Masdeu Lab

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About Our Lab

Our Team

Using the tools of human neuroimaging, including magnetic resonance imaging (MRI), positron emission tomography (PET) and electroencephalography (EEG), the neuroimaging lab aims to clarify the neurobiology and improve the treatment of the following disorders causing cognitive impairment.
 
 
Alzheimer’s disease
  • Timing of beta-amyloid and tau deposition in preclinical stages
  • Genetic effects
  • Effect of treatment
  • Correlation of tau imaging with postmortem tau quantification

Frontotemporal dementia
  • Genetic underpinning of regional involvement patterns
  • Neuroimaging correlates of social cognition

Traumatic brain injury
  • Amyloid and tau imaging in acute and chronic concussion
  • Timing and brain localization of tau deposition in patients with repeated head trauma

Schizophrenia
  • Anti-synaptic antibodies and their effect on functional connectivity

Working with the MRI and PET facilities in the Translational Imaging Core of the Houston Methodist Research Institute and with the collaboration of a number of external researchers, the lab has utilized and implemented the following techniques:

MRI-related
  • Structural MRI
  • BOLD MRI
  • Activation
  • Resting, with functional connectivity
  • Diffusion tensor imaging (DTI)
  • Susceptibility weighted imaging (SWI)
  • Arterial spin labeling (ASL) 

PET
PET Radiopharmaceuticals
  • [18F] Fludeoxyglucose
  • [11C] Pittsburgh compound B
  • [18F] T807 (AV-1451)
  • [18F] Fluoro-L-DOPA
  • [11C] PBR28

 

Scientific Discoveries 

 

There is an inverse regional relationship between the amount of tau and metabolism in the brain
Our laboratory was the first to report that areas of the brain that have abnormal hyperphosphorylated tau deposition have decreased metabolism, with a high anatomical concordance. In the healthy brain, the protein tau stabilizes neurotubules and is therefore essential for normal neural function. However, in Alzheimer’s disease and other neurodegenerative disorders, tau becomes abnormally hyperphosphorylated, dysfunctional and misfolded, constituting the neurofibrillary tangles observed neuropathologically in Alzheimer’s disease and other tauopathies [1]. We discovered that there is an inverse regional relationship between the amount of tau in the brain and the metabolism in the same region: regions with high tau have low metabolism and vice-versa [2]. By contrast, this relationship does not apply to amyloid deposition: areas with high amyloid load (for instance, the calcarine cortex in Fig 1) may have normal metabolism. An image from the paper reporting this finding was used to illustrate the cover of the article where this research was published [2]. This finding has critical implications: because metabolism indicates the activity of the various regions of the brain, and it is depressed precisely in those areas with a high load of tau, but not amyloid, this finding suggests that it is tau that is critical, rather than amyloid, to the development of clinical impairment in the disease [1]. It also suggests that monitoring the spreading of tau will be a powerful biomarker for the progression of the disease and that tau imaging can be used to monitor the effectiveness of potential new therapies, perhaps using patient samples much smaller than needed when cognitive impairment is used as an outcome, as currently done.

 

This finding does not mean that therapeutic approaches targeting amyloid are useless. They may well work in the pre-tau stage of the disease, when people predisposed to developing Alzheimer’s are still asymptomatic, but they are unlikely to help once tau has spread to neocortical networks. This assumption is supported by the recent announcements of the failure of amyloid-removing clinical trials at the early Alzheimer’s disease stages.

 

 

 

Fig 1. 18F-FDG, 18F-florbetapir, and 18F-AV-1451 PET superimposed to native MRI. Yin-yang relationship between tau and metabolism in the brain of a patient with Alzheimer’s disease. Multimodality positron emission tomography (PET) images are superimposed to native MRI. Primary sensory-motor areas (asterisks), as well as the primary visual (striatal cortex) and auditory (Heschl’s gyrus) regions (arrowheads) have normal metabolism and no tau deposition. Areas with high tau deposition (e.g. inferior parietal lobule, arrows) have decreased metabolism. This relationship does not apply to amyloid: notice high amyloid uptake in the calcarine cortex on the 18F-florbetapir scan (central column, arrowheads). AVID Radiopharmaceu-ticals provided the precursor for 18F-AV-1451.

 

Tau propagates within  natural brain networks (“neurons that wire together degenerate together”)
Tau propagates within  natural brain networks (“neurons that wire together degenerate together”).

