Large-scale real-world data analysis of source plasma collections using a novel technology-enabled nomogram.

BACKGROUND: Source plasma collections are needed to satisfy the growing demand for plasma-derived medicinal products. The US plasma collection target volume has been guided by a standard weight-based FDA-issued nomogram (STAN) since 1992. In this research, large-scale US-based real-world data (RWD) were analyzed to confirm the safety and volume gains of a newly introduced personalized nomogram (PERS) that was previously studied in a premarket randomized controlled environment. STUDY DESIGN AND METHODS: A non-inferiority (NI) analysis was conducted to compare the novel nomogram's significant hypotensive adverse event (AE) incidence rate with large historical standard nomogram AE datasets. Additionally, the average target volumes and donor return rates were compared for collections following PERS and STAN. RESULTS: A total of 4,816,784 donations (PERS) by 414,957 donors resulted in a rate of 0.0998% (95% CI [0.0970, 0.1027]) significant hypotensive AEs. NI analysis suggested strong non-inferiority of the new technology (Δ = -0.0082%, 95% CI [-0.0113, -0.0050], prespecified NI margin = 0.1080). Average plasma collection target volumes increased by 66.39 mL (8.49%; p < .0001). Consecutive weekly donor return rates were consistent between the two nomograms (PERS: 73.6%, 95% CI [69.6%-76.7%]; STAN: 74.1%, 95% CI [66.1%-77.2%]). DISCUSSION: This analysis confirms in a large-scale real-world dataset the key safety parameter and collection benefit of a novel, technology-enabled nomogram. The nomogram may help meet the growing demand for plasma-derived therapies by providing approximately 8.5% more plasma per donation on average while maintaining donor safety and return rates.

Timing of hypotensive adverse events in U.S. source plasma donors: Exploratory analysis from the IMPACT trial.

BACKGROUND AND OBJECTIVES: There is less robust data describing adverse events (AEs) in source plasma donors than in whole blood donors, particularly regarding time to AEs (TAEs). We, therefore, sought to characterize TAE and the influence of donor characteristics in a large-scale clinical trial dataset. MATERIALS AND METHODS: TAE was calculated utilizing data from the IMPACT (IMproving PlasmA CollecTion) trial, with linear regression analyses performed to determine the influence of donor parameters on TAE. RESULTS: Linear regression revealed that repeat donors tended to have AEs ~6 min later than naïve donors in the IMPACT trial; however, this was not statistically significant (p = 0.781). Besides this, gender showed greatest difference in TAE; however, no covariates were statistically significant. AE rates were relatively constant throughout the donation process with higher rates beginning 40 min after initiation; no initial peak was observed (first 10-15 min). CONCLUSION: AEs occurred throughout the donation process. None of the analyzed factors could fully explain the difference in the dynamics of AE timing with that of whole blood donation, particularly the missing early peak. Therefore, other factors, e.g., expectation and attitude towards donating plasma and potential events during plasma collection, may explain this difference and should be the focus of future studies.

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity.

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

Repeat donation and deferral rates in US source plasma donors: Exploratory analysis from the IMPACT trial.

BACKGROUND: The IMPACT trial demonstrated the safety of a new personalized nomogram for plasma donation and provided an opportunity to explore short- to mid-term impact on repeat donation and deferral rates, and factors affecting these. STUDY DESIGN AND METHODS: In the IMPACT trial, participants were randomized to donate plasma using an established weight-based nomogram (control) versus a new personalized nomogram incorporating height, weight, and hematocrit (experimental). In this exploratory analysis, repeat donations (per donor, by study arm) were analyzed using negative binomial generalized linear regression models and descriptive statistics. The mean number of donor deferral events was compared between the two arms using logistic regression and count data modeling approaches and were analyzed by lead cause. RESULTS: The predicted mean number of repeat donations was similar between the control and experimental arms (6.82 vs. 6.62, respectively; p = .22). Overall, the predicted mean number of repeat donations was significantly higher in males compared with females (p < .0001). Naïve donors had on average 2.8/2.7 (control/experimental) fewer repeat donations compared with experienced donors. In 23, 137 donations from 3443 donors, 798 donors (376 control, 422 experimental, p = .80) had at least one deferral (for any cause). The predicted mean number of deferrals in all categories of interest was not statistically different between the study arms. CONCLUSION: Similar repeat donation and deferral rates between arms suggest that the new nomogram did not result in disruptions to subsequent donation. Further longitudinal research on mid- to long-term effects is warranted.

