High prevalence of diabetes and pre-diabetes in adults with Williams syndrome.

A standard oral glucose tolerance test (OGTT) was administered to 28 adults with Williams syndrome (WS). Three quarters of the WS subjects showed abnormal glucose curves, meeting diagnostic criteria for either diabetes or the pre-diabetic state of impaired glucose tolerance. Fasting mean glucose and median insulin levels did not differ significantly in the total WS cohort versus age-gender-BMI matched controls, though the glucose area under the curve was greater in the WS subjects. HbA1c levels were not as reliable as the OGTT in diagnosing the presence of diabetes. Given the high prevalence of impaired glucose regulation, adults with WS should be screened for diabetes, and when present should be treated in accordance with standard medical practice. Hemizygosity for a gene mapping to the Williams syndrome chromosome region (WSCR) is likely the major factor responsible for the high frequency of diabetes in WS. Syntaxin-1A is a prime candidate gene based on its location in the WSCR, its role in insulin release, and the presence of abnormal glucose metabolism in mouse models with aberrantly expressed Stx-1a.

Prevalence of low bone density in women with developmental disabilities.

This study was designed to assess the prevalence and severity of low bone mineral density in an institutionalized population of postmenopausal women (n = 79) with developmental disabilities, using quantitative ultrasound of the calcaneus. The results demonstrate that this population has a significantly lower quantitative ultrasound index (QUI) of the calcaneus compared with a referent population of age-matched control subjects without mental disabilities. We used the QUI T-score threshold of <-2.0 standard deviations (SDs) to define individuals at high risk for osteoporosis, and 82% of the study participants met this criterion. Furthermore, approx 43% of the population had a heel QUI that was more than 2 SDs below that of age-matched control subjects, consistent with a severe degree of demineralization.

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and tolerability of metrifonate in patients with probable Alzheimer disease. The Metrifonate Study Group.

A randomized, double-blind, placebo-controlled, parallel-group study was undertaken to evaluate the safety and tolerability of a once-daily oral administration of metrifonate in patients with probable mild to moderate Alzheimer disease. Metrifonate was given as a loading dose of 125-225 mg based on weight (2.5 mg/kg) for 2 weeks, followed by a maintenance dose of 50-90 mg based on weight (1.0 mg/kg) for 4 weeks. Twenty-nine patients received metrifonate, and 10 patients received placebo. Metrifonate produced a mean erythrocyte acetylcholinesterase inhibition at the end of treatment of 86.3%. The proportion of patients who experienced at least one adverse event was comparable between the metrifonate (76%) and placebo (80%) groups. Selected adverse events in disfavor of metrifonate (defined as those for which the incidence in the metrifonate and placebo groups differed by at least 10%) were diarrhea, nausea, leg cramps, and accidental injury. Adverse events were predominantly mild in intensity and transient. No severe adverse events were experienced by any patient. The most notable hemodynamic change observed during metrifonate treatment was a clinically insignificant mean decrease in the heart rate (by electrocardiogram) of approximately 9 beats/min, compared with an approximate 3-beats/min decrease for the placebo group. No muscle weakness was observed in this study. No clinically relevant laboratory abnormalities, such as liver toxicity, or changes in exercise tolerance or pulmonary function tests were found with metrifonate treatment. This metrifonate dose provided a high level of acetylcholinesterase inhibition, which was associated in these patients with a favorable safety and tolerability profile. Indeed, the magnitude of the peripheral acetylcholinesterase inhibition is the highest tolerable inhibition level yet observed.

Metrifonate treatment of AD: influence of APOE genotype.

OBJECTIVE: To investigate whether an interaction exists between APOE genotype and the response of AD patients to metrifonate treatment and whether APOE genotype independently affects the rate of AD progression. BACKGROUND: Metrifonate is a new acetylcholinesterase inhibitor for the treatment of AD symptoms. METHODS: Data were pooled from four prospective, randomized, double-blind, placebo-controlled clinical trials and analyzed retrospectively. A total of 959 patients who received once-daily placebo (n = 374) or metrifonate (30 to 60 mg based on weight or a 50-mg fixed dose, n = 585) for up to 26 weeks agreed to APOE genotyping. RESULTS: Metrifonate clearly improved the cognitive performance of the AD patients when compared with placebo (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], p = 0.0001). The interaction of APOE genotype and the metrifonate effect on cognitive performance were not significant (p = 0.25). Metrifonate also clearly improved the global function of the AD patients when compared with placebo (Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus], p = 0.0001). The interaction of APOE genotype with the metrifonate effect on global function also was not significant (p = 0.70). No significant three-way interactions were observed among APOE genotype, gender, and response to metrifonate treatment (ADAS-Cog, p = 0.68; CIBIC-Plus, p = 0.26). APOE genotype did not influence disease progression as evaluated by either cognitive performance (ADAS-Cog, p = 0.93) or global function (CIBIC-Plus, p = 0.64). CONCLUSIONS: The findings from these studies of up to 26 weeks' duration do not clearly support an interaction between APOE genotype and metrifonate treatment effects. They suggest that APOE genotypes do not necessarily predict an AD patient's response to metrifonate treatment and that APOE genotype may not influence the rate of disease progression for patients with mild to moderate AD.

