Jacobs Lab

About the lab

PI: Heidi Jacobs

The Jacobs lab focuses on the function and structure of various neuromodulatory nuclei (e.g. locus coeruleus) in the brainstem and subcortical regions to ultimately improve early detection of cognitive decline and neurodegenerative disorders. We also develop neuroimaging methodologies to improve the in vivo investigation of these nuclei, and  evaluate novel interventions aiming to delay cognitive decline by targeting the function of neuromodulatory nuclei.


Our research focuses on the following areas:

  • Optimizing neuroimaging methods (3T, 7T and PET) to investigate the neuromodulatory nuclei

Many of these neuromodulatory nuclei are tiny and difficult to detect with standard imaging methods. Our group has developed and validated the first 7T MRI sequence to visualize the locus coeruleus in vivo (Priovoulos et al., 2018). We also work on unravelling the source of this contrast in vivo and ex vivo and develop optimal pipelines that take physiological noise, partial volume effects as well as modelling the hemodynamic response function into account.sub

  • Investigating the functional and structural role of neuromodulatory nuclei in age-related cognitive changes

Norepinephrine, dopamine, acetylcholine and other neurotransmitters modulate various cognitive functions (attention, memory,..) and behaviors (sleep, mood, arousal,..) in a global and at the same time specific way. We recently demonstrated that greater functional connectivity between the locus coeruleus and nucleus basalis of Meynert or the ventral tegmental area were associated with lower memory performance in individuals older than 40 years of age (Jacobs et al., 2018. We also combine MRI data with other data modalities (physiological data, fluid data, PET data, pupil measurements) to determine how these nuclei fit into current disease models.

  • Mapping contributions of the function and structure of neuromodulatory nuclei to neuropathological changes in neurodegenerative disorders

These neuromodulatory nuclei are among the first to be affected by Alzheimer’s pathology (amyloid, tau). We recently showed that increased turnover of norepinephrine is associated with greater levels of amyloid and tau and worse cognitive performance (Jacobs et al., 2019).  Currently, we work on combining our developed MRI methodologies with amyloid, tau and FDG-PET, CSF and blood measurements in healthy individuals and patients to investigate regional patterns, temporal sequences as well as examining what makes these nuclei vulnerable to pathological events.

  • Exploring the potential to modulate neuromodulatory nuclei to delay cognitive decline

As these neuromodulatory nuclei plays an important role in cognition and behavior and are vulnerable to pathology early in life, it is our goal to delay cognitive decline as early as possible by modulating the function of these nuclei. We recently provided proof of concept evidence that transcutaneous vagus nerve stimulation, a non-invasive neurostimulation method that increases norepinephrine and targets the brainstem, can improve memory performance in older individuals (Jacobs et al., 2015). Establishing the underlying neural correlates and individual factors that contribute to a successful outcome is an important aim of the group.



    Prokopis Prokopiou – Post-doctoral fellow

    Kelsey Biddle, Clinical Research Coordinator



    Dr. Keith Johnson, MGH
    Dr. Reisa Sperling, MGH
    Dr. Julie Price, MGH
    Dr. Kenneth Kwong, MGH
    Dr. David Salat, MGH
    Dr. Jonathan Polimeni, MGH
    Dr. Vitaly Napadow, MGH
    Dr. Benedikt Poser, Maastricht University
    Dr. Dimo Ivanov, Maastricht University
    Dr. Kamil Uludag, Health Network Toronto

