Lea Grinberg, Professor

Closed (1) Validation of neuroimaging using high-resolution histology

Applications for Fall 2018 are now closed for this project.

This project aims to build tools to establish whole-brain, point-to-point correlations between high-resolution histology data and in-vivo imaging, focusing especially on scans with PET tracers, including tau tracers.

In recent years, there have been considerable efforts to develop biomarkers for neurodegenerative diseases. Imaging markers that directly detect core pathologic features are particularly appealing, as demonstrated by the transformative impact that amyloid-beta (Aβ) PET has had on Alzheimer’s disease (AD) research and drug development. Analogously, the recent advent of PET tracers specific for tau brain aggregates could be a “game changer” by enabling “molecular diagnosis” of individuals with underlying tauopathies. Furthermore, tau tracers have the potential benefit to inform on disease progression and detect subtle effects of modifying-treatments.

Postmortem examination is the gold standard for the diagnosis of neurodegenerative diseases. The use of histological examination as a reference matrix in a voxel-by-voxel approach to validate neuroimaging findings provides a unique tool to understand the nature of in vivo imaging signals. The Grinberg Lab has developed a pipeline using ex-vivo and in-vivo MRI scans to map in-vivo images point-to-point to their histological counterpart at an unprecedented 0.1x0.1x0.1mm resolution. This pipeline overcomes challenges faced by previous attempts to co-register MRI to histology as the innovative brain-tissue processing was specially designed to yield higher quality images with considerably fewer distortions and to support big-data analysis.


A. The incumbent will work with Maryana Alegro, Ph.D a computer scientist specializing in using advanced computing tools for microscopic imaging analysis. Dr. Alegro is a post-doc and fellow of the Berkeley Institute of Data Science. The incumbent will help Maryana in building algorithms using python language, testing, implementing and applying this algorithms in different projects at the Grinberg Lab. This is an excellent opportunity for students with a strong background in coding and interest in biology to acquire hands on experience in applying the computing skills in real case scenarios with a unique collection of data from human postmortem studies and neuroimaging. Please check the Grinberg Lab website for more details on our use of computing tools and publications in this field.

Day-to-day supervisor for this project: Maryana Alegro, Post-Doc

Qualifications: - strong background in coding - experience with python language is a plus - interest in neuroscience and imaging analysis

Weekly Hours: 9-11 hrs

Off-Campus Research Site: the work is held at the Grinberg Lab located at UCSF - Mission Bay campus. It is possible that after the initial training, part of the work will take place at the facilities of the Berkeley Institute of Data Science at UC Berkeley campus

Related website: http:\\grinberglab.ucsf.edu

Closed (2) Neuropathological changes underlying clinical heterogeneity in Alzheimer disease

Applications for Fall 2018 are now closed for this project.

Alzheimer's disease has been widely considered to be a rather homogeneous clinical feature. AD characteristic neuropsychological deficits would be a reflection of the spread of neuritic plaques and neurofibrillary tangles (NFT) throughout a non-random anatomical sequence across specific neural networks. However, the concept of clinicopathological homogeneity in AD has been challenged by studies showing atypical clinical presentations differing from the classical amnestic deficits. This is well-illustrated by cases of posterior cortical atrophy and logopenic variant progressive primary aphasia (PPA),
which almost universally show AD pathology. Interestingly, the
neuropathological progression of atypical AD presentations fit the semi-quantitative schemes (i.e., CERAD score, Thal, and Braak staging) devised for typical cases.
Recent work suggests that a localized changes in the cortical/hippocampal ratio of neurofibrillary tangles may contribute to an atypical presentation in AD cases. For example, the limbic type is correlated with a milder and slower progression and the hippocampus-sparing type with a more aggressive
clinical presentation. Furthermore, a growing number of studies suggests that recently identified neurodegenerative changes may potentially modify clinical AD presentation when co-occurring with a primary AD pathology.
In the same line, a distinctive limbic form of TDP-43 proteinopathy potentially accelerates clinical progression and increase symptoms severity in AD cases. Finally, argyrophilic grain disease, (AGD), an underrecognized but frequent, 4R-tau neurodegeneration may slow the progression of AD amnestic symptoms, albeit enhancing neuropsychiatric symptoms. Structured studies in well-characterized clinicopathological cohorts are needed to decipher the impact of these novel neurodegenerative changes in AD clinical phenotype. Such studies may indicate how these neurodegenerative changes interact with the recently described AD neuropathological subtypes, in which situations and how they
affect the clinical presentation and AD progression and, whether they correlate with specific genetic variations.
The long-term goal is to provide an integrated picture of the neuropathological basis of dementia in AD and identify risk factors and antemortem markers corresponding to these changes. The short term goal is to take advantage of a very well-characterized clinicopathological collection, enriched for atypical AD cases to identifying clinical features and genomic variants associated with recently described neuropathological changes in the context of AD pathology. The central hypothesis for this proposal is that particular neurodegenerative changes may results in harmful but also beneficial clinical effects when overlapping with a primary AD pathology. Modulating these changes may affect the clinical outcome and quality of life of these patients.


