Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.

OBJECTIVES: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). METHODS: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. RESULTS: A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. CONCLUSIONS: Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Normal values for sincalide cholescintigraphy: comparison of two methods.

PURPOSE: To establish normal gallbladder ejection fraction (GBEF) values for two sincalide (cholecystokinin [CCK]) infusion dose rates, 0.01 microg per kilogram of body weight infused for 3 minutes and 0.01 microg/kg infused for 60 minutes. MATERIALS AND METHODS: Twenty healthy subjects were examined. GBEFs were calculated for the 3-minute infusion and for each 15-minute interval for the 60-minute infusion. Normal values were determined by using the mean +/- 2 SDs and a more rigorous statistical analysis. RESULTS: With the 3-minute infusion, GBEFs were significantly more variable than with the 45- and 60-minute values for the 60-minute infusion (P < .01, .002). With intervals including 95% of the population, the GBEF lower normal range was 16.8% for the 3-minute infusion but 31% and 41% for the 45- and 60-minute values, respectively. GBEFs of less than 35% were noted in six (30%) of 20 healthy subjects with the 3-minute infusion but in only one with the 60-minute infusion. Hepatobiliary ultrasonography was performed in six of seven subjects with GBEF of 36% or less, and US findings in all six were normal. CONCLUSION: A 3-minute infusion of sincalide, 0.01 microg/kg, produces too variable a GBEF response to establish a clinically useful normal range. With 0.01 microg/kg infused for 60 minutes, clinically useful normal values were established at 45 and 60 minutes.

No change in health risk behaviors over time among HIV infected adolescents in care: role of psychological distress.

PURPOSE: To investigate the association of psychological distress and health risk behaviors among HIV infected adolescents. It was hypothesized that higher levels of distress would be associated with increased sexual risk behaviors, and increased use of alcohol and drugs. METHODS: HIV infected adolescents (N = 323) were recruited into an observational study in 15 clinical sites; for the 323 subjects, a total of 1212 visits were used in a repeated measures analysis. Data on depression (using the CES-D), anxiety (manifest anxiety scale), sexual behaviors and alcohol and marijuana use were obtained through computer-assisted self-administered interview. RESULTS: Approximately 65% of the sample was sexually active across all six study visits, with approximately 43% consistently reporting having unprotected sex at last intercourse. Higher levels of depression were associated with frequent alcohol use and with unprotected sex at last intercourse, with depressed adolescents significantly more likely to have had unprotected sex than those who were not depressed. Health anxiety was associated with frequent marijuana use and with recent sexual activity, and physiological anxiety was also associated with recent sexual activity. CONCLUSIONS: Despite the fact that these HIV infected adolescents are all engaged in primary care, overall the sample is maintaining its high-risk sexual behavior. In addition, these adolescents may be self-medicating to deal with health-related anxiety. Health interventions for HIV infected adolescents should examine whether psychological distress is contributing to maintenance health risk behaviors.

The relationship of unsafe sexual behavior and the characteristics of sexual partners of HIV infected and HIV uninfected adolescent females.

