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Robert M Cohen

Publications and source records attributed to Robert M Cohen.

At least 19 recordsLinked to original sources
PubMed2006

Functional magnetic resonance imaging and magnetoencephalography differences associated with APOEepsilon4 in young healthy adults.

Functional neural alterations are present in middle-aged to late-aged healthy individuals carrying the epsilon4 allele of the apolipoprotein E (APOEepsilon4) gene, a known risk factor for Alzheimer's disease. Neural activity was measured in young adults with and without the epsilon4 allele (APOEepsilon4+ and APOEepsilon4-) by functional magnetic resonance imaging and magnetoencephalography while performing a visual working memory task on two separate days. Greater activity was observed in frontal areas and cingulate gyri in APOEepsilon4+ participants by both functional magnetic resonance imaging and magnetoencephalography with regional blood oxygenation level-dependent responses correlating with increased theta band power. The findings suggest that the presence of the APOEepsilon4 allele has physiological consequences before aging that may contribute to risk for Alzheimer's disease.

Adult↗
PubMed2006

Stability of CSF beta-amyloid(1-42) and tau levels by APOE genotype in Alzheimer patients.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42 )and tau differ between patients with Alzheimer's Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. METHODS: We assessed CSF beta-amyloid(1-42) and tau in 20 mild-to-moderate AD patients, 11 APOE epsilon4+ and 9 APOE epsilon4-, over a mean time of 3.8 years (range 1-11.1 years). RESULTS: Over the period measured, CSF beta-amyloid(1-42) levels were lower in APOE epsilon4+ compared to APOE epsilon4- patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. CONCLUSIONS: While this is a limited clinical sample, the further decrease in CSF beta-amyloid(1-42 )(i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that beta-amyloid(1-42 )and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF beta-amyloid(1-42) and tau are used as measures of treatment response.

Aged↗
PubMed2006

Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease.

OBJECTIVE: Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects. METHODS: Nicotinic acetylcholine receptors were imaged in 10 nondemented Parkinson's disease patients and 15 age-matched healthy subjects using a single-photon emission computed tomography ligand [(123)I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus nondisplaceable), as well as the delivery (K(1)). RESULTS: Parkinson's disease showed a widespread significant decrease (approximately 10%) of V in both cortical and subcortical regions without a significant change in K(1). INTERPRETATION: These results indicate the importance of extending the study to demented patients.

Aged↗
PubMed2006

Age and APOE-epsilon4 genotype influence the effect of physostigmine infusion on the in-vivo distribution volume of the muscarinic-2-receptor dependent tracer [18F]FP-TZTP.

The apolipoprotein E-epsilon4 allele (APOE-epsilon4) confers greater susceptibility to age-related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE-epsilon4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F-18 labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), in aging healthy subjects with an APOE-epsilon4 allele. To examine the effects of aging and the APOE-epsilon4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [18F]FP-TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline (n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE-epsilon4 allele and 7 without an APOE-epsilon4 allele). Using a multiple regression analysis, both AGE (beta = 0.621 +/- 0.135, B = 0.353 +/- 0.077, t(10) = 4.61, P < 0.001) and APOE-epsilon4 genotype (beta = 0.742, B = 14.8 +/- 2.69, t(10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R2 for the model as a whole was 0.786 (F(2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE-epsilon4 allele modifying the response to physostigmine in the direction of larger decreases in [18F]FP-TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE-epsilon4 genotype, contribute to the growing body of evidence that suggests that the APOE-epsilon4 genotype is likely to contribute to brain structure and function prior to aging.

Adult↗
PubMed2006

Biomarkers in the diagnosis of Alzheimer's disease: are we ready?

Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.

Adult↗
PubMed2006

Evidence for independent heritability of the glycation gap (glycosylation gap) fraction of HbA1c in nondiabetic twins.

OBJECTIVE: HbA(1c) (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C - A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C. RESEARCH DESIGN AND METHODS: We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range. RESULTS: GG was more strongly correlated between monozygotic (r = 0.65) than dizygotic (r = 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r = 0.55) and dizygotic (r = 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r = 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C. CONCLUSIONS: Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment.