Our  laboratory has produced the first direct in  vivo demonstration that tau spreads across the language network. We  evaluated with tau (18F-AV-1451) PET a group of patients with the  nonfluent variant of primary progressive aphasia (nfvPPA), a progressive  neurodegenerative disorder that is, like Alzheimer’s disease, tau-dependent [3], and a  group of healthy controls. Both patients and controls were amyloid-negative,  and did not differ significantly in age and sex. PET images from 80 to 100 min  were averaged, and standardized uptake value ratios were calculated using the  mean activity in the cerebellar gray matter as the reference region.  Additionally we determined functional connectivity with BOLD MRI in a group of  healthy volunteers group-matched to the patients, using as seed the volume of  the largest tau cluster in the nfvPPA group.

On  voxel-wise analysis and compared to controls, patients with nfvPPA had  increased tau uptake (p < 0.001) in two major clusters. The larger cluster  was in Broca’s area. The smaller cluster was located in the planum temporale of  the superior temporal gyrus, extending to the supramarginal gyrus (Wernicke’s  area). As expected, MRI functional connectivity from the location of the larger  tau cluster was greatest with a region located in the same area as the smaller  tau cluster [4]. 

 

 

Fig  2. Tau, detected with 18F-AV-1451 PET in patients with non-fluent  primary progressive aphasia, propagates in the language network. Significant  areas of increased 18F-AV-1451 deposition in patients compared to  age and sex-matched healthy controls (p < 0.001). The largest cluster is in  the premotor region of the frontal lobe (Broca’s area). The smaller cluster is  in the planum  temporale (Wernicke’s  area), immediately posterior to the transverse temporal gyrus of Heschl.

 

 

Fig  3. Functional MRI connectivity map of the language network. Using  resting functional MRI data from healthy volunteers matched to the patients  whose data is shown in Fig 2, a seed was placed in the region with the greatest  tau deposition in the patients. This region was shown to connect most strongly  with precisely the region of the brain containing the second strongest tau peak  in patients, in Wernicke’s area.

 

 

Regions of “off-target-binding” in 18F-AV-1451 PET of healthy older people have increased permeability in older as compared to younger persons
In older healthy subjects, [18F]AV-1451, which is supposed to bind to hyperphosphorylated tau, also seems to bind to regions (putamen and other nuclei) known not to have abnormal tau deposition on neuropathology (Fig 4). This so-called “off-target” binding has caused reports of abnormal tau deposition in tau PET studies of people who were actually normal. Our aim was to determine whether apparently increased specific [18F]AV-1451 binding in areas unlikely to harbor hyperphosphorylated tau, such as the substantia nigra, globus pallidus and putamen, of older subjects could be related to greater vascular permeability of these regions in older subjects as compared to younger ones.

For this purpose we measured dynamic [18F]AV-1451 uptake over a three-hour period in younger (23±2.1 years of age) and older (68.8±7.6 years) healthy subjects. In the same subjects we obtained dynamic gadolinium concentrations before and after a bolus injection of gadolinium, a large molecule commonly used to assess the permeability of the blood-brain barrier, by performing a pre-contrast 3D T1 map (five flip angle acquisitions) followed by a dynamic contrast enhanced MRI (DCE-MRI). During and after infusion, we acquired 180 consecutive T1-weighted volumes (3.4 sec per volume) over 10 minutes. Non-displaceable binding potential (BPND) of [18F]AV-1451 and permeability parameters (Ktrans) of gadolinium were analyzed by volume-of-interest methods and compared using Spearman’s correlation coefficients.

We found that there was greater BPND of [18F]AV-1451 in the globus pallidus and putamen (but not in cerebellum or cerebral cortex) of older as compared to younger subjects (Fig 4). Gadolinium concentration and permeability (Ktrans) was similar in the cerebellum, temporal cortex, and choroid plexus of younger and older subjects, but there was higher permeability in the substantia nigra, globus pallidus, and putamen (all p<0.05) of older as compared to younger subjects (Fig 5). Correlations between BPND and Ktrans were significant for substantia nigra, globus pallidus and putamen (all p<0.05) [5].

 

 

Fig 4. Tau ([18F]AV-1451) PET shows greater uptake in “off-target” regions in older than in younger people. [18F]AV-1451 PET superimposed to native MRI in a younger (left) and an older (right) adult. Uptake in these regions has been misinterpreted in some publications to represent tau deposition, when several neuropathological studies have failed to show abnormal tau in these regions. 