PURPOSE: To compare characteristics of sexual relationships in HIV infected and HIV uninfected female adolescents and their association with condom use. METHODS: HIV infected and uninfected subjects, aged 13-19 years, were enrolled in a prospective HIV study from 15 sites in 13 U.S. cities. Baseline data on demographic information, substance use, sexual behavior, partner information, and condom use were collected through direct and computer-assisted interviews from currently sexually active females. Univariate, multiple logistic regression, and repeated measures analyses were employed. RESULTS: Data from 153 HIV infected and 90 HIV uninfected female subjects showed, on average, that current partners were 4-6 years older. In multivariate analysis, HIV infected subjects were older (OR = 1.37; 95% CI: 1.04-1.81), had more lifetime partners (OR = 2.23; 95% CI: 1.03-4.82), initiated consensual vaginal sex earlier (OR = .74; 95% CI:.58-.95), perceived partner to also be HIV infected (OR = 7.46; 95% CI: 3.2-17.4), and had less unprotected sex (OR = .27; 95% CI:.16-.45). Length of relationship was associated with more unprotected sex for both HIV infected and uninfected subjects (OR = 2.59, 95% CI: 1.27-5.27, OR = 4.13; 95% CI: 1.31-13.05, respectively). Mean partner age difference was greater among HIV infected than for HIV uninfected (OR = 1.06; 95%CI: 1.01-1.12); this greater age difference for HIV infected females was associated with less protection (OR = 1.09; 95% CI: 1.03-1.15). HIV disclosure influenced condom use: without disclosure, less condom use was reported (OR = 6.8; 95% CI: 2.29-20.24) controlling for perception that partner was also HIV infected (OR = 1.1; 95% CI: 1.02-1.21). CONCLUSIONS: Because age differential influenced reported condom use, more research, particularly qualitative, is needed into the dynamics of these relationships. Prevention efforts must address partners, particularly older ones.

Effects of chronic lithium administration on rat brain phosphatidylinositol cycle constituents, membrane phospholipids and amino acids.

OBJECTIVE: There is evidence linking affective disorders and their treatment to alterations in membrane phospholipid metabolism, the phosphatidylinositol (PtdIns) second messenger cycle and brain excitatory and inhibitory amino acids. This study examines lithium effects on rat brain metabolites associated with the above systems and their reversal by myo-inositol. METHODS: Thirty rats were treated for 14 days with i.p. lithium, saline or lithium plus myo-inositol. 1H, 31P and 7Li NMR were used to measure brain metabolites. RESULTS: Lithium, administered alone or with myo-inositol, resulted in brain lithium concentrations of approximately 0.6 microM/gram brain tissue. Brain myo-inositol was unchanged when lithium was co-administered with myo-inositol. Lithium increased brain inositol-1-phosphate (I1P) by 98% compared with saline and this effect was not attenuated by the addition of myo-inositol. Lithium treatment decreased phosphatidylserine (PtdSer) and PtdIns by 3% and 8%, respectively. Lithium also decreased taurine levels by 8% and increased aspartate levels by 9%. The above effects of lithium on PtdSer, PtdIns and taurine were attenuated or abolished by the co-administration of myo-inositol. CONCLUSIONS: Lithium alters levels of key membrane phospholipids and appears to affect the balance between inhibitory and excitatory amino acids in rat brain. Co-administration of myo-inositol attenuates some of these lithium effects on brain metabolites.

Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA.

Adherence to highly active antiretroviral therapy (HAART) was investigated among HIV-infected adolescents recruited from 13 US cities into the REACH (Reaching for Excellence in Adolescent Care and Health) project, the first large-scale disease progression study of HIV-positive adolescents infected through sexual behaviour or injection drug use. Of 161 subjects, 7% could not correctly identify all their prescribed medications; 11% could identify them but reported never taking at least one medication. The majority (83%) reported taking all of their medications at least some of the time, but only 50% of these subjects reported full adherence. Therefore, only 41% of the sample reported full adherence. A strong association was found between adherence and reduced viral load. A CD4 level of > or = 500 cells/mm3 was also associated with adherence. Higher levels of depression were significantly associated with decreased adherence, and a trend was found for an association between number of medications prescribed and adherence. Strict adherence to HAART is critical for sustained suppression of viral replication allowing for immune recovery and reducing the risk of the selection of antiviral resistance. Adherence appears to be a serious problem among HIV-positive adolescents. Better education, intervention to relieve depression, and efforts to improve ease of medication use are essential.

Psychological distress among HIV(+) adolescents in the REACH study: effects of life stress, social support, and coping. The Adolescent Medicine HIV/AIDS Research Network.