Adult↗
PubMed2005

A magnetoencephalography spatiotemporal analysis of neural activities during feature binding.

Previous literature shows that feature binding processes elicit fronto-hippocampal areas. The time course of this process, however, remains unknown. This is the first study that investigates feature binding using magnetoencephalography. Synthetic aperture magnetometry analysis was used to localize sources of increased power in the theta band during the encoding phases of a feature-binding task in the left and right medial frontal gyri (Brodmann's area 10) and left and right anterior cingulate gyri. Theta band synchronization was observed in many of these same areas, but also in other areas not noted to have increased theta band power suggesting a broad network of regions subserving the encoding phase of feature binding.

Adult↗
PubMed2005

Hippocampal atrophy in the healthy is initially linear and independent of age.

Patients with minimal cognitive impairment (MCI) or Alzheimer's disease (AD) have smaller hippocampal volumes (HV) and increased rates of HV loss (rHVL). A 6-year study was conducted to assess rHVL in healthy aging subjects (HC) in which four MRI scans, each 2 years apart, were obtained on 26 HC with a mean age of 58.8 years when entering the study. rHVLs were linear and significantly differed among subjects, even those sharing an identical apoliporotein E genotype, ranging from .027 to .191 cc/year (S.D. = .022 cc/year), and were not affected by age or sex. rHVL, but not HV, at time of subject entry, was found to predict performance on the delayed recall measure of the Selective Reminder Task obtained 6 years after subject entry into study. Although the molecular events underlying rHVL are unclear, the significance of rHVL in subjects in their sixth and seventh decades of life for predicting age-related cognitive trajectories and whether changes in rHVLs foreshadow the development of MCI are the subject of ongoing study.

Age Factors↗
PubMed2005

PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease.

PURPOSE: The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). METHODS: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. RESULTS: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. CONCLUSION: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

Alzheimer Disease↗
PubMed2005

Frequency of abnormal carbohydrate metabolism and diabetes in a population-based screening of adolescents.

OBJECTIVE: To document the frequency of glucose intolerance in adolescents in a population-based study of primarily African-American/Non-Hispanic whites in an urban-suburban school district. STUDY DESIGN: Measurement of fasting and 2-hour post-glucose load plasma glucose concentrations. RESULTS: Carbohydrate intolerance (either impaired fasting glucose, impaired glucose tolerance, or both) was identified in 8.0%, near-diabetes (1 fasting glucose > or = 126 mg/dL [7.0 mmol/L] and/or 2-hour glucose > or = 200 mg/dL [11.1 mmol/L]) in 0.3%, and diabetes in 0.36% (type 1A = 0.24%; type 2 = 0.08%; undiagnosed type 2 = 0.04%). A model for abnormal carbohydrate metabolism was constructed with regression analysis in the Carbohydrate Intolerance (CI)/near-diabetes group and with logistic regression in the entire study population. Risk factors for the development of CI/near-diabetes included having a 1 unit increase in body mass index (BMI) z-score and either being non-Hispanic white or in the pubertal group. Increased fasting glucose correlated with having puberty and decreased BMI z-score, whereas 2-hour glucose correlated with increased BMI z-score. By using National Health and Nutrition Survey (NHANES) III (1988-1994) definitions, impaired fasting glucose was present in 2.0% in this study versus 1.7% (NHANES III). CONCLUSION: The prevalence of CI/near-diabetes was 8.3%. Undiagnosed diabetes mellitus was rare. One third of adolescents with diabetes mellitus could be classified as having type 2 diabetes mellitus. The adult model of the progression of insulin resistance to type 2 diabetes mellitus in adolescents may be valid. Despite the increase in the overweight population since NHANES III, abnormalities in glucose metabolism have not changed significantly.

Adolescent↗
PubMed2005

Effects of previous major depressive illness on cognition in Alzheimer disease patients.