The undergraduate will work directly with the PI in organizing, annotating, and keeping track of the experiments involved in this project.
The undergraduate will be exposed to lab routines, learn how to organize scientific projects and if interested learn the neuropathology of Alzheimer's disease.
The candidate will be a member of the UCSF/Memory and Aging Center and have access to all training programs offered by the MAC and Grinberg lab.
The student will have the opportunity to work with immunohistochemistry and microscopy techniques.

Qualifications: The candidate must demonstrate great organizing and communication skills. Interest in dementia is desirable. Knowledge of statistics is a plus.

Weekly Hours: 9-11 hrs

Off-Campus Research Site: UCSF - MISSION BAY
675 Nelson rising Lane, room 292
San Francisco, CA 94158

Related website: http:\\grinberglab.ucsf.edu

Closed (3) Polarized light imaging (PLI) of gross histological human brain sections

Closed. This professor is continuing with Spring 2018 apprentices on this project; no new apprentices needed for Fall 2018.

Characterizing microstructural changes that occur in neurodegenerative diseases is vital for understanding pathogenesis and developing effective treatments. Diffusion tensor imaging (DTI) is an extremely useful technique to illustrate microstructural anatomy in the brain in vivo. A drawback to this imaging technique is a relatively low isotropic resolution (2mm.) At this resolution, axonal pathways – especially crossing pathways – become distorted. With the use of histological sections, there are higher-resolution alternatives to DTI. One of these is the use of polarized light imaging (PLI).

PLI utilizes the physical properties of myelin to infer axon direction. The myelin sheaths surrounding axons contain lipids and proteins. The radial arrangement of these biomolecules leads to predictable birefringence of linearly-polarized light. By measuring the degree of birefringence, the 3-D orientation of axons can be calculated based off of the refractive properties of the surrounding myelin. Utilizing image-processing algorithms, the tissue section can be viewed with the DTI color-scheme at a resolution on the micron scale. In collaboration with Prof. Dr. med. Hubertus Axer at Jena University Hospital, Germany, we are developing protocols and equipment to capture PLI images of whole-brain histological sections with an aim to characterize disease-related changes to neuronal connectivity and brain microanatomy.

The incumbent will work with Maryana Alegro, Ph.D a computer scientist specializing in using advanced computing tools for microscopic imaging analysis. Dr. Alegro is a post-doc and fellow of the Berkeley Institute of Data Science. The incumbent will help Maryana will building algorithms using python language, testing, implementing and applying this algorithms in different projects at the Grinberg Lab. This is an excellent opportunity for students with a strong background in coding and interest in biology to acquire hands on experience in applying the computing skills in real case scenarios with a unique collection of data from human postmortem studies and neuroimaging. Please check the Grinberg Lab website for more details on our use of computing tools and publications in this field

Day-to-day supervisor for this project: Maryana Alegro, Post-Doc

Qualifications: - strong background in coding - experience with python language is a plus - interest in neuroscience and imaging analysis

Weekly Hours: 9-11 hrs

Off-Campus Research Site: the work is held at the Grinberg Lab located at UCSF - Mission Bay campus. It is possible that after the initial training, part of the work will take place at the facilities of the Berkeley Institute of Data Science at UC Berkeley campus

Related website: http:\\grinberglab.ucsf.edu

Closed (4) Diagnosing and monitoring prodromal Alzheimer’s Disease using novel locus ceruleus-based imaging volumetry

Applications for Fall 2018 are now closed for this project.

