Psychiatry and
Behavioral Sciences

Memory & Cognition

Cellular Mechanism underlying Memory

Robert Malenka MD, PhD

Dr. Malenka's primary interest is in the detailed mechanisms by which activity, neurotransmitters and drugs modify synaptic transmission in a variety of brain regions including the hippocampus, somatosensory cortex, nucleus accumbens and ventral tegmental area. A major goal of his laboratory is to elucidate both the specific molecular events that are responsible for the triggering of various forms of synaptic plasticity and the exact modifications in synaptic proteins that are responsible for the observed, long-lasting changes in synaptic efficacy. His work on the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) has led to the novel hypothesis that activity can rapidly and profoundly influence the synaptic distribution of glutamate receptors.

Effects of oxybutynin on cognition in children

Barbara R. Sommer, MD
William Kennedy, MD
Ruth O'Hara, PhD

Dysfunctional voiding in children is a surprisingly common problem, occurring in about 15% of children who present to the pediatric urology clinic at Lucile Packard Children's Hospital (LPCH). Specifically, detrusor instability causing daytime incontinence is an embarrassing difficulty that may lead to impaired quality of life. The standard treatment is with anticholinergic medications, begun when behavioral interventions have failed.

Anticholinergic drugs have been associated with memory loss in the elderly, and their administration is a known cause of cognitive impairment in this population. Despite the frequent use of oxybutynin, the prototype anticholinergic drug for detrusor instability, memory testing during its use has never been done in children.

We propose to assess the effects on cognition of oxybutynin in young girls and boys presenting to the LPCH at Stanford pediatric urology clinics, located both at LPCH Stanford and at the Stanford satellite clinic on South Bascom in San Jose. Patients will undergo specific memory testing analogous to the testing done in a previous study of older adults that showed significant decreases in several areas of intellectual function (Katz et al. 1998). Cognitive testing will be performed both before and one month after treatment with oxybutynin. Our hypothesis is that just as in the older adults, children will demonstrate subtle yet significant decrements in both verbal memory and in attention.

This will be a pilot project that will be the first study of its kind, as even in the elderly, deficits from oxybutynin have been evaluated only after one "challenge dose," without follow-up testing. This is potentially a particularly important project because children taking oxybutynin do so for extended periods. Metabolites of the drug may accumulate over time, thus increasing blood levels of the medication. The impact on learning in the classroom could therefore be great.

The project will involve a psychologist administering specific memory tests to children before and one month after the initiation of oxybutynin therapy. Subjects will learn the results of the testing at the completion of the project. A total of 36 subjects will be evaluated along with age-matched control subjects from the pediatric urology clinics. At the completion of the study, we will invite the LPCH psychology staff to a seminar explaining the project's rationale. We will also discuss the importance of testing the cognition of children exposed to anticholinergic medications and the exact test instruments will be reviewed and taught if necessary. As newer medications for dysfunctional voiding become available, LPCH will be in a unique position to quickly evaluate this neglected side effect. The test instruments purchased for this project will be available to LPCH psychologists for future use.

Intravenous dopamine increases the risk for delirium

Barbara R. Sommer, MD
William Kennedy, MD
Ruth O'Hara, PhD

We hypothesized that the administration of intravenous dopamine (DA) increases the risk for delirium as manifested by need for haloperidol. We evaluated the records of all inpatient admissions to Stanford University Hospital over a one year period (N=21,844). To examine the unique contribution of DA in the prediction of need for haloperidol, a multivariate logistic regression model was used. DA administration nearly tripled the odds of also needing the antipsychotic drug (C2=101, d.f.=1, p=.0001, odds ratio 2.9), second as a predictor only to ICU admission. With stratification by illness acuity, DA continued to produce an odds ratio of about 3. We further found that in the ICU setting (N=3309) not even age was as highly correlated with need for haloperidol as was DA administration.

