• Alert community physicians and psychologists about ongoing clinical studies.
• Make neuropsychological and psychiatric evaluations available to qualified participants.
• Communicate study results to patients and clinicians in the community.
• Develop advanced neuroimaging techniques for clinical memory studies.
• Bring basic science findings to the clinic.
• Serve as an educational resource for the patients and clinicians in the community.

The MERI provides a framework for several ongoing research programs at NKI.


Geriatric Psychopharmacology Research Program [top of page]

The Geriatric Psychopharmacology Research Program focuses on the identification of potential cognitive toxicity associated with commonly prescribed psychotropic medications (those which act on the mind) in the elderly. It also seeks to identify pharmacokinetic and genetic mechanisms that may contribute both to the increased sensitivity of drug-induced cognitive toxicity in elderly persons and to individual susceptibility to these adverse effects. The Alzheimer’s disease component of our research program focuses on the development of more effective pharmacological strategies for the treatment of Alzheimer’s disease and the identification of neurobiological predictors of therapeutic response.

Ongoing Studies

(1) "Long-term lorazepam use and acute toxicity in the aged" - NIMH

This project is examining whether elderly people on long-term treatment with lorazepam develop a tolerance to the acute adverse performance effects of the medication. Those 60 years of age and older who are anxious and currently receiving daily lorazepam (Ativan) treatment are being sought for this study. The study is also conducted in Manhattan, in collaboration with the New York University School of Medicine General Clinical Research Center.

(2) "ApoE e₄ allele and lorazepam effects on the elderly" - NIMH

We are also determining whether elderly healthy individuals with the ApoE e₄ allele, a proven genetic risk factor for late onset Alzheimer’s disease, show greater memory impairments in response to acute single doses of lorazepam than individuals without the e₄ allele.

(3) "ApoE e₄ allele and trihexyphenidyl HCl (Artane) effects on the elderly"

In a related project, we are examining the relationship between allele variability of the ApoE gene and sensitivity to the performance effects of acute doses of Artane, a commonly prescribed anticholinergic agent; again, our subjects are individuals 60 years of age and older.


Our center is a collaborating clinical site for the following NIA/NIMH funded studies:

(1) "Comparative effectiveness of antipsychotic medications in patients with Alzheimer’s disease" (CATIE-AD Protocol)

This 36-week multicenter study will evaluate the effectiveness of FDA-approved antipsychotic medications (Risperdal, Zyprexa, Seroquel & Celexa) for Alzheimer’s patients who suffer delusions, hallucinations, agitation or aggression severe enough to disrupt functioning.

(2) "A randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of vitamin E and donepezil HCl (Aricept) to delay clinical progression of mild cognitive impairment (MCI) to Alzheimer’s disease" (MCI Protocol)

Individuals ages 55 to 90 experiencing mild memory problems are being examined to determine whether vitamin E or donepezil HCl (Aricept) can delay clinical progression to Alzheimer’s disease.

(3) "Estrogen to prevent Alzheimer’s disease and loss of memory in women"

Women who take estrogen are less likely to develop memory problems. A nationwide study is underway to determine estrogen’s effects on memory loss in healthy women who are over the age of 65 and have a family history of memory loss.

(4) "Vitamin E in aging persons with Down syndrome"

This multicenter study will determine whether treatment with vitamin E 1000 IU twice daily slows the rate of cognitive/functional decline in individuals with Down syndrome 50 years of age or older.


In collaboration with various pharmaceutical companies, we are conducting the following clinical trials in patients with Alzheimer’s disease:

(1) "A 24-week, multicenter, randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of donepezil hydrochloride (E2020) in patients with severe Alzheimer’s disease followed by a 12 week open-label extension period" - Pfizer, Inc./Eisai, Inc.

Aricept, a cholinesterase inhibitor, has been approved by the FDA for the treatment of cognitive dysfunction associated with mild to moderate Alzheimer’s disease. This study will evaluate whether this medication is also effective for patients ages 50 or older with severe Alzheimer’s disease.

(2) "A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of memantine in patients with mild to moderate dementia of the Alzheimer’s type" - Forest Laboratories

This medication has a pharmacological action quite different from cholinesterase inhibitors and involves blockage of the NMDA glutamate receptor. Patients ages 50 or older with mild to moderate Alzheimer’s disease may be eligible for this study.


