The AlzMatch Pilot Study - Feasibility of Remote Blood Collection of Plasma Biomarkers for Preclinical Alzheimer's Disease Trials.

BACKGROUND: Advances in plasma biomarkers to detect Alzheimer's disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimer's Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD. OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based phlebotomy centers and plasma biomarker quantification to assess an individual's eligibility for AD preclinical trials. DESIGN: Pilot feasibility study with co-primary outcomes. SETTING: This pilot feasibility study included participants from the APT Webstudy, the remote assessment arm of the Trial-ready cohort for Preclinical and Prodromal AD (TRC-PAD) Platform. Novel design included collection of electronic consent, use of community laboratories for plasma collection, mass spectrometry-based biomarker assay, and telephone communication of plasma biomarker screening eligibility. PARTICIPANTS: Participants invited to the AlzMatch pilot feasibility study were active in the APT Webstudy, 50 years of age or older, resided within 50 miles of both a Quest Diagnostics Patient Services Center (a national diagnostic laboratory with convenient locations for sample collection and processing) and one of six TRC-PAD vanguard clinical trial sites, had no self-reported dementia diagnosis, were able to communicate in English and engaged with the APT Webstudy within the prior 6 months. MEASUREMENTS: Primary feasibility outcomes were completion of electronic consent (e-consent) for invited participants and collection of usable blood samples. Additional feasibility outcomes included invitation response rate, plasma biomarker eligibility status (based on amyloid beta-42/40 [Aß42/40] concentration ratio), ApoE proteotype, and trial inclusion criterion), and completion of telephone contact to learn eligibility to screen for a study. RESULTS: 300 APT Webstudy participants were invited to consent to the AlzMatch study. The AlzMatch e-consent rate was 39% (n=117) (95% CI of 33.5%-44.5%) overall, which was higher than the expected rate of 25%. Similar consent rates were observed across participants based on self-defined sex (41% Female (n=75), 37% Male (n=42)) and race and ethnicity (37% from underrepresented groups (URG) (n=36), 40% not from URG (n=79)). Among those that consented (n=117), plasma was successfully collected from 74% (n=87) (95% CI of 66%-82%), with similar rates across sex (76% Female (n=57), 71% Male (n=30)) and race and ethnicity (75% URG (n=27) and 75% not from URG (n=59)). 60% (n=51) of participants with plasma biomarker results were eligible to screen for future preclinical AD trials. CONCLUSION: Electronic consent of participants through an online registry, blood sample collection at community-based centers, plasma biomarker quantification and reporting, and biomarker assessments for study eligibility were all feasible with similar engagement rates across demographic groups. Although this pilot was a small and selective sample, participants engaged and consented at higher than expected rates. We conclude that collecting blood at community laboratories for biomarker analyses may improve accessibility beyond research, and may facilitate broader access for clinical use of AD plasma biomarkers. Based on our results, an expanded version of the AlzMatch study is underway, which involves expanding invitations to additional APT Webstudy participants and clinical trial sites.

Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer's Disease.

BACKGROUND: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer's disease and reduce decline on clinical endpoints of cognition and function at 18 months. OBJECTIVES: To describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial. DESIGN: Clarity AD was an 18-month, multi-center, double-blind, phase 3 trial. SETTING: Early Alzheimer's disease. PARTICIPANTS: Individuals 50-90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer's disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation. INTERVENTION: Placebo or lecanemab 10-mg/kg IV biweekly. MEASUREMENTS: HRQoL was measured at baseline and every 6 months using the European Quality of Life-5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI). RESULTS: A total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit. CONCLUSIONS: Lecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.

Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab.

OBJECTIVES: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. DESIGN: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. SETTING: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. PARTICIPANTS: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. INTERVENTION: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. MEASUREMENTS: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. RESULTS: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. CONCLUSIONS: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.

Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.

Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Individuals with Early Alzheimer's Disease: Amyloid Imaging Positron Emission Tomography and Safety Results from a Phase 2 Study.