Personalized collection of plasma from healthy donors: A randomized controlled trial of a novel technology-enabled nomogram.

BACKGROUND: Source plasma is essential to support the growing demand for plasma-derived medicinal products. Supply is short, with donor availability further limited by the coronavirus disease 2019 (COVID-19) pandemic. This study examined whether a novel, personalized, technology-based nomogram was noninferior with regard to significant hypotensive adverse events (AEs) in healthy donors. STUDY DESIGN AND METHODS: IMPACT (IMproving PlasmA CollecTion) was a prospective, multicenter, double-blinded, randomized, controlled trial carried out between January 6 and March 26, 2020, in three U.S plasma collection centers. Donors were randomly assigned to the current simplified 1992 nomogram (control) or a novel percent plasma nomogram (PPN) with personalized target volume calculation (experimental). Primary endpoint was the rate of significant hypotensive AEs. Noninferiority (NI) was tested with a margin of 0.15%. Collected plasma volume was a secondary endpoint. RESULTS: A total of 3443 donors (mean [SD] BMI: 32 [7.74] kg/m2 ; 65% male) underwent 23,137 donations (median [range]: 6 [1-22] per subject). Ten significant hypotensive AEs were observed (six control; four experimental), with model-based AE incidence rate estimates (95% CI) of 0.051% (0.020%-0.114%) and 0.035% (0.010%-0.094%), respectively (p = .58). NI was met at an upper limit of 0.043% versus the predefined margin of 0.15%. There was no statistical difference between total AEs (all AE types: p = .32). Mean plasma volume collected was 777.8 ml (control) versus 841.7 ml (experimental); an increase of 63.9 ml per donation (8.2%; p < .0001). CONCLUSION: This trial showed that a novel personalized nomogram approach in healthy donors allowed approximately 8% more plasma per donation to be collected without impairing donor safety.

Efficacy and Safety of PF-06651600 (Ritlecitinib), a Novel JAK3/TEC Inhibitor, in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate.

OBJECTIVE: To evaluate the efficacy and safety of PF-06651600 (ritlecitinib), an irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, in comparison with placebo in patients with rheumatoid arthritis (RA). METHODS: An 8-week, phase II, double-blind, parallel-group study was conducted. Seventy patients who were seropositive for anti-citrullinated protein antibodies and/or rheumatoid factor were randomized 3:2 to receive oral PF-06651600 (200 mg once daily) or placebo for 8 weeks. Eligible patients had an inadequate response to methotrexate, and the study design allowed up to 50% of patients to have previously received 1 tumor necrosis factor inhibitor that was inadequately effective and/or not tolerated. The primary end point was change from baseline in the Simplified Disease Activity Index (SDAI) score at week 8, assessed by Bayesian analysis using an informative prior distribution for placebo response. RESULTS: Mean change from baseline in the SDAI score at week 8 was greater in the PF-06651600 group (-26.1 [95% credible interval -29.7, -22.4]) than in the placebo group (-16.8 [95% credible interval -20.9, -12.7]; P < 0.001). Most adverse events (AEs) were mild in severity, and no treatment-related serious AEs, severe AEs, or deaths were reported. The most common classes of AE were infections and infestations as well as skin and subcutaneous tissue disorders; there was 1 mild case of herpes simplex in the PF-06651600 group that was considered to be treatment related, which resolved within 3 days without study treatment discontinuation or antiviral therapy. CONCLUSION: Treatment with the oral JAK3/TEC inhibitor PF-06651600 (200 mg once daily) was associated with significant improvements in RA disease activity and was generally well-tolerated in this small 8-week study.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects.

