Recent Publications

Sepulcre article in Nature Medicine


Dr. Jorge Sepulcre, an Assistant Professor of Radiology at HMS and Assistant in Neuroscience at the MGH Gordon Center, leads a lab that focuses on brain imaging studies aimed at the understanding of large-scale brain networks implicated in human cognition and neurodegenerative disorders.

His article titled “Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.” has been published in Nature Medicine.

Summary:  Tau and beta-amyloid (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease (AD). Unraveling the genetic background for the regional vulnerability of these proteinopathies can help understand the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau PET imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau- and Aβ-propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as “axon-related” and the Aβ profile as “dendrite-related”. This is the first study revealing distinct genetic profiles that may confer vulnerability to tau- and Aβ-in-vivo-propagation in the human brain.

Neurogenetic profiles delineate large-scale connectivity dynamics of the human brain


Dr. Jorge Sepulcre, an Assistant Professor of Radiology at HMS and Assistant in Neuroscience at the MGH Gordon Center. His research focuses on large-scale brain networks implicated in human cognition and neurodegenerative disorders.

His article titled “Neurogenetic profiles delineate large-scale connectivity dynamics of the human brain” has been published in Nature Communications on the 24th of September 2018.


Experimental and modeling work of neural activity has described recurrent and attractor dynamic patterns in cerebral microcircuits. However, it is still poorly understood whether similar dynamic principles exist or can be generalizable to the large-scale level. Here, we applied dynamic graph theory-based analyses to evaluate the dynamic streams of whole-brain functional connectivity over time across cognitive states. Dynamic connectivity in local networks is located in attentional areas during tasks and primary sensory areas during rest states, and dynamic connectivity in distributed networks converges in the default mode network (DMN) in both task and rest states. Importantly, we find that distinctive dynamic connectivity patterns are spatially associated with Allen Human Brain Atlas genetic transcription levels of synaptic long-term potentiation and long-term depression-related genes. Our findings support the neurobiological basis of large-scale attractor-like dynamics in the heteromodal cortex within the DMN, irrespective of cognitive state.


Refining Models of Amyloid Accumulation in Alzheimer’s Disease


Changes in MMSE and PET uptake over time

A new study published in Alzheimer’s and Dementia, the Journal of the Alzheimer’s Association, proposes to stage amyloid PET images using regional information. The research was conducted by Dr. Bernard Hanseeuw, instructor at MGH Gordon Center, and Dr. Keith Johnson, leader of the Aging NeuroImaging Program at the MGH Gordon Center, and the Harvard Aging Brain Study.

Using longitudinal amyloid PET imaging data collected over three years in more than 1,400 participants including clinically normal (CN) older adults and patients with mild cognitive impairment (MCI) or Alzheimer’s dementia (AD), the authors provided in-vivo evidence that amyloid deposits first in neocortex and then in striatum, a subcortical brain structure. This progressive regional involvement from neocortex to striatum had been suspected for long from autopsy data (referred to in the literature as “Thal phases”), but it had never been demonstrated in living humans.

The results of the study showed that regional expansion of amyloid pathology in striatum was predictive of subsequent cognitive decline and progression to Alzheimer’s dementia. Participants with striatal amyloid declined faster than those who only had cortical amyloid. Higher levels of striatal amyloid were also associated with higher levels of tau pathology and hippocampal atrophy, confirming that striatal amyloid was indicative of disease progression.

Amyloid-PET is commonly expressed as a binary measure of cortical deposition (low/high). However, not all individuals with high-cortical amyloid experience rapid cognitive decline. Using a three-stage PET classification (low cortex/high cortex, low striatum/high striatum) allow a better identification of the most at-risk individuals. Such a staging system could also help preventive trials for selecting normal participants based on their risk of developing the disease in the following years.

View full paper

Novel PET Imaging Tracer May Improve Monitoring of Multiple Sclerosis


[18F]3F4AP in the brain of healthy rhesus monkeys.

Multiple sclerosis is an immune-mediated neurological disease that affects around 400,000 people in the U.S. and 2.5 million worldwide. In the last few years, there has been a large effort by the academic community and pharmaceutical industry to develop drugs that can reverse demyelination and restore neurological function. One challenge for the translation of these therapies to humans is how to accurately measure their effects. Positron emission tomography (PET) has the potential to provide quantitative images of underlying biochemical processes such as demyelination.

In a recent paper* published by the journal Scientific Reports, Dr. Pedro Brugarolas and his colleagues describe the development and testing in animal models of a new PET tracer for demyelination. Their new tracer is based on the MS drug 4-aminopyridine (4AP, dalfampridine) which binds to potassium channels in demyelinated axons allowing the visualization of demyelinated lesions in animal models of MS noninvasively.

Dr. Brugarolas is an Assistant Professor of Radiology at Harvard Medical School and a Radiochemist at the MGH Gordon Center. His research at the Center focuses on developing novel small molecule PET tracers labeled with fluorine-18 and carbon-11

*Brugarolas, P., Sánchez-Rodríguez, J. E., Tsai, H.-M., Basuli, F., Cheng, S.-H., Zhang, X., et al. (2018). Development of a PET radioligand for potassium channels to image CNS demyelination. Scientific Reports, 8 (1), 607.

Study Reveals Association between Aβ, Tau, Circuitry and Cognition


A new study published in Nature Neuroscience revealed an association between Aβ, Tau, Circuitry and Cognition. The study was conducted by Dr. Heidi Jacobs, instructor at MGH Gordon Center and a Marie Curie Fellow, and Dr. Keith Johnson, leader of the Aging NeuroImaging Program at the MGH Gordon Center, and the Harvard Aging Brain Study.