BACKGROUND: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer's disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). INTERVENTION: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

Extended-release physostigmine in Alzheimer disease: a multicenter, double-blind, 12-week study with dose enrichment. Physostigmine Study Group.

BACKGROUND: The efficacy of extended-release physostigmine salicylate, an acetylcholinesterase inhibitor, was evaluated in 850 subjects with mild-to-moderate Alzheimer disease (AD) in a multicenter trial. METHODS: Subjects initially entered a dose-enrichment phase in which they received 1 week each of physostigmine salicylate, 24 mg/d and 30 mg/d, and daily placebo. Among the subjects who completed this phase, 35.9% responded to physostigmine treatment, whereas 62.4% were considered nonresponders, and 1.6% could not be evaluated because of missing data. After a 4-week placebo-washout phase, 176 responder subjects were randomized to receive their best dose of physostigmine or placebo in a 12-week double-blind phase. Primary efficacy measures included the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC+), and the Clinical Global Impression of Change (CGIC). RESULTS: In the intent-to-treat analysis of the double-blind phase, physostigmine-treated subjects scored -2.02 points better than placebo-treated subjects on the ADAS-Cog (F1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F1,150 = 5.68 [P = .02]). No significant improvement was observed on the CGIC or the secondary outcome measures. Nausea and vomiting were experienced by 47.0% of all physostigmine-treated subjects during the double-blind phase. CONCLUSIONS: Physostigmine demonstrated a statistically significant benefit compared with placebo on a clinical global rating of change and an objective test of cognitive function. Given the frequency of gastrointestinal side effects, the role of this agent in clinical use remains to be determined.

Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography.

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.

The effects of 5-HT3 receptor antagonists on cognitive performance in aged monkeys.

The serotonin 5-HT3 receptor antagonists ondansetron and SEC-579 were tested over a wide dose range (0.000001-0.5 mg/kg, PO) for cognitive-enhancing effects in aged rhesus monkeys. Animals were tested on the following cognitive and motor tasks: 1) acquisition of a visual object discrimination; 2) reversal of a visual object discrimination; 3) the delayed response task, a spatial working memory task; and 4) a fine motor task. This study found enhanced acquisition of a visual object discrimination following very low doses (0.000001-0.00001 mg/kg, PO) of either 5-HT3 receptor antagonist. This finding replicates a previous study in marmosets. However, unlike the marmoset research, no reliable improvement was found on the reversal condition. Similarly, no improvement was observed on the delayed response or fine motor tasks. No side effects were observed at any dose, consistent with reports in both animals and humans. These results suggest that 5-HT3 receptor antagonists may be helpful in treating a subset of cognitive functions.

Age-related decline in central serotonin transporter availability with [(123)I]beta-CIT SPECT.

Postmortem studies have provided limited and conflicting data regarding aging effects on the central serotonin transporter (SERT). The present study investigated the effect of age on SERT availability in the human brainstem and diencephalon with single photon emission computed tomography (SPECT) using the ligand [(123)I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([(123)I]beta-CIT). Healthy control subjects (n = 126) who ranged in age from 18 to 88 were injected with 6.0 +/- 0.8 (mean +/- SD) mCi [(123)I]beta-CIT and imaged 23.1 +/- 1.9 h later under equilibrium conditions. A ratio of specific to nondisplaceable brain uptake (i.e. , V(3)" = [brainstem-diencephalon -occipital]/occipital), a measure proportional to the binding potential (B(max)/K(D)), was derived. SERT availability (V(3)") showed a significant inverse correlation with age (r = -0.40, P < 0.0001). Linear regression analysis revealed that V(3)" declined by 29.5% over the age range 18 to 88, or approximately 4.2% per decade. These results demonstrate reductions in the availability of central SERT binding sites with age in living human subjects.

[123I]beta-CIT SPECT imaging of striatal dopamine transporter binding in Tourette's disorder.