Major Academic/Scientific Achievements
[top of page]

In the area of Alzheimer’s disease research, we have made a number of contributions including:

(1) A. We provided the first in vivo evidence consistent with the presence of altered muscarinic receptor mediated neurobiologcal responses in this patient population. This was demonstrated for peripheral ^{1, 2} and central muscarinic receptors ³.

B. The findings from these investigations suggested the presence of muscarinic receptor devervation supersensitivity in Alzheimer’s disease and led to a critical reconsideration of the cholinergic hypothesis ^{4, 5, 6}.

C. We conducted numerous experiments to clarify the basis for the lack of efficacy of cholinergic precursors for the treatment of cognitive dysfunction associated with Alzheimer’s disease. We showed that these compounds do not increase peripheral indices of cholinergic activity ⁷ and cause a down regulation of muscarinic receptors ⁸. We also sought and identified a neurobiological measure that might predict therapeutic response to a cholinesterase inhibitor in patients with Alzheimer’s disease ⁹.

(2) We demonstrated that Alzheimer’s disease and normal aging are accompanied by increased activity of the Hypothalamic-Pituitary Adrenal (HPA) axis ^{10, 11}.

This work, together with other pre-clinical data showing that excessive glucocorticoids exposure could result in hippocampal damage, led to the first clinical pilot study of the antiglucocorticoid receptor antagonist, mifepristone (RU 486), in the treatment of Alzheimer’s disease. This clinical trial was conducted at the New York University School of Medicine in collaboration with Dr. Steven Ferris. The results of this pilot study suggest that this approach merits further investigation.

(3) In a related project, we provided further evidence of the presence of abnormalities in other aspects of the Hypothalamic-Pituitary axis by showing an absence of the expected cortisol increase following acute single dose administration of the opiate antagonist, naltrexone, in patients with Alzheimer’s disease ^{12, 13}.

(4) We also conducted a number of studies to investigate potential alterations in various neurotransmitters or metabolites in the cerebrospinal fluid (CSF) of Alzheimer’s patients. These studies found that Alzheimer’s patients in early stages of the disease exhibited an elevation of glutamate, reductions in 5HIAA, HVA, normal concentrations of MHPG and CRF ^{14, 15, 3}.

Interestingly, we found an elevation of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS) which is known to modulate stress-response, in caregivers of Alzheimer’s patients ¹⁶.

(5) More recently, in a study conducted in collaboration with Dr. Thomas Wisniewski (NYU), we examined the relationship between ApoE e₄ allele, the major genetic risk factor for late onset Alzheimer’s disease, and plasma amyloid beta concentration in normal elderly people. Increased amyloid beta deposition is now believed to contribute to neuronal death in Alzheimer’s disease. We found an association between age and plasma Ab in individuals with the e₄ allele but not in those without this allele. This finding merits further study and could provide insight into potential mechanisms for the increased risk for Alzheimer’s disease associated with the ApoE e₄ allele ¹⁷.

(6) Another important focus of our geriatric psychopharmacology program is the delineation of the cognitive toxicity and other side effects associated with commonly prescribed psychotropic medications in the elderly.

All of these projects have been funded by the NIMH since 1985.

The studies completed to date have examined the performance effects of acute and multiple doses of various benzodiazepines (diazepam, lorazepam, alprazolam) as well as nortriptyline (a commonly prescribed tricyclic antidepressant (TCA)) in the elderly.

We have demonstrated that acute doses of all benzodiazepines are associated with profound impairments in various aspects of cognition. Contrary to the prevailing opinion that the elderly are more sensitive to drug-induced cognitive toxicity, we found that for most cognitive measures, acute doses of diazepam produced a similar change from baseline in both the elderly and the young. However, because the elderly have a significantly lower baseline performance than the young, any drug-induced impairment is more likely to result in clinically adverse events. We have also shown that the presence of an anxiety disorder does not attenuate benzodiazepine-induced cognitive toxicity. Additionally, we revealed that the administration of acute single doses of various benzodiazepines after chronic 21-day daily treatment still produced significant impairments relative to placebo. These findings suggest a lack of complete tolerance development to these adverse effects ^{18, 19, 20, 21, 22, 23, 24}.