 

 

Fig 5. Gadolinium concentration was greater in “off-target” regions in older than in younger people. Anatomic panels on the left show the position of the volumes of interest for the graphs depicted on the right. Each graph shows gadolinium concentration in the Y axis and time post bolus injection in the X axis.

 

In summary, our work showed that increased vascular permeability in substantia nigra, pallidum and putamen of healthy older subjects could underlie some of the regional differences in [18F]AV-1451 uptake observed in older as compared to younger healthy subjects. These data are most relevant for the correct interpretation of the findings present in [18F]AV-1451 PET scans. This compound is now widely used to measure abnormal tau at all stages of the Alzheimer’s disease neurobiological continuum.

 

Most Recent Publications on Alzheimer’ Disease and Related Disorders (cited above):

  • Masdeu, J. (2016) Misfolded tau, Alzheimer's bogeyman, exposed. JAMA Neurol in press.
  • Pascual, B. and Masdeu, J.C. (2016) Tau, amyloid, and hypometabolism in the logopenic variant of primary progressive aphasia. Neurology 86, 487-488.
  • Masdeu, J.C. and Pascual, B. (2016) Genetic and degenerative disorders primarily causing dementia. Handb Clin Neurol 135, 525-564.
  • Pascual, B., Zanotti-Fregonara, P., Funk, Q., Rockers, E., Pal, N., Yu, M., . . . Masdeu, J. (2017) Nonfluent variant of primary progressive aphasia: Tau deposition in the language network. In Human Amyloid Imaging Conference.
  • Pascual, B., Rockers, E., Bajaj, S., Yu, M., Karmonik, C., Xue, Z., and Masdeu, J. (2016) Older healthy people have increased vascular permeability in regions showing “off-target” [18F]AV-1451 uptake. In Alzheimer's Association International Conference.

Our Team

Local Collaborators

Distant Collaborators

  • Brad C. Dickerson, MD, MGH/HST Athinoula A. Martinos, Boston, MA
  • Nikos Makris, MD, PhD, MGH/HST Athinoula A. Martinos, Boston, MA
  • Paolo Zanotti Fregonara, MD, PhD, NIH

Lab Alumni

  • M. Samy Abdullah, MD, Postdoctoral fellow (Neurology Resident at UT San Antonio)
  • Sahil Bajaj, PhD, Postdoctoral fellow
  • Jordan Ashcraft, BS, Research assistant (graduate school of med., Univ. of Florida)
  • David Dalton, BS, Research assistant (graduate school of med., UT San Antonio)
  • Nate Lee, BS, Research assistant (graduate school of medicine, Georgetown Univ.)
  • Mark Hollenbeck, BS, Programmer / Data analyst 
  • Clarisa D. Ting, BS, Research assistant
  • Neha Pal, BS, (graduate school of medicine, Texas A&M)
  • Carolina Sirias, Undergraduate student (undergraduate school, UT Austin)

 

Open Positions

Houston Methodist in Houston, Texas is a leading academic hospital system dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. Throughout the department of neurology at Houston Methodist, our mission is to deliver superb patient care, to apply state-of-the-art translational research methods to discover the causes of and treatments for human nervous system disorders and to educate each generation of medical students, neurology residents, and postdoctoral fellows. By fostering cross-disciplinary interactions among scientists around the world, we accelerate the pace of discovery and champion global health initiatives. For any positions at Houston Methodist, the first step is to apply online. To find out about open positions, please visit Houston Methodist’s career page and select search openings. The neuroimaging lab often has opportunities available.  

 

Research Assistant:

Primary responsibilities include neuroimaging data analysis, behavioral analysis, data management, and general scientific programming. Standard software tools will be used for the statistical analysis of structural and functional magnetic resonance imaging (MRI), as well as positron emission tomography (PET). A strong background in computer programming and Linux is essential. Applicants must hold a bachelor’s or master’s degree in computer science, engineering, math or physics, although other backgrounds with requisite experience will be considered.  Proficiency in Matlab, shell scripting, and python is strongly encouraged. Familiarity with common neuroimaging tools is a plus (Freesurfer, FSL, AFNI, SPM, Slicer, etc.). The candidate is also expected to assist in the management of neuroimaging data, therefore, database experience (MySQL, PostgreSQL) and/or experience with neuroinformatics software (XNAT) is highly beneficial. The ideal candidate must be mature and responsible, with excellent organizational, as well as oral and written communication skills. You must be able to work independently in a fast-paced environment, juggle and prioritize multiple tasks, and seek help when required.

 

For more information call 713.441.1150 or e-mail alzheimer@houstonmethodist.org 

 

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