The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's disease patients. Metrifonate Study Group.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of metrifonate, a long-acting acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease of mild-to-moderate severity. METHOD: This was a prospective, multicenter, 26-week, double-blind, parallel group study. The 264 randomized patients met diagnostic criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association for probable Alzheimer's disease. Patients had Mini-Mental State Examination (MMSE) scores of 10-26 and ischemic scores (Rosen modification) of <4. Metrifonate-treated patients received a single 50-mg dose once daily. The efficacy of metrifonate was investigated with respect to 3 symptom domains. Cognitive performance was analyzed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the MMSE. Psychiatric and behavioral disturbances were analyzed using the Neuropsychiatric Inventory (NPI) and the ADAS-Noncognitive subscale (ADAS-Noncog). The ability to perform instrumental and basic activities of daily living was evaluated using the Disability Assessment for Dementia (DAD) scale. Additionally, global state was assessed using the Clinician Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus) scale. RESULTS: After 26 weeks of metrifonate therapy, a statistically significant benefit of metrifonate was observed in the cognitive performance of Alzheimer's disease patients (ADAS-Cog, t = 2.55, df = 237, p = .012; MMSE, t = 4.60, df = 237, p = .0001). Metrifonate also significantly attenuated the deterioration in activities of daily living of the patients (DAD total score, t = -2.11, df = 233, p = .036) and relieved patients' psychiatric and behavioral disturbances (NPI total score, t = 2.51, df = 233, p = .013). In addition, metrifonate significantly improved the scores for the global state of the patients (CIBIC-Plus, t = 2.07, df = 232, p = .039). Metrifonate was well tolerated; adverse events were predominantly mild in intensity, and no hepatotoxicity was observed. CONCLUSION: In this study, metrifonate was safe and well tolerated. It benefited the cognitive decline, psychiatric and behavioral disturbances, impaired ability to perform instrumental and basic activities of daily living, and global state of patients diagnosed with mild-to-moderate Alzheimer's disease.

Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized, double-masked, placebo-controlled trial. Metrifonate Study Group.

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in this study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.

Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Metrifonate Study Group.

The efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, was evaluated clinically in patients diagnosed with mild to moderate Alzheimer's disease (AD). This was a prospective, 30-week, multicenter, double-blind, randomized, parallel group, dose-finding study, which included a 2-week screening period, a 12-week treatment period, and follow-up visits at 8 and 16 weeks post-treatment. Patients received placebo or metrifonate once daily. Metrifonate-treated patients received a loading dose of 0.5 mg/kg (25 to 45 mg), 0.9 mg/kg (45 to 80 mg), or 2.0 mg/kg (100 to 180 mg) for 2 weeks, followed by a maintenance dose of 0.2 mg/kg (10 to 20 mg), 0.3 mg/kg (15 to 25 mg), or 0.65 mg/kg (30 to 60 mg) for 10 weeks. Four hundred eighty patients were enrolled. Percentages of patients completing double-blind treatment were 96% in the placebo group and 89 to 94% in the metrifonate group. Metrifonate significantly improved cognitive ability, as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and enhanced global function, as assessed the Clinicians's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus). At 3 months, in the intent-to-treat patients, the treatment difference for the change in ADAS-Cog score in favor of metrifonate was 2.94 points (95% CI, 1.61 to 4.27; p = 0.0001). These patients also exhibited a 0.35-point improvement on the CIBIC-Plus relative to the placebo patients (95% CI, 0.15 to 0.54; p = 0.0007). Patients receiving lower drug doses had scores intermediate to those of the placebo and the 0.65 mg/kg metrifonate groups on both performance scales. The drug was well tolerated; side effects were predominantly gastrointestinal in nature, and no hepatic toxicity was observed. Therefore, in this study, metrifonate safely improved the cognitive deficits and benefited the global function of AD patients.

Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease.

OBJECTIVE: To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity. METHODS: A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations. RESULTS: After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed. CONCLUSIONS: Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD.

Safety and tolerability of metrifonate in patients with Alzheimer's disease: results of a maximum tolerated dose study.

Metrifonate, a pro-drug that is transformed non-enzymatically into a potent inhibitor of acetylcholinesterase (AChE), has been used in the tropics for over 30 years for the treatment of schistosomiasis. A pilot study, and Phase I and Phase II studies of metrifonate in Alzheimer's disease (AD) patients conducted prior to the current study showed benign, dose-dependent adverse event profiles consisting primarily of gastrointestinal events, optimal daily dosing with a loading phase (in the absence of a loading dose phase, 6-8 weeks were required to attain steady-state AChE inhibition levels), and an improvement in Alzheimer's Disease Assessment Scale (ADAS) scores. The current open-label study was designed to evaluate the safety and tolerability of relatively high loading doses, followed by lower maintenance doses of metrifonate in the same patient population, and to determine the maximum tolerated dose (MTD) of metrifonate. Accordingly, the first cohort of 8 probable AD patients (per National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria) were administered once-daily loading doses of 2.5 mg/kg (125-225 mg) for 14 days, followed by 4.0 mg/kg (200-360 mg) for an additional 3 days. These patients were maintained on once-daily doses of 2.0 mg/kg (100-180 mg) for 14 days. AChE inhibition for this cohort ranged from 88% to 94%. On Day 28 of 31, this cohort was discontinued due to moderate to severe side effects in 6 patients; consequently, the second cohort of 8 probable AD patients received a once-daily loading dose of 2.5 mg/kg (125-225 mg) for 14 days followed by a once-daily maintenance dose of 1.5 mg/kg (75-135 mg) for 35 days. This maintenance dose yielded an AChE inhibition level ranging from 89% to 91%. In spite of an AChE inhibition level comparable to that achieved with the higher dose, the reduced dose was associated with a more favorable adverse event profile which was mainly gastrointestinal and musculoskeletal in nature. The maximum tolerated dose was established at 1.5 mg/kg/day (75-135 mg/day) for maintenance dosing in AD patients.

Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease.

Metrifonate is converted nonenzymatically to 2.2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day, randomized, double-blind, placebo-controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225 mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65 mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose-independent mean values for time to Cmax (tmax) and half-life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long-term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.

The Alzheimer's Disease Assessment Scale: patterns and predictors of baseline cognitive performance in multicenter Alzheimer's disease trials.

The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is used as an efficacy measure in clinical drug trials of Alzheimer's disease (AD). We used data from 1,648 AD participants in two identical 26-week multicenter drug trials to examine the distribution of baseline ADAS-Cog scores in relation to selected demographic and clinical variables, Mini-Mental State Exam (MMSE), Global Deterioration Scale (GDS), and Geriatric Evaluation by Relative's Rating Instrument (GERRI) scores. At baseline, the mean (+/-SD) MMSE score was 18 +/- 4, the ADAS-Cog score was 28 +/- 11, and most subjects were in GDS stage 4 or 5. The ADAS-Cog score was statistically significantly correlated with MMSE (R = -0.76, p < 0.0001) and GERRI (R = 0.40, p < 0.0001) total scores. Correlations among the ADAS-Cog items ranged from 0.19 to 0.59 and all were statistically significant (p < 0.0001). In a multiple regression model, younger age, male gender, older age at onset of dementia, use of concurrent estrogen, and use of concurrent anti-inflammatory agents were statistically significantly associated with superior cognitive performance. We also present data on the distribution of ADAS-Cog scores in relation to subjects' age, level of education, MMSE score, and GDS stage. Because age, MMSE score, and GDS stage (and not the ADAS-Cog) are commonly used to select subjects for AD clinical trials, our data should improve the ability of sponsors to predict ADAS-Cog scores of the subjects in their trials on the basis of the inclusion criteria used. Our data also suggest that age, gender, age at onset of dementia, level of education, and use of estrogen (in women) or anti-inflammatory drugs are related to cognitive abilities in AD. Further studies are needed to assess how and when cognitive differences related to these variables arise.

Memory, language, and praxis in Alzheimer's disease: norms for outpatient clinical trial populations.

