Lea Grinberg, Professor

Closed (1) Neurobiological basis of sleep/wake disturbances in PSP

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

The great majority of PSP patients suffer from sleep problems. In many instances, the sleep problems are apparent even before other symptoms caused by PSP. Sleep is a restorative process, as it conserves metabolic energy, participates in the formation of immunological memory and it is vital to survival. The sleep/wake cycle is regulated by a complicated interplay of several interwoven neuronal centers, each one with distinctive features.
Proper treatment depends on which part of the network is dysfunctional. Medication to treat specific sleep problems is elusive. The most used sleep drug on the market, Zolpidem works by shutting the brain down, rather than targeting the dysfunction. Through the support of the Tau Consortium we found that PSP hits the sleep centers in a specific way. It may explain why PSP patients have a unique pattern sleep disorders as identified by consortium members. To further understand the neurobiological basis of sleep disturbances in PSP, we will use unbiased quantitative methods to investigate sleep-regulating areas in postmortem PSP brains and compare the results with other tauopathies. Our goal in this cycle is to compose a picture of differential vulnerability of sleep regulating neurons across these related diseases.
The knowledge gained will be the first step for correlating the clinical symptoms with specific brain damage, may suggest new biomarkers and potential therapies. Integrative histopathological studies in humans remain critical to understanding neurodegenerative and serve as a foundation for ongoing and future translational research, in line with the Tau Consortium Mission.

Role of the undergraduate: To learn neuronal estimation using stereology and count neurons of the cases being studied

Qualifications: Required: coursework in neurosciences Desirable: previous experience with human brain anatomy Desirable: previous experience with neurostereology

Weekly Hours: more than 12 hrs

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

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

Open. Apprentices needed for the fall semester. Enter your application on the web beginning August 15th. The deadline to apply is Monday, August 27th at 9 AM.

Alzheimer's disease has been widely considered to be a rather homogeneous clinical feature. AD
characteristic neuropsychological deficits would be a reflect of the spread of neuritic plaques and neurofibrillary
tangles (NFT) throughout a non-random anatomical sequence across specific neural networks (Duyckaerts et
al. 2009). However, the concept of clinicopathological homogeneity in AD has been challenged by studies
showing atypical clinical presentations differing from the classical amnestic deficits (Korczyn 2013). This is
well-illustrated by cases of posterior cortical atrophy and logopenic variant progressive primary aphasia (PPA),
which almost universally show AD pathology (Gorno-Tempini et al. 2008; Crutch et al. 2012). 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 (Tang-Wai et al. 2004; Mesulam et al. 2008).
Recent work suggests that a localized changes in the cortical/hippocampal ratio of neurofibrillary tangles may
contribute to an atypical presentation in AD cases (Murray et al. 2011) . 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. Munoz et al. identified so-called argyrophilic thorny astrocyte clusters (ATACs) in seven out of
eight patient with AD pathology underlying a non-fluent (nf) PPA clinical presentation (Munoz et al. 2007). In
the same line, a distinctive limbic form of TDP-43 proteinopathy potentially accelerates clinical progression and
increase symptoms severity in AD cases (Josephs et al. 2014). Finally, argyrophilic grain disease, (AGD), an
underrecognized but frequent, 4R-tau neurodegeneration may slow the progression of AD amnestic symptoms
(Grinberg et al. 2013; Steuerwald et al. 2007), 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.
My 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. My 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. My 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. I plan to test our central hypothesis by pursuing the following three specific aims:
Specific Aim #1: To identify the impact of co-occurring argyrophilic grain disease (AGD) in AD

Specific Aim #2: To identify the impact of co-occurring argyrophilic thorny astrocyte clusters (ATACs)
in AD

Specific Aim #3: To identify the impact of co-occurring limbic-type TDP43 proteinopathy in AD

the undergraduate will work directly with the PI in organizing, keeping track and annotating 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

Qualifications: the candidate must demonstrate great organizing and communication skills. Interest in dementia is desirable.

Weekly Hours: 6-8 hrs

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

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

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

Open. Apprentices needed for the fall semester. Enter your application on the web beginning August 15th. The deadline to apply is Monday, August 27th at 9 AM.

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: grinberglab@ucsf.edu