BACKGROUND: PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects. METHODS: Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD. RESULTS: PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (Tmax of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased Cmax by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9-fold to 1.3-fold for Cmax. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ≥ 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed. CONCLUSIONS: PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015.

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease.

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10-4 L/[h·kg]; central volume of distribution 457 × 10-4 L/kg; maximum elimination rate 17.5 × 10-4 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10-4 h-1 ; complex removal rate 90 × 10-4 h-1 ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD.

Statistical Monitoring in Clinical Trials: Best Practices for Detecting Data Anomalies Suggestive of Fabrication or Misconduct.

BACKGROUND: Traditional site-monitoring techniques are not optimal in finding data fabrication and other nonrandom data distributions with the greatest potential for jeopardizing the validity of study results. TransCelerate BioPharma conducted an experiment testing the utility of statistical methods for detecting implanted fabricated data and other signals of noncompliance. METHODS: TransCelerate tested statistical monitoring on a data set from a chronic obstructive pulmonary disease (COPD) clinical study with 178 sites and 1554 subjects. Fabricated data were selectively implanted in 7 sites and 43 subjects by expert clinicians in COPD. The data set was partitioned to simulate studies of different sizes. Analyses of vital signs, spirometry, visit dates, and adverse events included distributions of standard deviations, correlations, repeated values, digit preference, and outlier/inlier detection. An interpretation team, including clinicians, statisticians, site monitoring, and data management, reviewed the results and created an algorithm to flag sites for fabricated data. RESULTS: The algorithm identified 11 sites (19%), 19 sites (31%), 28 sites (16%), and 45 sites (25%) as having potentially fabricated data for studies 2A, 2, 1A, and 1, respectively. For study 2A, 3 of 7 sites with fabricated data were detected, 5 of 7 were detected for studies 2 and 1A, and 6 of 7 for study 1. Except for study 2A, the algorithm had good sensitivity and specificity (>70%) for identifying sites with fabricated data. CONCLUSIONS: We recommend a cross-functional, collaborative approach to statistical monitoring that can adapt to study design and data source and use a combination of statistical screening techniques and confirmatory graphics.

Fasting glucose and glucose tolerance as potential predictors of neurocognitive function among nondiabetic older adults.

INTRODUCTION: Significant evidence has demonstrated that Type 2 diabetes mellitus and related precursors are associated with diminished neurocognitive function and risk of dementia among older adults. However, very little research has examined relations of glucose regulation to neurocognitive function among older adults free of these conditions. The primary aim of this investigation was to examine associations among fasting glucose, glucose tolerance, and neurocognitive function among nondiabetic older adults. The secondary aim was to examine age, gender, and education as potential effect modifiers. METHOD: The study employed a cross-sectional, correlational study design. Participants were 172 older adults with a mean age of 64.43 years (SD = 13.09). The sample was 58% male and 87% White. Participants completed an oral glucose tolerance test as part of a larger study. Trained psychometricians administered neuropsychological tests that assessed performance in the domains of response inhibition, nonverbal memory, verbal memory, attention and working memory, visuoconstructional abilities, visuospatial abilities, psychomotor speed and executive function, and motor speed and manual dexterity. Linear multiple regressions were run to test study aims. RESULTS: No significant main effects of fasting glucose and 2-hour glucose emerged for performance on any neurocognitive test; however, significant interactions were present. Higher fasting glucose was associated with poorer short-term verbal memory performance among men, but unexpectedly better response inhibition and long-term verbal memory performance for participants over age 70. Higher 2-hour glucose values were associated with reduced divided attention performance among participants with less than a high school education. CONCLUSIONS: Mixed findings suggest that glucose levels may be both beneficial and deleterious to neurocognition among nondiabetic older adults. Additional studies with healthy older adults are needed to confirm this unexpected pattern of associations; however, findings have implications for the importance of maintaining healthy glucose levels in older adulthood.