While ours is a retrospective analysis, it is the first to attempt to fully evaluate DA administration as an independent risk factor for delirium. Despite the retrospective nature of this study and the inexact method to assess acuity (DRG weights) and presence of delirium, it seems likely that the use of DA in either the ICU or non-ICU setting significantly increases the risk for delirium. This study suggests the need for prospective studies to evaluate pre-treatment for delirium to decrease morbidity.

Effects of rivastigmine on neuroprotection when given prior to anesthesia in hip and knee surgery patients

Barbara R. Sommer, MD
William Kennedy, MD
Ruth O'Hara, PhD

Post-operative cognitive decline is well-documented in older patients recovering from major surgery. Researchers often attribute this association either to the anesthesia used during the surgery or to some vague and subtle phenomenon that is poorly understood. A recent literature review confirms that the cognitive impairment is multi-factorial, and that anesthesia alone cannot be blamed (Ritchie K et al 1997).

This study aims to acquire preliminary data on cognitive decline in non- cardiac patients and furthermore, to collect data on the prevention of such decline. We suggest that as in Alzheimer's disease, hippocampal damage occurs in these patients and in this case, may be preventable by pre-medication with the cholinesterase inhibitor rivastigmine.

Our specific hypothesis is that patients subjected to the prolonged stress of surgery and post-operative rehabilitation, manifested by abnormally high serum cortisol levels, patients genetically predisposed to cognitive decline, such as those with the APO E4 allele, and those in need of a long and difficult rehabilitation are at risk for cognitive decline. In particular, deficits in verbal learning and semantic memory, reflective of the hippocampal damage seen in other stressful conditions, are anticipated to be the most pronounced.

We propose to prescribe rivastigmine or placebo to 40 elderly patients about to undergo total knee or hip replacements at Stanford University Hospital for a period of 8 weeks after baseline cognitive testing has been administered by an academic cognitive psychologist (ROH). The medication will be continued for one month post-operatively until follow-up testing has been performed. The rivastigmine will be discontinued 5 days prior to surgery in order to avoid intra-operative complications, and re-continued after the patients are out of the intensive care unit.

Stanford Alzheimers Disease Center

In October 2000 Stanford University was awarded a National Institute of Aging Alzheimer's Disease Center. This successful application was led by Dr. Yesavage and is build upon collaborations with several investigators across the University. The overall goal of our NIA Center would be to enable research in several areas by providing Core resources and by fostering interactions between three main groups at Stanford: the neuroscience group (Dr. Mobley and associates); the neuroimaging/neuropsychology group (Dr. Gabrieli and associates); and the sleep group (Dr. Mignot and associates). Key clinical resources are provided by Dr. Tinklenberg's State of California Alzheimer's Disease Center. These new ties will build upon existibng collaborations which include the Stanford/VA Aging Clinical Research Center , VA Geriatric Research Center, Mental Illness Research Education and Clinical Center (MIRECC)

Stanford/VA Aging Clinical Research Center

The Stanford/VA Aging Clinical Research Center (ACRC) has performed research in gerontology for over 20 years. The current major emphasis is Alzheimer's Disease and memory losses associated with normal aging. Our Alzheimer's Disease Center is funded by the National Institute on Aging (NIA). Substantial additional resources are provided by the Department of Veterans Affairs (VA) and the Center is located at the VA Palo Alto Health Care System in Palo Alto, California.

Current studies include:

Investigational Pharmacologic Treatments Study of Early Onset Alzheimer's Disease.

Researchers at the Stanford/VA Alzheimer's Center are conducting a study of women and men between the ages of 45 and 65, using the drug Acetyl-L-Carnitine Hydrochloride (ALCAR). Enrollment for the study has ended, but qualified patients are encouraged to come in for a diagnostic evaluation. For an evaluation, call Maria Alvarado at (650) 858-3915. For information about future drug studies, contact Cinnamon Bloss at (650) 858-3915.