OBJECTIVE: Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored. METHODS: Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment. RESULTS: After controlling for age, education, duration of illness, gender, and medication status, subjects with a history of MDD had significantly lower scores, as a group, on cognitive performance tests, including the Mini-Mental State Exam, WAIS Full-Scale and Verbal Scale I.Q., and the Initiation/Perseveration subscale of the Mattis Dementia Rating Scale. These subjects also developed symptoms of dementia at a significantly earlier age than the subjects who had no premorbid history of MDD. CONCLUSIONS: Although previous studies have shown that late-onset MDD may increase risk for subsequent dementia, the current results suggest that premorbid MDD is associated with more severe cognitive deficits during the actual course of dementia.

Aged↗
PubMed2004

Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. METHODS: We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. RESULTS: When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). CONCLUSIONS: The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Age Factors↗
PubMed2004

Obesity and the development of insulin resistance and impaired fasting glucose in black and white adolescent girls: a longitudinal study.

OBJECTIVE: Age at onset of type 2 diabetes has decreased during the past 20 years, especially in black women. Studies of factors associated with insulin resistance and hyperglycemia in preadolescent and adolescent populations are essential to understanding diabetes development. RESEARCH DESIGN AND METHODS: The National Heart, Lung, and Blood Institute (NHLBI) Growth and Health Study (NGHS) is a 10-year cohort study of the development of obesity in black and white girls. Two NGHS centers examined the associations of obesity, puberty, and race with fasting insulin, glucose, and homeostasis model assessment of insulin resistance (HOMA-IR; a calculated index of insulin resistance) measures at 9-10 years of age (baseline) and 10 years later. RESULTS: Black girls had greater baseline and year-10 BMI than white girls, with a greater 10-year incidence of obesity. BMI-insulin correlations were positive in both black and white girls at both visits, but insulin remained higher in black girls after controlling for BMI. In black girls, insulin and HOMA-IR were higher in the prepubertal period (before the emergence of racial differences in BMI), increased more during puberty, and decreased less with its completion. Baseline BMI predicted year-10 glucose and the development of impaired fasting glucose (IFG) in black girls. In white girls, the rate of BMI increase during follow-up predicted these outcomes. The 10-year incidence of diabetes in black girls was 1.4%. CONCLUSIONS: Black-white differences in insulin resistance are not just a consequence of obesity, but precede the pubertal divergence in BMI. The development of IFG appears to be a function of the rate of increase of BMI in white girls and early obesity in black girls.

Adolescent↗
PubMed2003

Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-epsilon4 allele.

The apolipoprotein E-epsilon4 allele confers an increased susceptibility to age-related memory problems and Alzheimer's disease. Abnormalities in the cholinergic system are also likely contributors to memory deficits associated with aging and AD. To determine the effect of the APOE-epsilon4 allele on the muscarinic component of the cholinergic system of aging subjects, 10 healthy subjects with APOE-epsilon4 alleles (APOE-epsilon4+) and 10 without (APOE-epsilon4-), ranging in age from 52 to 75 years, were tomographically scanned with the F-18-labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[(18)F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([(18)F]FP-TZTP). The distribution volumes (V(T)) of [(18)F]FP-TZTP were determined by compartmental modeling of partial volume and free fraction corrected PET scans. Regional cerebral blood flow (rCBF) measurements with H(2) (15)O were also performed. Global Gray V(T) (840 +/- 155 ml plasma/ml tissue) was greater in APOE-epsilon4+ subjects than APOE-epsilon4- subjects (660 +/- 113 ml plasma/ml tissue, P = 0.01), and previously studied younger subjects. There were no significant differences between the groups with respect to rCBF, but within the APOE-epsilon4+ group there was a trend for subjects with the higher Global Gray V(T)s to have lower Global Gray CBFs (r = -0.65, P < 0.06). A lower concentration of acetylcholine in the synapse of APOE-epsilon4+ older individuals is a likely explanation for the greater [(18)F]FP-TZTP distribution volumes.

Aged↗
PubMed2003

In vivo muscarinic 2 receptor imaging in cognitively normal young and older volunteers.