Central site monitoring: results from a test of accuracy in identifying trials and sites failing Food and Drug Administration inspection.

BACKGROUND: Site monitoring and source document verification account for 15%-30% of clinical trial costs. An alternative is to streamline site monitoring to focus on correcting trial-specific risks identified by central data monitoring. This risk-based approach could preserve or even improve the quality of clinical trial data and human subject protection compared to site monitoring focused primarily on source document verification. PURPOSE: To determine whether a central review by statisticians using data submitted to the Food and Drug Administration (FDA) by clinical trial sponsors can identify problem sites and trials that failed FDA site inspections. METHODS: An independent Analysis Center (AC) analyzed data from four anonymous new drug applications (NDAs) where FDA had performed site inspections overseen by FDA's Office of Scientific Investigations (OSI). FDA team members in the OSI chose the four NDAs from among all NDAs with data in Study Data Tabulation Model (SDTM) format. Two of the NDAs had data that OSI had deemed unreliable in support of the application after FDA site inspections identified serious data integrity problems. The other two NDAs had clinical data that OSI deemed reliable after site inspections. At the outset, the AC knew only that the experimental design specified two NDAs with significant problems. FDA gave the AC no information about which NDAs had problems, how many sites were inspected, or how many were found to have problems until after the AC analysis was complete. The AC evaluated randomization balance, enrollment patterns, study visit scheduling, variability of reported data, and last digit reference. The AC classified sites as 'High Concern', 'Moderate Concern', 'Mild Concern', or 'No Concern'. RESULTS: The AC correctly identified the two NDAs with data deemed unreliable by OSI. In addition, central data analysis correctly identified 5 of 6 (83%) sites for which FDA recommended rejection of data and 13 of 15 sites (87%) for which any regulatory deviations were identified during inspection. Of the six sites for which OSI reviewed inspections and found no deviations, the central process flagged four at the lowest level of concern, one at a moderate level, and one was not flagged. LIMITATIONS: Central data monitoring during the conduct of a trial while data checking was in progress was not evaluated. CONCLUSION: Systematic central monitoring of clinical trial data can identify problems at the same trials and sites identified during FDA site inspections. Central data monitoring in conjunction with an overall monitoring process that adapts to identify risks as a trial progresses has the potential to reduce the frequency of site visits while increasing data integrity and decreasing trial costs compared to processes that are dependent primarily on source documentation.

Web-based versus paper administration of common ophthalmic questionnaires: comparison of subscale scores.

OBJECTIVE: To compare participants' responses to Web-based and paper-and-pencil versions of an ophthalmic, patient-reported outcome (PRO) questionnaire. DESIGN: Questionnaire development. PARTICIPANTS: Matched subjects with ocular surface disease (OSD) (n = 68) and without OSD (controls, n = 50). METHODS: Subjects completed a standard, paper-and-pencil and a Web-based version of the same questionnaire in randomized order. The administered questionnaire included several ophthalmic PRO subscales: the National Eye Institute's (NEI's) Refractive Error Quality of Life Instrument's Clarity of Vision, Near Vision, Far Vision, Glare, Symptoms, Worry, and Satisfaction with Correction subscales; the Ocular Surface Disease Index's (OSDI's) Symptoms subscale; and the NEI's Visual Function Questionnaire's Driving subscale. Possible scores for each subscale ranged from 0 (no difficulty) to 100 (most difficulty). Agreement of subscale scores between modes of administration was assessed using the Bland-Altman approach and multivariable logistic regression. MAIN OUTCOME MEASURES: Subscale scores and an unweighted average total score for each mode of administration. RESULTS: Mean differences in scores between modes of administration ranged from -2.1 to +2.3 units. Although no differences were found to be statistically significant, the Worry and Satisfaction with Correction subscales approached statistical significance (P = 0.07 and 0.08, respectively). Although most subscale mean differences in score did not differ significantly by gender, age (≥40 vs. <40 years), disease status (OSD vs. control), order of administration, or time between completion of the questionnaires, women had slightly greater score differences than men for the Driving (P = 0.04) and Clarity of Vision (P = 0.03) subscales; those with OSD had greater score differences for Clarity of Vision than did controls (P = 0.0006); and those aged ≥40 years had slightly greater differences in OSDI Symptoms subscale than those aged <40 years (P = 0.04). CONCLUSIONS: To our knowledge, this Food and Drug Administration and NEI collaboration is the first study to evaluate the equivalence of Web-based and paper versions of ophthalmic PRO questionnaires. We found no evidence of clinically significant differences between scores obtained by the 2 modes for any of the examined subscales. A Web-based instrument should yield scores equivalent to those obtained by standard methods, providing a useful tool that may facilitate ophthalmic innovation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Interactive relations of blood pressure and age to subclinical cerebrovascular disease.