PURPOSE: To investigate the effects of life events, social support, and coping on anxiety and depression among human immunodeficiency virus (HIV)-infected adolescents. It was hypothesized that higher levels of stressful events would be associated with higher levels of anxiety and depression, but that this association would be moderated by satisfaction with social support and by adaptive coping. METHODS: HIV-infected adolescents from 16 locations in 13 U.S. cities (N = 230, median age 16.09 years, standard deviation 1.2, range 13-19; 77% females) were recruited into the Reaching for Excellence in Adolescent Care and Health (REACH) project. REACH is the first large-scale disease progression study of HIV(+) adolescents infected through sexual behavior or injection drug use. The adolescent assessment was conducted by audio-computer assisted self-interview. Least squares regressions were used to test hypotheses. RESULTS: Life events with high impact were associated with higher levels of depression and anxiety. Frequently reported events included: being prescribed medications (74%), family financial problems (61%), and parental alcohol abuse (20%). Contrary to expectations, the buffering hypotheses of social support and adaptive coping were not supported. Satisfaction with social support and adaptive coping methods were both associated directly with lower levels of depression, but no association was detected between these two measures and anxiety. CONCLUSIONS: Although life event distress was directly associated with psychological distress, neither social support nor adaptive coping seemed to moderate this association. However, both satisfaction with support and adaptive coping were associated directly with depression in HIV-infected adolescents.

Marijuana use among HIV-positive and high-risk adolescents: a comparison of self-report through audio computer-assisted self-administered interviewing and urinalysis.

The validity of self-report of drug use has been found to vary widely. Moreover, previous research has focused on samples of adults. In 1996-1998, human immunodeficiency virus (HIV)-infected adolescents and high-risk, noninfected adolescents (n = 182) were recruited at 16 locations in 13 US cities into the Reaching for Excellence in Adolescent Care and Health (REACH) project, to the authors' knowledge, the first national study of disease progression among HIV-positive adolescents who were infected through sexual behavior or injection drug use. Self-report of marijuana use was assessed through audio computer-assisted self-administered interviewing (ACASI). Urines were tested for marijuana at a certified laboratory by using the enzyme-multiplied immunoassay technique. Conditional kappas for 2-, 5-, and 7-day self-reports were 0.57, 0.71, and 0.69, respectively. Maximum sensitivity was obtained from a combination of ACASI and urine drug testing. Contrary to previous studies, the data suggest that if a single evaluative instrument is to be used for prevalence, ACASI is more sensitive than urine drug testing for marijuana overall, but particularly for HIV-infected adolescents.

Treatment for depression following the 1996 National Depression Screening Day.

OBJECTIVE: Characteristics of the subsequent treatment received by people who screened positive for depression in the 1996 National Depression Screening Day were investigated. METHOD: A follow-up telephone survey was completed by 1,502 randomly selected participants from 2,800 sites. RESULTS: Of 927 people for whom additional evaluation was recommended, 602 (64.9%) obtained evaluations and 503 (83.6%) received treatment. Of these 503, 260 (51.7%) received psychotherapy and medication, 130 (25.8%) received medication only, and 93 (18.5%) received psychotherapy only. Compared with people without health or mental health insurance, individuals with health insurance (66.7% versus 57.5%) and mental health insurance (74.6% versus 55.3%) were more likely to comply with the recommendation to obtain follow-up evaluation. CONCLUSIONS: One-half of the people treated for depression received a combination of psychotherapy and medication. Lack of insurance was associated with not following the recommendation to obtain further evaluation and treatment.

The relationship of self-efficacy expectancies to relapse among alcohol dependent men and women: a prospective study.