    Selected Publications

    Key publications

    • Prokopiou PC, Engels-Domínguez N, Schultz AP, Sepulcre J, Koops EA, Papp KV, Marshall GA, Normandin MD, El Fakhri G, Rentz D, Sperling RA, Johnson KA, Jacobs HIL. Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease. Neurology 2023 101 (12):e1206-e1217
    • Van Egroo M, Riphagen JM, Ashton NJ, Janelidze S, Sperling RA, Johnson KA, Yang HS, Bennett DA, Blennow K, Hansson O, Zetterberg H, Jacobs HIL. Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau. Mol Psychiatry 2023 ():1-11
    • Prokopiou PC, Engels-Domínguez N, Papp KV, Scott MR, Schultz AP, Schneider C, Farrell ME, Buckley RF, Quiroz YT, El Fakhri G, Rentz DM, Sperling RA, Johnson KA, Jacobs HIL. Lower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals. Nat Commun 2022 13 (1):1571
    • Van Egroo M, van Hooren RWE, Jacobs HIL. Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer’s disease plasma biomarkers: a 7T MRI study. Alzheimers Res Ther 2021 13 (1):159
    • Pagen LHG, Smeets T, Schmiedek L, Yassa MA, Verhey FRJ, Jacobs HIL. Elevated Activity of the Sympathetic Nervous System Is Related to Diminished Practice Effects in Memory: A Pilot Study. J Alzheimers Dis 2021 80 (4):1675-1685
    • van Hooren RWE, Verhey FRJ, Ramakers IHGB, Jansen WJ, Jacobs HIL. Elevated norepinephrine metabolism is linked to cortical thickness in the context of Alzheimer’s disease pathology. Neurobiol Aging 2021 102 ():17-22
    • Riphagen JM, van Egroo M, Jacobs HIL. Elevated Norepinephrine Metabolism Gauges Alzheimer’s Disease-Related Pathology and Memory Decline. J Alzheimers Dis 2021 80 (2):521-526
    • Jacobs HIL, Becker JA, Kwong K, Engels-Domínguez N, Prokopiou PC, Papp KV, Properzi M, Hampton OL, d’Oleire Uquillas F, Sanchez JS, Rentz DM, El Fakhri G, Normandin MD, Price JC, Bennett DA, Sperling RA, Johnson KA. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline. Sci Transl Med 2021 13 (612):eabj2511
    • Jacobs HIL, Schoemaker D, Torrico-Teave H, Zuluaga Y, Velilla-Jimenez L, Ospina-Villegas C, Lopera F, Arboleda-Velasquez JF, Quiroz YT. 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. Brain Connect 2021 ():
    • Jacobs HIL, Riphagen JM, Ramakers IHGB, Verhey FRJ. Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry 2021 26 (3):897-906
    • Riphagen JM, Schmiedek L, Gronenschild EHBM, Yassa MA, Priovoulos N, Sack AT, Verhey FRJ, Jacobs HIL. (2020) Associations between pattern separation and hippocampal subfield structure and function vary along the lifespan: A 7 T imaging study. Sci Rep, 10(1):7572
    • Jacobs HIL, Augustinack JC, Schultz AP, Hanseeuw BJ, Locascio J, Amariglio RE, Papp KV, Rentz DM, Sperling RA, Johnson KA. (2020) The presubiculum links incipient amyloid and tau pathology to memory function in older persons. Neurology, 94(18):e1916-e1928
    • Riphagen JM, Ramakers IHGM, Freeze WM, Pagen LHG, Hanseeuw BJ, Verbeek MM, Verhey FRJ, Jacobs HIL. (2020) Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer’s pathology. Neurobiol. Aging, 85():96-103
    • Jacobs HIL. Focus on the blue locus for learning. Nature Human Behaviour, (IF 10.586)
    • Priovoulos N, Poser BA, Ivanov D, Verhey FR, Jacobs HIL. (2019). In vivo imaging of the nucleus of the solitary tract with Magnetization Transfer at 7 Tesla. Neuroimage​, 201():116071  (IF 5.812)
    • Jacobs HIL, Riphagen JM, Ramakers IHGB, Verhey FRJ. (2019). Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory and neuropsychiatric symptoms. ​Molecular Psychiatry. accepted (IF 11.973)
    • Jacobs HIL, Müller-Ehrenberg L, Priovoulos N, Roebroeck A. (2018) Curvilinear locus coeruleus functional connectivity trajectories over the adult lifespan: a 7T MRI study. Neurobiology of Aging, 69, 167-176 (IF 4.398)
    • Jacobs HIL, Hedden T, Schultz AP, Sepulcre J, Perea RD, Amariglio RE, Papp KV, Rentz DM, Sperling RA & Johnson KA (2018). Structural tract alterations predict down-stream tau accumulation in amyloid positive older individuals. Nature Neuroscience, 21(3), 424-431 (IF 21.126)
    • Priovoulos N., Jacobs H.I.L., Ivanov D., Ululdag K., Verhey F.R.J., Poser B.A.. (2018). High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. Neuroimage, 168, 427-436 (IF 5.812)
    • Jacobs H.I.L.,Hopkins D.A., Mayrhofer H.C., Bruner E., van Leeuwen F.W., Raaijmakers W. & Schmahmann J.D. (2017). The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline. Brain​, 141(1), 37-47 (IF 11.814)
    • Jacobs, H.I.L.,Riphagen, J.M., Razat, C.M., Wiese, S. & Sack, A.T. (2015) Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. Neurobiology of Aging, 36(6), 1860-7 (IF 4.398)
    • Jacobs, H.I.L.,Wiese, S., van de Ven, V., Gronenschild, E.H.B.M., Verhey, F.R.J. & Matthews, P.M. (2015) Relevance of parahippocampal – locus coeruleus connectivity to memory in early dementia. Neurobiology of Aging, 36(2), 618-26 (IF 4.398)


    Other recent publications

    • Duecker F, Mayrhofer HC, Jacobs HIL, Sack AT (2019). No effect of cold pressor test-induced arousal on attentional benefits and costs in an endogenous spatial orienting paradigm. Neuropsychologia, Volume 135, December 2019, 107250
    • Bischof GN, Jacobs HIL. (2019) Subthreshold amyloid and its biological and clinical meaning. Neurology. 2019 Jul 9;93(2):72-79
    • Jacobs H.I.L.,Buckley R.F. (2018). Where do white matter alterations dovetail with the cascade model of Alzheimer’s disease? Brain. 141 (10), 2830-2833 (IF 11.814)
    • Müller-Ehrenberg L, Riphagen JM, Verhey FRJ, Sack AT, Jacobs HIL(2018). Alzheimer’s disease biomarkers have distinct associations with specific hippocampal subfield volumes. Journal Of Alzheimer’s Disease, 66(2), 811-823 (IF 3.517)
    • van Hooren RWE, Riphagen JM, Jacobs HIL(2018). Internetwork connectivity and amyloid-beta linked to cognitive decline in preclinical Alzheimer’s disease: a longitudinal cohort study. Alzheimer’s Research and Therapy, 10:88 (IF 6.142)
    • Riphagen JM, Gronenschild EHBM, Salat DH, Freeze WM, Ivanov D, Clerx L, Verhey FRJ, Aalten P, Jacobs HIL(2018). Shades of white: diffusion properties of T1- and FLAIR defined white matter signal abnormalities differ in stages from cognitively normal to dementia. Neurobiology of Aging, 68, 48-58 (IF 4.398)
    • Lee CM*, Jacobs HIL*,Marquié M, Becker JA, Andrea NV, Jin DS, Schultz AP, Frosch MP, Gómez-Isla T, Sperling RA, Johnson KA (2018). 18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus signal. Journal Of Alzheimer’s Disease, 62, 1691-1702 (IF 3.517)

    Funding sources

    Major funding sources:
    NIH/NIA R01: "Tracking the origin of tau pathology"

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