OBJECTIVE: To examine interactive relations of blood pressure (BP) and age to MRI indices of subclinical cerebrovascular disease in middle-aged to older adults. METHODS: One hundred and thirteen stroke-free and dementia-free, community-dwelling adults (ages 54-81 years; 65% men; 91% white) engaged in (1) clinical assessment of resting SBP and DBP; (2) MRI rated for periventricular white matter hyperintensities (WMH) and deep WMH silent brain infarction (SBI) and brain atrophy (i.e. ventricular enlargement and sulcal widening ). Principal components analysis of the MRI ratings yielded a two-component solution--(1) periventricular and deep WMH SBI; and (2) ventricular enlargement, sulcal widening. RESULTS: Relations of SBP, DBP and pulse pressure (PP) (and their interactions with age) to each MRI component were examined in multiple regression analyses adjusted for age, sex, fasting plasma glucose and cholesterol, and antihypertensives. For component 1, results indicated significant interactions of SBP and PP with age (P < 0.05); higher levels of SBP and PP were associated with greater white matter disease and brain infarction at younger ages (≤ 68 years). Significant interactions of SBP and DBP with age were also noted for component 2 (P < 0.05); higher levels of BP were associated with greater brain atrophy at younger ages (≤ 63 years). CONCLUSION: : Higher BP and PP are associated with greater subclinical cerebrovascular disease most prominently in the 'young old'. Appropriate management of hypertension and arterial stiffening may be critical to the preservation of brain structure with ageing.

Reduced cerebral blood flow in older men with higher levels of blood pressure.

OBJECTIVE: To examine relations of blood pressure (BP) with single photon emission computed tomography (SPECT)-derived estimates of cerebral blood flow in older men and women. METHODS: Seventy-four stroke and dementia-free, community-dwelling older adults (ages 54-83 years; 68% men; 91% white) free of major medical, neurological, or psychiatric disease, engaged in clinical assessment of resting SBP and DBP, MRI rated for brain atrophy, and brain single photon emission computed tomography (SPECT) studies with computerized coding of cortical and select subcortical regions of interest. RESULTS: Given significant interactions of BP and sex with respect to multiple SPECT outcomes, sex-stratified multiple regression models were computed. Models were adjusted for age, fasting glucose levels, antihypertensive medication, BMI, and MRI ratings of brain atrophy. In men (n = 50), higher levels of SBP and/or DBP were associated significantly with lower estimates of cerebral perfusion in the right and left frontal, temporal, parietal, and occipital cortex, thalamus, head of caudate, and cingulate cortex accounting for up to 28% of the variance in these measures (P < 0.05). In women (n = 24), higher DBP was related marginally to higher levels of perfusion in the right temporal cortex (P = 0.05). CONCLUSION: Higher resting SBP or DBP was associated with lower levels of cerebral perfusion in otherwise healthy older men, but not women, in the present sample. Reduced cerebral blood flow may play a pathogenic role in increasing risk for stroke, dementia, and/or cognitive decline, particularly among older men with high BP.