OBJECTIVE: We studied the relationship of self-efficacy expectancies measured during inpatient alcohol treatment and time to first drink and time to relapse following hospitalization. We also examined whether the relationship of in-hospital self-efficacy and posttreatment drinking outcome differed by gender. METHOD: We measured self-efficacy expectancies using the Situational Confidence Questionnaire (SCQ) in 100 subjects (59 men) during inpatient treatment for alcohol dependence. We followed subjects monthly for 1 year and examined the relationship of their in-hospital SCQ scores to posttreatment drinking behavior, as measured by time to first drink, time to relapse and percent abstinent days. RESULTS: Self-efficacy during hospitalization was related to relapse during the 12 months following hospitalization. Survival analysis demonstrated that in-hospital SCQ scores greater than 45 were predictive of better drinking outcomes. The median number of days to relapse after treatment were 30 and 135, respectively, in those with in-hospital SCQ scores less than or equal to 45 compared with those with SCQ scores greater than 45. There were no gender differences in self-efficacy measured during hospitalization, nor were there gender differences in the relationship of self-efficacy to time to relapse. However, men with SCQ scores less than or equal to 45 had fewer abstinent days during follow-up. CONCLUSIONS: Among both men and women being treated for alcohol dependence, a cut-off score of 45 on the SCQ may be especially important in helping clinicians assess patients who are at high risk for more rapid return to drinking after hospitalization.

A randomized clinical trial of acellular pertussis vaccines in healthy adults: dose-response comparisons of 5 vaccines and implications for booster immunization.

The safety and immunogenicity of 5 acellular pertussis vaccines (ACVs) were compared in a multicenter, randomized, double-blind trial. A total of 481 healthy adults were given a single intramuscular booster dose of ACV or placebo. Three different dose levels were tested for 4 ACVs: full strength (the dose level proposed for infant immunization), one-third strength, and one-tenth strength. For 1 multicomponent vaccine, only the pertussis toxoid dose level varied. Minor injection site reactions were common and similar in frequency among vaccinated groups. Late-onset injection site reactions were seen in all ACV groups. Dose-related increases in mean antibody titers against vaccine antigens were seen after immunization with all ACVs. Antibody responses against antigens not known to be present in the vaccines were detected after immunization with 4/5 ACVs. Antibody levels fell significantly during the year after immunization. These data support evaluation of ACVs for broader use among adolescents and adults.

Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study.

BACKGROUND: This was a multicenter investigation examining the efficacy of 4 psychosocial treatments for cocaine-dependent patients. METHODS: Four hundred eighty-seven patients were randomly assigned to 1 of 4 manual-guided treatments: individual drug counseling plus group drug counseling (GDC), cognitive therapy plus GDC, supportive-expressive therapy plus GDC, or GDC alone. Treatment was intensive, including 36 possible individual sessions and 24 group sessions for 6 months. Patients were assessed monthly during active treatment and at 9 and 12 months after baseline. Primary outcome measures were the Addiction Severity Index-Drug Use Composite score and the number of days of cocaine use in the past month. RESULTS: Compared with the 2 psychotherapies and with GDC alone, individual drug counseling plus GDC showed the greatest improvement on the Addiction Severity Index-Drug Use Composite score. Individual group counseling plus GDC was also superior to the 2 psychotherapies on the number of days of cocaine use in the past month. Hypotheses regarding the superiority of psychotherapy to GDC for patients with greater psychiatric severity and the superiority of cognitive therapy plus GDC compared with supportive-expressive therapy plus GDC for patients with antisocial personality traits or external coping style were not confirmed. CONCLUSION: Compared with professional psychotherapy, a manual-guided combination of intensive individual drug counseling and GDC has promise for the treatment of cocaine dependence.

"Seeking safety": outcome of a new cognitive-behavioral psychotherapy for women with posttraumatic stress disorder and substance dependence.

Women with current posttraumatic stress disorder (PTSD) comprise 30-59% of substance abuse treatment samples and experience a more severe course than women with either disorder alone. As yet, no effective treatment for this population has been identified. This paper reports outcome results on 17 women who completed a new manual-based 24-session cognitive behavioral group therapy protocol treatment, based on assessments at pretreatment, during treatment, posttreatment, and at 3-month follow-up. Results showed significant improvements in substance use, trauma-related symptoms, suicide risk, suicidal thoughts, social adjustment, family functioning, problem solving, depression, cognitions about substance use, and didactic knowledge related to the treatment. Patients' treatment attendance, alliance, and satisfaction were also very strong. Treatment completers were more impaired than dropouts, yet more engaged in the treatment. Overall, our data suggest that women with PTSD and substance abuse can be helped when provided with a treatment designed for them. All results are clearly tentative, however, due to the lack of a control group, multiple comparisons, and absence of assessment of dropouts.

