UCSF Achieves Major NIH Designation for Moving in on Alzheimer's Disease and Other Dementias

By Jennifer O'Brien

With the aim of accelerating the pace of discovery regarding dementing diseases, the UCSF Memory and Aging Center has been designated an Alzheimer’s Disease Research Center by the National Institutes of Health, making it the only new center in the United States to receive the highly competitive funding designation in 2004.

The Center, which will receive $6.5 million in funding over five years (with the opportunity for renewal), will fuel the integration of resources between the strong clinical and basic research programs focused on dementia and aging at UCSF and its affiliated institutions, and will tap into UCSF’s genetics and neurosciences programs more broadly.

The Center is one of the few NIH-designated centers that will focus not only on Alzheimer’s disease, but also on non-Alzheimer’s forms of dementia, such as frontotemporal dementia and prion diseases, including Creutzfeldt Jakob disease and new variant CJD, the human form of “mad cow” disease.

Clinician-scientists pioneering novel strategies for diagnosing and treating patients, and basic researchers working in cell and animal models, will now have the infrastructure to significantly increase their ability to share data and collaborate on studies regarding the clinical, neuroimaging, neuropathological and molecular features of Alzheimer’s disease and non-Alzheimer’s disease dementias.

Clinical data on well-characterized patients will be correlated with patients’ brain scans and autopsied brain tissue. Behavioral and pathological changes observed in animal models will inform efforts to understand and treat dementias in humans. Patients seen in the center could prove candidates for therapeutic strategies and diagnostic tests developed by basic researchers.

“UCSF’s neurosciences are among the finest in the world,” says Bruce Miller, MD, Director of the UCSF Memory and Aging Center and principal investigator of the newly designated Center. “By promoting the integration of data between clinician-scientists and basic researchers at UCSF, the SF Veterans Affairs Medical Center and the UCSF-affiliated Gladstone Institute for Neurological Disease, we hope to enhance our understanding of the heterogeneity and overlapping presentations of different neurodegenerative disorders, expand investigations into the early clinical manifestations of dementia and improve diagnostic and therapeutic strategies.”

## Clinical Research

Funding for the Center’s Clinical Core will significantly increase the number of patients examined at the two sister clinics, the UCSF Memory and Aging Center at UCSF Medical Center Hospital and the SF VA Medical Center, where physicians are working to develop new strategies for diagnosing patients, focusing on cognitive, behavioral, psychological, genetic and anatomical characteristics.

Many patients will be referred to the Center’s Imaging Core, directed by Michael Weiner, MD, UCSF professor of radiology at the SF VA Medical Center. His team, using a newly NIH-funded 4.0 Tesla magnet, will carry out one of the first comprehensive dementia studies using MRI at high magnetic fields, and will produce novel structural, chemical and physiological data that will be used to study brain-behavior relationships and the role of MRI in the differential diagnosis of dementias.

Meanwhile, biological specimens (brain tissue from biopsies and autopsies) correlated with diagnostic, clinical, neuropsychiatric and genetic information will be sent to the Neuropathology Core, directed by Steven DeArmond, MD, PhD, UCSF professor of pathology and neuropathology. Once there, specimens will be transferred to scientists carrying out studies on specific forms of dementia, from Alzheimer’s disease, to frontotemporal dementia, to prion diseases.

The excitement is palpable. “We’ve already started receiving biological samples from autopsied patients,” said a swiftly moving DeArmond recently, as he passed through the halls on Parnassus Ave., one of the sites of the research. DeArmond is interested in the mechanisms of prion diseases and in identifying targets for treatment.

The data accrued on patients will be disseminated through a Data Management and Biostatistical Core, directed by Patrick Fox, PhD, UCSF professor of sociology and health policy and co-director of the UCSF Institute for Health & Aging, which will maintain high patient-confidentiality standards, including HIPPA guidelines.

Meanwhile, an Administration, Education and Outreach Core will enable UCSF and VA clinicians to increase their outreach to underserved patient populations (particularly Asian-Pacific-Islander populations) and community physicians in San Francisco, working to educate them about the latest diagnostic techniques and treatment options. Culturally sensitive material in the appropriate native language will be used to recruit minorities.

This Core, which will be co-directed by Miller and Lennart Mucke, MD, director of the UCSF-affiliated Gladstone Institute of Neurological Disease and Joseph B. Martin Distinguished Professor of Neuroscience at UCSF, will also promote education within UCSF’s clinical and research neuroscience community, which includes programs in neuroscience, genetics, neurology, psychiatry, nursing, pharmacy and medicine.

## Basic Research

The new designation also funds two new basic research investigations—one on Alzheimer’s disease, led by Mucke, the other on prion diseases, led by Nobel laureate Stanley B. Prusiner, MD, UCSF professor of neurology and director of the Institute for Neurodegenerative Diseases at UCSF. It also funds several smaller research projects concerning dementia and other forms of neurodegeneration.

Demonstrating the cross over between studies in animals and humans, Mucke will continue his investigation both in mouse models of Alzheimer’s disease and in biological specimens from humans into the relationship between cognitive deficits and calcium-dependent proteins in two memory centers of the brain affected in Alzheimer’s disease, the hippocampus and dentate gyrus. He has already shown that one such protein, known as calbindin, is severely depleted in the dentate gyrus of people with Alzheimer’s disease, and in mouse models simulating this condition. In the mice, these molecular alterations strongly correlated with learning deficits, and preliminary results suggest that they may also correlate with the severity of dementia in humans.

In his ongoing work, Mucke and his coworkers will search for additional molecular markers and mediators of Alzheimer’s disease-related neurological deficits. They also plan to study why so many patients with this condition have a tendency to wander and are unable to find their way back home. If scientists understood the mechanisms that underlie this problem, he says, they might be able to identify ways to prevent patients from getting lost, which would spare the patients and their families a great deal of emotional turmoil.

“The functions of path-finding and returning to one’s home can be readily studied in Alzheimer mouse models, and the results of such studies could offer valuable insights into what goes wrong in humans with the disease,” says Mucke.

Prusiner, who won the 1997 Nobel Prize in Physiology or Medicine for discovering prion (PREE-on) protein, and determining that it has the susceptibility to be converted to a lethal form, known as a prion, will also carry out a study funded through the ADRC. The investigation is aimed at identifying the structure of a component of the normal protein that is believed to be central to the process by which the protein is converted to the disease causing form of the disease.

A study that will tap into the resources of the ADRC, though it will be funded by The Larry L. Hillblom Foundation, will be led by Aimee Kao MD, the chief resident of neurology at UCSF Medical Center Hospital. Illuminating the synergy being fostered by the new Center, Kao will spend her next year as a clinical fellow in the UCSF Memory and Aging Center seeing patients with dementia with Lewy Bodies. Subsequently, she will study a model of this disease in roundworms in the laboratory of Cynthia Kenyon, PhD, UCSF Herbert Boyer Professor of Biochemistry and Biophysics.

“This is the way to advance at this point,” says Miller, “We have a team of extraordinarily talented and highly dedicated people. We’re embarking on an extremely exciting endeavor that should benefit many people in the Bay area and beyond.”