These findings are consistent with epidemiological data suggesting that elderly patients on long-term treatment with benzodiazepines face an increased risk for falls and hip fracture. We are now conducting an NIMH-funded study to determine whether elderly patients with Generalized Anxiety Disorder (GAD) receiving long-term treatment of a morning dose of lorazepam exhibit significant impairments in cognition and postural sway.

Another aspect of our research aims to illustrate that the neurochemical effects of these agents may contribute to benzodiazepine-induced toxicity. This work has been conducted in collaboration with various researchers. To date, we have completed the following projects which are being prepared for submission: in collaboration with Dr. Henry Sershen, we have examined the effect of acute doses of lorazepam on plasma levels of HVA, MHPG, and 5 HIAA; and in collaboration with Dr. Jim Ritchie, Charles Nemeroff and David J. Greenblatt, we have also examined the effects of benzodiazepines on plasma cortisol levels. We have found that diazepam and alprazolam produce profound reductions in plasma cortisol.

A major focus of our research is on identifying factors that may be associated with increased susceptibility to drug-induced impairment in the elderly. In a study conducted with Mr. Tom Cooper, Director of the NKI Analytic Psychopharmacology Laboratory, we examined the relationship between plasma GABA and lorazepam-induced impairment. In addition, we also investigated the role of genetic factors and susceptibility to drug-induced cognitive toxicity in the elderly. Preliminary data from our group indicates that a genetic factor, ApoE e₄ allele, may be associated with increased susceptibility to benzodiazepine-induced cognitive toxicity in the elderly ²⁵.

We are now completing an NIMH-funded project which tests this hypothesis by examining the relationship between allele variability of the APOE gene and sensitivity to lorazepam-induced cognitive toxicity.

In a related pilot study, we are evaluating the selectivity of this relationship by examining whether the e₄ allele also predicts susceptibility to the adverse performance effects of Artane, a drug with strong central antimuscarinic activity.

In addition to the use of genetic markers, we have been evaluating whether measures of brain structure and function, as derived from various neuroimaging techniques, may also be employed to predict vulnerability to drug-induced cognitive toxicity in the elderly. In a preliminary study conducted with Dr. Kelvin Lim at NKI, we found that a measure of white matter organization, as determined by diffusion tensor imaging which we have shown to be sensitive to HIV-1 induced CNS changes ²⁶, could be used as a predictor of vulnerability to benzodiazepine-induced cognitive toxicity in the elderly. Our current NIMH-funded study will also test this hypothesis.

In contrast to the benzodiazepines, we demonstrated that acute and chronic treatment with nortriptyline with plasma drug levels maintained within the therapeutic range, did not result in significant cognitive toxicity in young and elderly individuals suffering from depression.

Interestingly, we were the first group to report that gender may modulate heart rate increase during nortriptyline treatment; males experience a significantly greater heart rate increase than females.

References

1 Sitaram N, Pomara N. Increased pupillary miotic response to pilocarpine in cognitively impaired elderly subjects. IRCS Med. Sci. 9:409-410, 1981.

2. Pomara N, Sitaram N. Detecting Alzheimer’s disease [ letter ]. In: Science. 267(5204): 1579-80; discussion 1508-1, 1995.

3. Pomara, N, Stanley, M, LeWitt, P. A.,Galloway, M., Singh, R., Deptula, D. Increased CSF HVA response to arecoline challenge in Alzheimer’s disease. Journal of Neural Transmission. 90:53-65, 1992.

4. Pomara N, Stanley M. The cholinergic hypothesis of memory dysfunction in Alzheimer’s disease-revisited. Psychopharmacology Bulletin 22:110-118, 1986.

5. Pomara N, Bagne CA, Stanley M, Yarbrough GC. Prospective strategies for cholinergic interventions in Alzheimer's disease. Progress in Neuropsychopharmacology and Biological Psychiatry 10:553-569, 1986.

6 Pomara N, Stanley M. The functional status of central muscarinic receptors in Alzheimer's disease: Assessment and therapeutic implications. In: Treatment Development Strategies for Alzheimer's Disease. Edited by T Crook, S Ferris, R Bartus, S Gershon, New Canaan, CT: Mark Powley Associates Inc., pp. 451-472, 1986.