The effect of depression on return to drinking: a prospective study.

BACKGROUND: The effect of depression on return to drinking among individuals with alcohol dependence is controversial. From February 1, 1993, to April 15, 1996, we consecutively recruited 40 women and 61 men hospitalized for alcohol dependence and followed them up monthly for 1 year to assess the effect of depression on drinking outcomes. METHODS: We conducted structured interviews during hospitalization and monthly following discharge for 1 year to determine whether depression at treatment entry affected the likelihood of return to drinking and whether this effect differed between sexes. Using survival analysis, we examined the effect of depressive symptoms and a diagnosis of current major depression at treatment entry on times to first drink and relapse during follow-up. RESULTS: A diagnosis of current major depression at the time of hospitalization was associated with shorter times to first drink (hazard ratio, 2.03; 95% confidence interval [CI], 1.28-3.21; P=.003) and relapse (hazard ratio, 2.12; 95% CI, 1.32-3.39; P=.002). There was no significant difference between women and men in this effect. Depressive symptoms as measured by the Beck Depression Inventory did not predict time to first drink or relapse in women or men. CONCLUSIONS: A diagnosis of current major depression at entry into inpatient treatment for alcohol dependence predicted shorter times to first drink and relapse in women and men. Our results differ from earlier reports that men and women differ in the effect of depression on return to drinking.

Cocaine dependence with and without PTSD among subjects in the National Institute on Drug Abuse Collaborative Cocaine Treatment Study.

OBJECTIVE: This study examined the prevalence of lifetime traumatic events and current symptoms of posttraumatic stress disorder (PTSD) among treatment-seeking cocaine-dependent outpatients and compared patients with and without PTSD on current substance use, psychopathology, and sociodemographic characteristics. METHOD: The subjects were 122 adult cocaine-dependent outpatients participating in a treatment outcome study of psychosocial therapy. In addition to standard self-report and interview measures of psychopathology and substance use, the subjects completed the Trauma History Questionnaire and the PTSD Checklist before entering treatment. RESULTS: These patients experienced a large number of lifetime traumatic events (mean = 5.7); men experienced more general disasters and crime-related traumas than women, and women experienced more physical and sexual abuse than men. According to self-report measures, 20.5% of the subjects currently met the DSM-III-R criteria for PTSD; the rate of PTSD was 30.2% among women and 15.2% among men. Patients with PTSD had significantly higher rates of co-occurring axis I and axis II disorders, interpersonal problems, medical problems, resistance to treatment, and psychopathology symptoms than patients without PTSD. Psychopathology symptoms represented the most consistent difference between the two groups and provided the best prediction of PTSD status in a logistic regression. However, the groups did not differ significantly in current substance use or sociodemographic characteristics. CONCLUSIONS: These findings underscore the value of screening substance abusers for PTSD, because it can identify a small but substantial number who might require additional treatment. Further studies of the relationship between PTSD and substance abuse appear warranted.

Effectiveness of community-based screening for depression.

OBJECTIVE: The effectiveness of a voluntary depression screening program was assessed by determining 1) whether participants in the 1994 National Depression Screening Day went for recommended follow-up examinations and 2) the characteristics that differentiated those who did and did not return. METHOD: Randomly selected participants (N = 1,169) from 99 facilities completed a follow-up telephone survey. RESULTS: Of 805 people for whom follow-up was recommended, 56.5% (N = 455) went for an appointment. The severity of depressive symptoms in these subjects ranged from severe (33.4%, N = 152) and marked (41.3%, N = 188) to minimal (17.1%, N = 78) and normal (8.1%, N = 37). Subjects with marked or severe depression were more likely to respond to the screening recommendation than were those with minimal depressive symptoms. However, at each level of symptom severity, subjects who had received previous treatment were more likely to adhere to the screening recommendation than were those with no previous treatment. Of those who returned for a recommended follow-up, 72.1% were diagnosed with depression. Of those who did not return, 29.5% cited lack of insurance, under insurance, or inadequate finances, and 38.0% felt they could "handle" depression on their own. CONCLUSIONS: Voluntary screening for depression is an effective way to bring certain untreated depressed individuals to treatment. Inadequate insurance and the belief that individuals can manage depression on their own continue to be barriers to seeking treatment among some depressed individuals who attend a depression screening program.

Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12.

Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization.

Prediction of compliance with outpatient referral in patients with schizophrenia and psychoactive substance use disorders.

BACKGROUND: Most patients with concurrent schizophrenia and psychoactive substance use disorders may be adequately treated as outpatients. However, many do not comply with outpatient referrals and are therefore at heightened risk for rehospitalization. METHOD: Drawing on standardized interview data collected during an index hospitalization, we developed a logistic regression model to predict compliance with outpatient treatment. The model was tested on a confirmatory sample, and its sensitivity and specificity were further evaluated in a cross-validation study of 1000 random samples. RESULTS: In a reference sample, the logistic function distinguished compliant from noncompliant patients in 37 (76%) of 49 cases. In a confirmatory sample, compliance status was predicted for 11 (78%) of 14 patients with a sensitivity of 1.00 and a specificity of 0.67. Women and patients with negative syndrome schizophrenia were compliant with outpatient referral, whereas those with mixed syndromes were most likely to be noncompliant. Cross-validation supports the stability of the model. CONCLUSION: While most persons with schizophrenia and concurrent substance abuse comply with integrated outpatient treatment, most who cannot may be predicted in advance.

Early prediction of initiation of abstinence from cocaine. Use of a craving questionnaire.

The authors administered a five-item craving questionnaire daily to 86 outpatients to determine whether initial craving scores predicted the likelihood of initiation of abstinence within a 30-day period. Patients with higher mean craving scores during the first 3 days of the study were less likely to initiate abstinence. However the relationship between craving and abstinence initiation was not linear. Rather, patients in the top quartile of craving scores were significantly less likely to abstain than were patients in the lower three quartiles. The findings suggest that this rapid, easily administered craving questionnaire may have short-term predictive validity.

Effects of aging on the cerebral distribution of technetium-99m hexamethylpropylene amine oxime in healthy humans.

Some brain functions decline at a linear rate throughout adulthood. Others remain relatively stable until very late in the life cycle. This study characterized the effects of aging on the regional cerebral distribution of hexamethylpropylene amine oxime (HMPAO) in healthy human volunteers. The sample consisted of 26 men and 18 women with a mean age of 41.6+/-14.9 years (range: 19-73). Their past medical histories, physical examinations, and laboratory screening tests were normal. Single-photon emission tomography (SPET) scans of the brain were performed with a standardized acquisition and processing protocol on a triple-headed camera equipped with fan beam collimators. A 3-D restorative filter and a correction for uniform attenuation were applied before the images were reinterpolated in planes parallel to the line connecting the frontal and occipital poles. Mean counts per pixel were measured in multiple regions of interest (ROIs) within each hemisphere by custom fitting a set of templates to the images. The mean activity in each ROI was compared with the mean activity per pixel in the whole brain. Regression analyses were used to relate the activity ratios to age with both linear and nonlinear models. The relative concentration of radioactivity decreased significantly with age in most, but not all, gray matter structures. It increased in the white matter regions. The nonlinear model of aging fit the data significantly better than a straight line did. Most of the changes with age occurred during young adulthood. No further changes were detectable after the onset of middle age. The median breakpoint age at which the rate of change became negligible was 36.6 years. Aging significantly affects the relative uptake of HMPAO in healthy humans. It decreases in many gray matter regions and increases in most white matter regions. However, the changes do not appear to be linear. Most seem to occur during young adulthood before people reach their late thirties. The distribution then appears to remain relatively stable throughout middle age.