The precise effects of normal aging on the cholinergic system are unknown, as both in vitro and PET studies have shown conflicting results. In vivo determination of muscarinic receptor distribution and density has been hampered by both poor subtype selectivity and/or blood-brain barrier permeability of known ligands. Previous in vitro and in vivo work with the F-18 labeled muscarinic agonist, 3-(3- (3-[(18)F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ((18)FP-TZTP) suggested the use of (18)FP-TZTP to selectively quantify M2 receptors in humans. In this study, we used (18)FP-TZTP to infer M2 receptor avidity in the brains of 15 healthy younger subjects (mean age = 28.3 +/- 5.5 years) and 20 healthy older subjects (mean age = 62.1 +/- 7.7 years). Corrections for subject motion during the 120-min acquisition and partial voluming (PVC) were performed. A one-tissue compartment model was used to estimate the volumes of distribution (V(T)) of (18)FP-TZTP. Within both groups of subjects, volumes of distribution (K(1)/k(2)) in cortical, subcortical, and cerebellar areas were consistent with M2 receptor topography. Compared to younger subjects older subjects had significantly higher means and standard deviations for the volumes of distribution of (18)FP-TZTP throughout much of the cerebellum, cortex, and subcortex (Global Gray V(T) = 742 +/- 163 in older subjects and 645 +/- 74 in younger subjects, P < 0.03). Across all subjects (18)FP-TZTP, regional, and Global Gray distribution volumes were significantly correlated to age (Global Gray V(T,) r = 0.41, P < 0.01). A lower concentration of acetylcholine in the synapse of some older subjects is one possible explanation for the data.

Acetylcholine↗
PubMed2003

Efficacy response of inhaled HFA-albuterol delivered via the breath-actuated Autohaler inhalation device is comparable to dose in patients with asthma.

Handling difficulties, such as poor coordination of actuation and inhalation, are common in patients using press and breathe (P&Bs) metered-dose inhalers to administer asthma medication. Although spacers can help overcome some difficulties, the cumbersome nature of these devices often detracts from their use for the administration of rescue medications, where portability is important. This randomized, placebo-controlled, multicenter, crossover study investigated the efficacy, dose-response and safety of HFA-albuterol delivered via a breath-actuated Autohaler inhalation device in comparison with the same medication delivered using a conventional P&B device. In total, 39 patients received six study treatments in a random sequence at clinic visits separated by 2-7 days: 2 puffs from a HFA-placebo Autohaler; 1, 2, or 4 puffs from a HFA-albuterol Autohaler; I or 2 puffs from a HFA-albuterol P&B. Both active inhalers delivered 90 microg albuterol base equivalent/actuation from the actuator. The change from baseline in forced expiratory volume in 1 s (FEV1) and the area under the FEV1 curve (FEV1 AUC) were significantly greater than placebo for all active treatment groups (p < or = 0.01) and were suggestive of a dose response for each inhaler. Examination of the pooled slope of the dose responses for the Autohaler and P&B using Finney's Parallel Line Bioassay Methodology found a highly statistically significant relationship indicating the equivalence of the two inhalers on both parameters (p < or = 0.002). The relative potency of the two inhalers was 0.8 (95% CI: 0.47, 1.46) for the mean change from baseline in FEV1 and 0.9 (95% CI, 0.56, 1.48) for the change from baseline in FEV1 AUC. There was also a trend toward an increase in the mean percentage change from baseline in FEV1 as the number of puffs increased for both inhalers. Furthermore, there were no significant differences between the treatment groups with regard to time to onset of bronchodilator effect and the duration of effect was significantly greater than placebo (p < or = 0.01) in each of the active groups. Adverse events were generally mild to moderate in nature and were of similar incidence (< or = 18% of patients) in each group. This study demonstrates a dose-response for HFA-albuterol on bronchodilation using both the Autohaler and P&B devices and illustrates that, in patients with good coordination of inhalation with actuation, the efficacy and safety of the two inhalers is similar at equivalent doses.

Administration, Inhalation↗