion: These findings support LC integrity as marker of disease progression in preclinical ADAD. [ABSTRACT FROM AUTHOR]

Published
2023
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100. Defining the ATN framework using longitudinal biomarker trajectories reveals an emerging amyloid accumulation group.

Author

Boyle, Rory Thomas, Coughlan, Gillian T, Properzi, Michael J, Archdeacon, Claire, Chou, Hsiang‐Chin Lori, Klinger, Hannah, Jacobs, Heidi I.L., Papp, Kathryn V., Amariglio, Rebecca E., Farrell, Michelle E., Donohue, Michael C., Hohman, Timothy J., Mormino, Elizabeth C., Hanseeuw, Bernard J, Chhatwal, Jasmeer P., Rentz, Dorene M., Price, Julie C, Johnson, Keith A., Schultz, Aaron P., and Sperling, Reisa A.

Abstract

Background: The ATN framework is defined by cross‐sectional biomarkers of β‐amyloid (Aβ), tau and neurodegeneration. Given that prevention trials, e.g., AHEAD 3‐45, are focused on individuals who have lower Aβ than established thresholds, we investigated whether defining the ATN framework using longitudinal biomarker trajectories might better identify an at‐risk sample within this boundary. Here, we applied a data‐driven method to re‐define the ATN with longitudinal biomarker data from the Harvard Aging Brain Study (HABS) and we then replicated this longitudinal framework in ADNI. Method: 157 HABS participants were clinically‐normal at baseline and underwent at least two Pittsburgh Compound‐B [PiB]‐PET, Flortaucipir‐PET, and T1‐weighted MRI scans. To define longitudinal ATN, we applied latent class mixture models (LCMM) to each biomarker (global Aβ DVR, entorhinal tau SUVr, ICV‐adjusted hippocampal volume) separately, adjusting for age, and including random intercept and slopes. Akaike information criteria (AIC) determined the best‐fitting models out of two‐group or three‐group solutions with linear or spline‐link functions. We compared longitudinal ATN profiles on demographics and an optimized estimate of cognitive change (derived from longitudinal Preclinical Alzheimer Cognitive Composite (PACC) data). Result: Aβ trajectories (Fig.1a) were best categorized by one stable (A→) and two accumulating subgroups, a predominantly amyloid‐negative at baseline subgroup (A‐↑) and an entirely amyloid positive at baseline subgroup (A+↑). Tau (Fig.1b) and neurodegeneration (Fig.1c) were optimally defined by stable (T→/N→) vs accumulating/atrophying (T↑/N↑) groups, respectively. These groups were replicated in ADNI (Fig.2). The entire A‐↑ subgroup were stable on T and N (A‐↑/T→/N→) and were predominantly A‐/T‐/N‐ at baseline (86%; Table 1). By contrast, 38% of A+↑ individuals changed on T, or T&N. A‐↑/T→/N→ demographically most closely resembled the longitudinally‐stable ATN group (A→/T→/N→), but were older, more likely to carry e4+ and exhibited higher baseline Aβ (Table 2). Although demonstrating Aβ accumulation, A‐↑/T→/N→ did not exhibit greater cognitive decline versus the stable group (A→/T→/N→; Fig. 3). Conclusion: Our findings suggest that a longitudinal biomarker run‐in of Aβ‐PET may be useful for the identification of early‐risk groups for prevention trials. Future work will establish whether other features (e.g. genetics, neuroinflammatory markers, functional imaging) can help to distinguish this cohort. [ABSTRACT FROM AUTHOR]

Published
2022
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