Alzheimer Disease: Mulnard R

Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ, Anonymous00151. · Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California-San Diego, 8950 Villa La Jolla Drive, Suite 227, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #14732621 links to  free full text

Abstract: BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Thal LJ, Thomas RG, Mulnard R, Sano M, Grundman M, Schneider L. · Department of Neurosciences, University of California, San Diego, School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093, USA. · Arch Neurol. · Pubmed #12580705 links to  free full text

Abstract: OBJECTIVE: To investigate whether an association exists between estradiol and estrone levels and measures of cognitive functioning in women with Alzheimer disease (AD) treated with conjugated equine estrogen (Premarin; Wyeth-Ayerst, Philadelphia, Pa). METHODS: We studied 120 postmenopausal women who underwent hysterectomy and who had AD treated with Premarin for 1 year. Plasma estradiol and estrone levels were determined at multiple points during the 1-year treatment trial. The change from baseline level at 2 and 12 months was associated with the change score on 7 different assessments of cognitive functioning. RESULTS: At baseline, estradiol levels were low and there were no associations between the estradiol level and the 7 neuropsychological measures. A similar pattern was observed for estrone treatment. During treatment with 0.625 mg/d of Premarin, estradiol levels increased about 4-fold; while receiving 1.25 mg/d of Premarin, estradiol levels increased about 8-fold. A similar pattern was seen with estrone treatment. For both estradiol and estrone levels, there were no significant associations between the change in plasma level and the change in neuropsychological test scores at either 2 or 12 months. CONCLUSION: Although Premarin elevated estradiol and estrone levels, there was no association between hormone levels and cognitive functioning after either 2 or 12 months of treatment.

Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. · Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, USA. · Arch Neurol. · Pubmed #16344336 links to  free full text

Abstract: CONTEXT: There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD). OBJECTIVE: To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men. DESIGN: Twenty-four-week, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Memory disorders clinics as well as general neurology and medicine clinics from University of California medical centers at Los Angeles, San Francisco, and Irvine. PATIENTS OR OTHER PARTICIPANTS: Sixteen male patients with AD and 22 healthy male control subjects. Healthy elderly control men were recruited from the community through advertisements as well as through the university-based clinics. INTERVENTION: Testosterone and placebo, in the form of hydroalcoholic gel (75 mg), were applied daily to the skin of the participants. MAIN OUTCOME MEASURES: Instruments assessing cognitive functioning (Alzheimer's Disease Assessment Scale-Cognitive Subscale, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation, Developmental Test of Visual-Motor Integration), neuropsychiatric symptoms (Neuropsychiatric Inventory), global functioning (Clinician's Interview-Based Impression of Change), and quality of life (Quality of Life-Alzheimer Disease Scale). RESULTS: For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale (P = .01). No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group (P = .09) compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo. CONCLUSIONS: Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.