Using longitudinal multimodal imaging data collected in healthy older individuals, they provided in vivo evidence in humans that amyloid deposition facilitates tau spread along structurally connected pathways and this combination of events is associated with memory decline.

Imaging modalities included positron-emission tomography (PET) and magnetic resonance imaging (MRI). PET imaging was performed using the tracer flortaucipir (FTP), which binds to tau pathology, and the tracer Pittsburg compound-B (PiB), which indicates amyloid deposition. MR imaging was performed using T1-weighted images to measure hippocampal volume, and diffusion tensor imaging (DTI) was used to measure tract diffusivity.

The results of this study showed that hippocampal volume at baseline, a proxy for neurodegenerative processes including tau pathology, predict changes in diffusivity in a tract innervating the hippocampus, the hippocampal cingulum bundle (HCB), and not in a control tract, the uncinate fasciculus (UF).

These diffusivity changes in the hippocampal cingulum bundle were in turn associated with accumulation of tau pathology outside the medial temporal lobe, in the connected posterior cingulate cortex (PCC), in individuals with elevated levels of amyloid pathology. Finally, the combination of these diffusivity changes in the hippocampal cingulum bundle and higher levels of posterior cingulate cortex tau were associated with memory decline in individuals with elevated levels of amyloid pathology. These findings suggests that amyloid plays a crucial role in driving neurodegenerative processes and cognitive decline, and that monitoring spread of tau pathology will be important in clinical trials focused on removing amyloid plaques in the earliest stages of the diseases.

A detailed summary of this study is featured in AlzForum.

Associations between tract diffusivity, tau accumulation in the PCC, amyloid pathology and memory performance

Jacobs HI, Hedden T, Schultz AP, Sepulcre J, Perea RD, Amariglio RE, Papp KV, Rentz DM, Sperling RA, Johnson KA. "Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals" Nat Neurosci. 2018 Feb 5;

Improving PET Quantitation with Denoising, Motion Compensation, and Deblurring


This article was published in the Nuclear & Plasma Sciences Society newsletter of September 2017

Positron emission tomography (PET) enables 3D visualization of vital physiological information, e.g., metabolism, blood flow, and neuroreceptor concentration by using targeted radioisotope-labeled tracers. Quantitative interpretation of PET images is crucial both in diagnostic and therapeutic contexts. As a result of its unique functional capabilities, PET imaging plays a pivotal role in diagnostics and in therapeutic assessment in many areas of medicine, including oncology, neurology, and cardiology. Accurate quantitation requires correction of PET raw data and/or images for a number of physical effects. These include attenuation correction, randoms and scatter correction, subject motion correction, and partial volume correction. We have developed a range of techniques that address the PET denoising, motion compensation, deblurring problems. Several of these methods greatly enhance the quantitative capabilities of PET particularly by incorporating information from an anatomical imaging modality such as magnetic resonance imaging (MRI).

Faced with a fundamental tradeoff between radiation dose and image noise, PET data is inherently noisy. The high levels of noise in PET images pose a challenge to accurate quantitation. This issue is particularly well pronounced at the early time frames of dynamic PET images, which are usually short to capture rapid changes in tracer uptake patterns. In order to improve image quality and quantitative accuracy, statistical image reconstruction algorithms model the Poisson characteristics of PET data and employ numerical optimization algorithms to solve the corresponding optimization problem [1, 2]. Common reconstruction procedures, such as ordered subsets expectation maximization, are therefore routinely followed by a post-filtering step for denoising the reconstructed image. A range of strategies have been proposed for post-reconstruction denoising of both static and dynamic PET images [3, 4]. In recent years, image denoising based on non-local means (NLM) has become popular [5]. Unlike conventional neighborhood filters, which use local similarities, in this technique, the search for voxels similar to a given voxel is no longer restricted to its immediate vicinity.

Full article in PDF

Heat-induced-radiolabeling and click chemistry


Yuan H, Wilks MQ, El Fakhri G, Normandin MD, Kaittanis C, Josephson L (2017) Heat-induced-radiolabeling and click chemistry: A powerful combination for generating multifunctional nanomaterials. PLoS ONE 12(2): e0172722. doi:10.1371/journal.pone.0172722


A key advantage of nanomaterials for biomedical applications is their ability to feature multiple small reporter groups (multimodality), or combinations of reporter groups and therapeutic agents (multifunctionality), while being targeted to cell surface receptors. Here a facile combination of techniques for the syntheses of multimodal, targeted nanoparticles (NPs) is presented, whereby heat-induced-radiolabeling (HIR) labels NPs with radiometals and socalled click chemistry is used to attach bioactive groups to the NP surface. Click-reactive alkyne or azide groups were first attached to the nonradioactive clinical Feraheme (FH) NPs. Resulting ªAlkyne-FHº and ªAzide-FHº intermediates, like the parent NP, tolerated 89Zr labeling by the HIR method previously described. Subsequently, biomolecules were quickly conjugated to the radioactive NPs by either copper-catalyzed or copper-free click reactions with high efficiency. Synthesis of the Alkyne-FH or Azide-FH intermediates, followed by HIR and then by click reactions for biomolecule attachment, provides a simple and potentially general path for the synthesis of multimodal, multifunctional, and targeted NPs for biomedical applications. Download Full Article in PDF

Outline of heat induced radiolabeling (HIR) and click chemistry surface functionalization used to obtain multimodal, targeted NPs.

Neuroplastic Changes in Blind Individuals



This article was initially published by the RSNA Daily Bulletin on November 30, 2016.

Dr. Laura Ortiz-Terán is a clinical radiologist and neuroimaging research scientist at the MGH Gordon Center. She works with Dr. Jorge Sepulcre to investigate the neuroplastic changes occurring in blind individuals, adults and children, using graph theory based resting-state functional connectivity analysis.