7 Pomara N, Domino EF, Yoon H, Brinkman S, Tamminga CA, Gershon S. Failure of single dose lecithin to alter aspects of central cholinergic activity in Alzheimer’s disease. Journal of Clinical Psychiatry 44: 293-295, 1983

8. Pomara N, Block R, Demetriou S, Fucek F, Stanley M, Gershon S. Attenuation of pilocarpine- induced hypothermia in response to chronic administration of choline. Psychopharmacology 80:129-130, 1983.

9. Pomara, N, Deptula, D, Singh, R. Pretreatment postural blood pressure drop as a possible predictor of response to the cholinesterase inhibitor velnacrine(HP 029) in Alzheimer’s disease. Psychopharmacology Bulletin, 27:301-307, 1991.

10. Pomara N, Oxenkrug GF, McIntyre IM, Block R, Stanley M, Gershon S. Does severity of dementia modulate response to dexamethasone in individuals with primary degenerative dementia? Biological Psychiatry 19:1481-1487, 1984.

11. Oxenkrug GF, Pomara N, McIntyre IM, Stanley M, Gershon S. Aging and cortisol resistance to suppression by dexamethasone: A positive correlation. Psychiatry Research 10:125-130, 1983.

12. Pomara N, Roberts R, Rhiew HB, Stanley M, Gershon S. Multiple, single-dose naltrexone administrations fail to effect overdose cognitive functioning and plasma cortisol in individuals with probable Alzheimer disease. Neurobiology of Aging 6:233- 236, 1985.

13. Pomara N, Stanley M, Rhiew HB, Bagne CA, Deptula D, Galloway MP, Tanimoto K, Verebey K, Tamminga CA. Loss of the cortisol response to naltrexone in Alzheimer's disease. Biological Psychiatry 23:726-733, 1988.

14. Pomara N, Singh R, Deptula D, Bissette G, Stanley M, Nemeroff C. CSF Corticotropin Releasing Factor (CRF) in Alzheimer's disease: Its relationship to severity of dementia and monoamine metabolites. Biological Psychiatry 26:500-504, 1989.

15. Pomara, N, Singh, R, Deptula, D, Banay-Schwartz, M, Chou, J, LeWitt, P.A. Glutamate and other CSF amino acids in Alzheimer’s disease. American Journal of Psychiatry, 1992.

16. Pomara N, Deptula D, Galloway MP, LeWitt PA, Stanley M. CSF GABA in caregivers- spouses of Alzheimer's patients. American Journal of Psychiatry 146:787-788, 1989.

17. Pomara N, Shao B, Wisniewski T, and Mehta PD. Decreases in plasma Ab1-40 levels with aging in non-demented elderly with ApoE-e₄ allele. Neurochemical Research 23(12):1563-1566, 1998.

18. Pomara N, Stanley B, Block R, Guido J, Stanley M, Greenblatt D, Newton R, Gershon S. Diazepam impairs performance in normal elderly subjects. Psychopharmacology Bulletin 20:137-139, 1984.

19. Pomara N, Stanley B, Block R, Guido J, Russ D, Berchou R, Stanley M, Greenblatt DJ, Newton RE, Gershon S. Adverse effects of single therapeutic dose of diazepam on performance in normal geriatric subjects: Relationship to plasma levels. Psychopharmacology 84: 342-346, 1984.

20. Pomara N, Stanley B, Block R, Stanley M, Newton ER, Greenblatt DJ, Gershon S. Increased sensitivity of the elderly to the central depressant effects of diazepam. Journal Clinical Psychiatry 46:185-187, 1985.

21. Pomara N, Deptula D, Rubinstein S, Stanley B, Stanley M. The effects of diazepam and aging on intrusions. Psychopharmacology Bulletin 24:228-231, 1988.

22 Pomara N, Deptula D, Medel M, Block RI, Greenblatt DJ. Effects of diazepam on recall memory: Relationship to aging, dose and duration of treatment. Psychopharmacology Bulletin 25:144-148, 1989.