Despite intensive research on AD, effective disease-modifying treatments remain elusive, and novel tools for non-invasively assessing early brains lesions are needed. Our lab confirmed that the brain structures that consistently exhibit the earliest neuropathologic changes in AD, including neuronal loss, are not classically AD-associated cortical regions, but rather are centered in key aminergic brainstem nuclei, including the locus ceruleus (LC) and dorsal raphe. Furthermore, with postmortem tissue, we found that in AD, but not in normally-aging controls, LC showed progressive, AD (Braak) stage-related quantifiable volumetric losses. Namely, LC volume shrinks by an average of 25% before onset of significant neuronal loss at Braak stage 3, which usually coincides with AD-defining clinical symptoms. These findings suggest that longitudinal MRI-based LC volumetry might provide a useful noninvasive tool for screening and monitoring AD progression for clinical studies and therapy trials in patients developing AD.

The overall goal of this project is to develop a histologically-validated magnetic resonance imaging (MRI)-based algorithm for assessing longitudinal LC volumetric changes that capture AD-associated neuropathological progression in single subjects, and this goal has widespread potential for application to clinical studies and research into AD.

We will generate templates by a step-wise strategy, using (1) 3D reconstructions of LC from whole postmortem brain tissues, (2) correspondence from 3D LC reconstructions to postmortem in cranio (pre-procurement) 7T MRIs, (3) landmark-based and intensity-based registration techniques that are superior to voxel-based morphometry (VBM) to detect the LC, (4) voxel-wise correspondence between postmortem in cranio 7T and 3T MRIs, and (5) mapping from postmortem to antemortem 3T MRI. Our optimized histological processing and automated reconstruction algorithms accelerate processing to permit scaling up discovery to many subjects in combination.

We hypothesize that MRI-based LC volumetric changes correlate directly with AD stage-related LC histological atrophy and that quantitative LC volumetry will yield a tool to monitor early AD pathology from asymptomatic stages. When effective therapies emerge, early diagnosis will offer the potential to rescue neuronal function and interdict AD progression. MRI-based LC volumetry could be developed for longitudinal screening to help select high-risk candidates for less accessible, more expensive and invasive studies (e.g. PET scan; CSF assays).

The Specific aims are:
1. Histology-centric: Create histology-based MRI template from postmortem 7T MRI and high-resolution histology in 20 subjects ranging Braak 0-6 in AD progression.
2. MRI-centric:Translate the 7T MRI template into a 3T MRI template using subjects with ante-mortem 3T MR scan, postmortem 3T and 7T MR scans, and postmortem assessment and 3D recon-struction.
3. Precision-centric: Assess extent to which A) longitudinal changes in LC volume detected on serial 3T structural MRIs are associated with changes in hippocampal volume, NbM, cognitive parameters and Aβ PET; and B) longitudinal changes in LC volume precede tau detection by PET Scans, and predict the magnitude and spatial extent of tau burden in ADNI 2 and UCSF subjects.



The student will assist in this project by working with digitizing histological images, tracing the regions of interest, learning how to do computer-assisted 3D histological reconstructions of the human brain and co-registering histological images to neuroimaging.

Day-to-day supervisor for this project: Maryana Alegro, PhD

Qualifications: - detailed-oriented - good team player - quick learner - dependable - knowledge of neuroanatomy, photoshop and passion for neurodegenerative disease research are pluses

Weekly Hours: 9-11 hrs

Off-Campus Research Site: UCSF
MISSION BAY CAMPUS
675 Nelson Rising Lane, 94158
San Francisco