It would be of considerable value to develop predictoors of susceptibility to drug-induced cognitive toxicity in the elderly, since centrally acting medications, such as the benzodiazepines, continue to be widely prescribed in this population and older individuals may be more sensitive to some of the adverse central effects. Moreover, normal age-related decline in cognitive functions may accentuate the significance of drug-induced deficits. Our preliminary data from studies examining the acute effects of various benzodiazepines (diazepam, alprazolam, and lorazepam) on performance of cognitively intact normal volunteers suggest that possession of the ApoE-oplison4 allele may increase susceptibility to drug-induced cognitive toxicity. Buschke total and delayed recall were imparied in subjects with the oplison4 allele but not in those without this allele. This relationship between impairment and the presence of the opsilon4 allele was found despite the inclusion of younger subjects in the study, and only one subject homozygous for the e4 allele, in a group of participants who were not selected on the basis of family history of Alzheimer's disease (AD). The proposed research will more directly assess whether the epsilon4 allele is associated with increased susceptibility to drug-induced cognitive toxicity in normal cognitively intact older persons. We will study the cognitive effects of one of the benzodiazepines in the population most at risk for the deleterious effects of the opsilon4 allele on brain function: older, non-demented cognitively intact individuals who have a documented history of AD in a first degree relative and are homozygous for the epsilon4 allele (ApoE epsilon4/epsilon4 genotype). They will be compared with an appropriate, age-matched control group without the epsilon4 allele.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH056994-01
Application #
2035629
Study Section
Mental Disorders of Aging Review Committee (MDA)
Project Start
1997-04-01
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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Bruno, Davide; Grothe, Michel J; Nierenberg, Jay et al. (2015) A study on the specificity of the association between hippocampal volume and delayed primacy performance in cognitively intact elderly individuals. Neuropsychologia 69:1-8
Pomara, Nunzio; Bruno, Davide; Sidtis, John J et al. (2011) Translocase of outer mitochondrial membrane 40 homolog (TOMM40) poly-T length modulates lorazepam-related cognitive toxicity in healthy APOE ?4-negative elderly. J Clin Psychopharmacol 31:544-6
Pomara, Nunzio; Yi, Linlin; Belzer, Ken et al. (2010) Retrograde facilitation of verbal memory by trihexyphenidyl in healthy elderly with and without the APOE epsilon4 allele. Eur Neuropsychopharmacol 20:467-72
Pomara, Nunzio; Belzer, Kenneth D; Silva, Raul et al. (2008) The apolipoprotein E epsilon4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge. Psychopharmacology (Berl) 201:125-35
Pomara, Nunzio; Belzer, Ken; Hernando, Raymundo et al. (2008) Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly. Am J Geriatr Psychiatry 16:116-24
Pomara, Nunzio; Facelle, Thomas M; Roth, Amy E et al. (2006) Dose-dependent retrograde facilitation of verbal memory in healthy elderly after acute oral lorazepam administration. Psychopharmacology (Berl) 185:487-94
Pomara, Nunzio; Willoughby, Lisa M; Sidtis, John J et al. (2005) Selective reductions in plasma Abeta 1-42 in healthy elderly subjects during longitudinal follow-up: a preliminary report. Am J Geriatr Psychiatry 13:914-7
Pomara, Nunzio; Willoughby, Lisa; Wesnes, Keith et al. (2005) Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults. Arch Gen Psychiatry 62:209-16
Nierenberg, Jay; Pomara, Nunzio; Hoptman, Matthew J et al. (2005) Abnormal white matter integrity in healthy apolipoprotein E epsilon4 carriers. Neuroreport 16:1369-72

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