23. Pomara N, Tun H, DaSilva D, Hernando R, Deptula D, and Greenblatt D. The acute and chronic performance effects of alprazolam and lorazepam in the elderly: Relationship to duration of treatment and self-rated sedation. Psychopharmacology Bulletin 34:139-153, 1998.

24. Pomara N, Tun H, DaSilva D, Deptula D, and Greenblatt D. Benzodiazepine use and crash risk in older patients. The Journal of the American Medical Association 279(2):113-114, 1998.

25. Pomara, N, Tun, H, Deptula, D, Greenblatt, D. ApoE- e₄ allele and susceptibility to drug-induced memory impairment in the elderly. Journal of Clinical Psychopharmacology 18:179-181, 1998.

26. Pomara N, Crandall DT, Choi SJ, Johnson G, and Lim KO. White matter abnormalities in HIV-1 infection: A diffusion tensor imaging study. Psychiatry Research: Neuroimaging Section 106:15-24, 2001.


Brain and Behavior Research Program [top of page]

The Brain and Behavior Research Program is a new addition to the Geriatrics Program. The goal of this Program is to design and conduct clinical studies of neurobehavioral disorders that integrate behavioral, pathophysiological, pharmacological, neuroimaging, and, when appropriate, genetic approaches to the study of brain-behavior relationships. The general aim of these studies to gain a greater understanding of behavior in normal and disease states. Such studies will allow us to:

• Better understand how specific brain areas interact during different behaviors.
• Develop more sensitive methods to detect abnormalities in brain function.
• Design more sensitive clinical trials to evaluate the effectiveness of new therapies.
  

To complement the studies described in the Geriatric Psychopharmacology Research Program, some of the initial studies are focusing on brain systems involved in normal and abnormal memory. These studies will involve normal individuals, individuals at risk for developing a memory impairment, and individuals with a diagnosis of Alzheimer’s disease. They will also provide the foundation for studies that will examine the effects of specific therapies or the impact of specific biological markers on the severity of a memory disorder. A second set of studies is examining the brain areas involved in the motor control of speech. Speech is affected by a range of degenerative diseases and a number of medications. Equally important, some of the brain areas involved in speech are also involved in a number of neurobehavioral disorders; understanding their function will have widespread applications.

In general, the Brain and Behavior Research Program facilitates the development of multidisciplinary clinical studies of neurobehavioral disorders with an emphasis on behavioral issues.

Selected Publications

Sidtis JJ, Gatsonis C, Price RW, Singer EJ, Collier AC, Richman DD, Hirsch MS, Schaerf FW, Fischl MA, Kieburtz K, Simpson D, Koch MA, Feinberg J and the AIDS Clinical Trials Group. Zidovudine Treatment of the AIDS Dementia Complex: Results of a Placebo-Controlled Trial. Annals of Neurology 33, 343-349, 1993.

Sidtis, JJ. Evaluation of the AIDS Dementia Complex in adults. In RW Price and SW Perry (Eds.) HIV, AIDS, and the Brain. New York: Raven Press, Ltd., 273-287, 1994.

Sidtis JJ, Dafni O, Clifford D, Hall C, Kieburtz K, Tucker T, Slasor P, Price RW. Neurological function in patients treated with 2'3'-dideoxyinosine (ddI, Didanosine, Videx). Journal of Neurovirology 3: 233-240, 1997.

Sidtis JJ, Gomez C, Anderson JR, Strother SC, Rottenberg DA. Establishing Functional Relationships Between Imaging Data and Speech Production in Cerebellar Ataxia Using Perceptual Ratings, Acoustic Analysis and PET. Brain and Language 69: 370 - 372, 1999.

Sidtis JJ, Strother SC, Anderson, JR, Rottenberg DA. Are brain functions really additive? Neuroimage 5: 490-496, 1999.

Sidtis JJ. From chronograph to functional image: What’s next? Invited contribution to a special millennium edition of Brain and Cognition 42: 75-77, 2000.

Sidtis JJ, Anderson JR, Strother SC, Rottenberg DA. Establishing behavioral correlates of functional imaging signals. In A. Gjedde (Ed.) Molecular and Pharmacological Brain Imaging with Positron Emission Tomography. San Diego: Academic Press, 2001.