The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is designed specifically to assess memory, language, and praxis dysfunctions characteristic of Alzheimer's disease (AD). In this report, we use data from 1,648 AD participants in two identical 26-week multicenter drug trials to derive clinical trial population-based norms for ADAS-Cog subtest scores. All 11 ADAS-Cog item scores were sensitive to differences in dementia severity judged either by baseline Mini-Mental State Exam (MMSE) scores or by Global Deterioration Scale (GDS) stage of dementia. Using ADAS-Cog subtest scores alone, 85 percent of GDS 4 subjects and 69 percent of GDS 5 subjects could be classified correctly. In a stepwise discriminant analysis, orientation was the item with the greatest discriminatory power between subjects with GDS 4 and GDS 5 stages of dementia. ADAS-Cog subtest scores also varied by age, gender, educational level, and concurrent use of anti-inflammatory drugs or estrogen (in women). Such normative data may facilitate the selection of appropriate outcome measures to investigate differential treatment effects on specific cognitive domains or in specific AD subpopulations.

Self-esteem and neuroendocrine response to challenge: MacArthur studies of successful aging.

The role of self-esteem in modulating patterns of neuroendocrine response to challenge at older ages was examined in 16 healthy 70-yr-olds. Responses to two challenges were examined: (1) a driving simulation designed to reflect a 'real life' challenge situation; and (2) a pharmacologic, corticotropin-releasing-hormone (CRH) challenge (1 micrograms/kg). Both challenges evoked significant elevations in cortisol and adrenocorticotropic hormone (ACTH). Levels of self-esteem were significantly and negatively associated with peak elevations in cortisol in response to the driving simulation challenge (r = -0.51, p = 0.04). ACTH responses showed similar trends (r = -0.41, p = 0.12). Self-esteem levels were not correlated with responses to the CRH challenge. These data indicate that psychological characteristics such as self-esteem may play a role in modulating patterns of neuroendocrine response to cognitive/behavioral challenges in everyday life in older individuals.

Cytoarchitectural relationships between [3H]ouabain binding and mRNA for isoforms of the sodium pump catalytic subunit in rat brain.

We examined the cell type-specific expression of the alpha 1, alpha 2, and alpha 3 subunits of the sodium pump in rat brain using in situ hybridization and [3H]ouabain autoradiography. These techniques allowed us to colocalize mRNA and functional alpha 2/alpha 3 pumps on adjacent sections. The perikarya of many neurons possessed high levels of alpha 1 and/or alpha 3 transcripts, while alpha 2 mRNA appeared to be present in only a few neuronal types. [3H]Ouabain binding in general paralleled the distribution of alpha 3 mRNA-positive neurons. The regional variation of alpha 1 and alpha 3 transcripts was complex and varied. Large neurons of the olfactory bulb and piriform cortex expressed high levels of alpha 3 transcripts, but low levels of alpha 1 mRNA. In frontal cortex, neurons of layers II-III were enriched in alpha 1 mRNA, while those in layer V exhibited high levels of alpha 3 transcripts. In the hippocampus, principal neurons expressed all three alpha subunit mRNAs. CA subfield pyramidal neurons exhibited a high alpha 3/alpha 1 ratio, while dentate granule cells and hilar pyramidal neurons expressed approximately equal levels of alpha 1 and alpha 3. In the cerebellum, Purkinje and Golgi cells were rich in alpha 3 mRNA, while the granule cells appeared to express only alpha 1 transcripts. The distribution of functional sodium pump protein, as localized by [3H]ouabain binding, was highest in the neuropil of the hippocampus and cerebral cortex, and lowest over perikarya and white matter. [3H]ouabain did not bind to alpha 1 pump units, as confirmed by the complete absence of labeling over the choroid plexus, a tissue expressing only alpha 1 mRNA. In the cerebellum, regions of dense [3H]ouabain binding were localized to the granule cell layer, the inner third of the molecular layer in the basket region, and the deep cerebellar nuclei. Surprisingly, the dense neuropil in the outer 2/3 of the molecular layer lacked high [3H]ouabain binding. Thus, functional alpha 3 sodium pump units appear distributed to the axon terminals and not to apical dendrites of Purkinje, Golgi and basket cells. A similar pattern of increased [3H]ouabain binding in axonal but not dendritic fields of alpha 3-enriched neurons was present in the cerebral cortex and the hippocampus. Considering that many alpha 3-enriched neurons are of the Golgi I type with long axons, the alpha 3 isoform may be preferentially directed into axons to function in presynaptic membranes.