Alzheimer's Disease

"A Double-Blind, Placebo-Contolled Trial of the Safety and Efficacy of C-1073 (Mifepristone) as Adjunctive Therapy in Alzheimer's Disease"
Stanford University School of Medicine is looking for subjects with a diagnosis of mild or moderate Alzheimer's Disease to participate in a six-month study. All study related clinic visits, tests and investigational drug are provided at no cost. Reimbursement for transportation is available. For more information, please contact Jessica Hawkins at (650) 723-8330 or e-mail jhawk@stanford.edu

Research Programs Sexuality Study

We are currently recruiting participants for our sexuality study. The primary purpose of the study is to look at the effects of dementia on intimacy and interpersonal relationships, noting how often difficulties occur. We want to gain a better understanding of these issues and the important needs of those with dementia so that we might develop appropriate ways of helping them stay connected. We wish to conduct interviews with individuals diagnosed with AD and/or partners of those diagnosed with AD. Interested individuals can contact Helen Davies, MS, RNCS or Cinnamon Bloss at (650) 858-3915.

Anti-Dementia Drugs

In collaboration with the Alzheimer's Disease Research Centers of California, we are conducting a study to assess the effectiveness of new Alzheimer's disease anti-dementia drug treatments, as they become available and are used in everyday clinical practice. We are currently looking at Aricept and gingko biloba. We hope to identify characteristics of patients who respond well to specific drug treatments as well as those who respond poorly and/or develop significant side effects. We are recruiting participants diagnosed with AD who are either considering using or are currently taking Aricept and/or gingko on a daily basis. It is preferable for those interested in the study, who have not yet taken either treatment, to contact us prior to doing so. For more information, contact Maria Alvarado at (650) 858-3915.

Other Research Programs

Dr. Dolores Gallagher-Thompson is a diplomate in clinical psychology whose work involves both the VA Palo Alto Health Care System (where she directs the Older Adult and Family Research and Resource Center) and Stanford Univ. Dept. of Psychiatry, where she is an Associate Professor of Research. Her current research focuses on evaluation of various intervention strategies to reduce psychological distress in family members who provide primary in-home care to older individuals with Alzheimer's disease or other forms of dementia.

For the past 5 years, she has been Principal Investigator at the Palo Alto site of a 6 site national study on caregiver interventions, funded by the National Institute on Aging, called Project REACH (Resources for Enhancing Alzheimer's Caregivers' Health). Overall results are still being compiled, but interim results indicate that a variety of interventions are efffective on a number of mental health indices, including classes to develop skills for enhanced coping with caregiving stress, which were uniquely developed at the Palo Alto site. Besides enrolling Anglo/Caucasian caregivers into REACH, we also enrolled Hispanic/Latina caregivers, and are in the process of analyzing differences in caregiving patterns (and in response to intervention) that may be linked with specific cultural beliefs and values of the Hispanic/Latina group.

In addition, she is currently in the midst of a project, funded by the national office of the Alzheimer's Association, to develop a culturally sensitive screening tool for early detection of dementia among Chinese and Japanese elders. This project addresses the need for early detection in these two specific cultural groups in which dementia is regarded in a shameful manner, thus resulting in delay of diagnosis until the disease is in an advanced stage, and little is left to be done to help the patient. To address the needs of Chinese and Japanese family caregivers, Dr. Gallagher-Thompson's research group is now developing culturally specific intervention programs for the family, as well as the patient.

Finally, her research will be going in several new directions in the coming years, reflecting new areas of interest in this field:

  1. In collaboration with others in the Department, and under the leadership of Dr. David Spiegel, a Program Project grant has been submitted to address 'Stress, the HPA and Health in Aging.' Dr. Gallagher-Thompson's component will evaluate several physiological parameters of stress in family caregivers, and determine whether or not there is improvement in these physiological indices following interventions to reduce caregiver stress.
  2. In collaboration with Dr. Jerome Yesavage and others in the Aging Clinical Research Center, she will be studying interventions to improve sleep efficiency in both Alzheimer's patients and their family caregivers. Severely interrupted and disturbed sleep is a common reason that caregivers give for institutional placement of their relative in a nursing home or similar facility, resulting in high costs for both the family and society.

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