OBJECTIVE: The authors examined whether subjects with Tourette's disorder have greater than normal striatal dopamine transporter densities, as suggested by previous post-mortem findings. METHOD: Single photon emission computed tomography (SPECT) and [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT) were used to assess dopamine transporter levels in five adult patients with Tourette's disorder and five age- and gender-matched healthy comparison subjects. RESULTS: Striatal [123I]beta-CIT binding was a mean of 37% (range = 6%-79%) higher in the subjects with Tourette's disorder than in the comparison subjects, and each Tourette's disorder patient had a higher level than his or her paired comparison subject. CONCLUSIONS: These findings corroborate post-mortem results and support the hypothesis of a dysregulation in presynaptic dopamine function in Tourette's disorder.

Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort.

OBJECTIVE: The authors previously observed an increase in striatal dopamine transmission following amphetamine challenge in 15 untreated patients with schizophrenia compared to 15 matched healthy subjects. The purpose of this study was to replicate this finding in a new cohort of schizophrenic patients and healthy subjects. METHOD: Fifteen patients with schizophrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeconomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia, had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg, intravenous bolus). Reduction in D2 receptor availability was measured with single photon emission computed tomography and the D2 receptor radiotracer [123I]IBZM. RESULTS: No differences were observed between patients with schizophrenia and the comparison group in D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger reduction in D2 receptor availability following acute amphetamine challenge than the comparison group. In this study, the effect size was smaller than in the first study. Excess dopamine release following amphetamine was associated with transient emergence or worsening of positive symptoms. CONCLUSIONS: In this new cohort of subjects the authors replicated their initial observation of a dysregulation of striatal dopamine release in schizophrenia.

Elevated striatal dopamine transporters during acute cocaine abstinence as measured by [123I] beta-CIT SPECT.

OBJECTIVE: The authors examined whether striatal dopamine transporters were altered in acutely (96 hours or less) abstinent cocaine-abusing subjects, as suggested by postmortem studies. METHOD: [123I] beta-CIT and single photon emission computed tomography were used to assess striatal dopamine transporter levels in 28 cocaine-abusing subjects and 24 comparison subjects matched as a group for age and gender. RESULTS: Results showed a significant (approximately 20%) elevation in striatal V3" values in acutely abstinent cocaine-abusing subjects relative to comparison subjects. An inverse correlation between dopamine transporter level and Hamilton Depression Rating Scale score was also observed. CONCLUSIONS: These findings indicate more modest elevations in striatal dopamine transporters in cocaine-abusing subjects than noted in previous postmortem reports and suggest a possible relationship between cocaine-related depression and dopamine transporter binding.

Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease.

BACKGROUND: The apolipoprotein E (Apo E) epsilon4 allele has been associated with parietal metabolic abnormalities and asymmetries in asymptomatic subjects at risk for Alzheimer disease (AD). However, previous research has shown minimal effect of the epsilon4 allele on regional cerebral blood flow (rCBF) and metabolism in patients with probable AD. OBJECTIVE: To determine whether the Apo E epsilon4 allele is associated with parietal rCBF abnormalities and asymmetries in patients with probable AD. PATIENTS AND METHODS: Thirty patients with AD with the epsilon4 allele (epsilon4+ AD), 22 patients with AD without the epsilon4 allele (epsilon4- AD), and 14 healthy control subjects underwent single-photon emission computed tomography (SPECT) scanning with 740 MBq technetium Tc 99m hexamethylpropyleneamine oxime. Ratios of parietal-unaffected regions and a left-right parietal asymmetry index were compared between both patient groups. RESULTS: The group with epsilon4- AD was younger (P = .005, Student t test) and had an earlier age of onset (P = .005) than the group with epsilon4+ AD. Analysis of covariance revealed no significant difference in the parietal rCBF ratio, controlling for age of onset and Mini-Mental State Examination score (F(1,48) = 0.06; P = .81). However, contrary to hypothesis, significantly greater parietal rCBF asymmetry was seen in patients with epsilon4- AD (mean +/- SD, 9.7% +/- 5.5%) than those with epsilon4+ AD (6.3% +/- 4.7%; F(1,50) = 5.89; P = .02; analysis of variance). When number of epsilon4 allele copies was considered, this effect appeared to accrue primarily from a difference between patients with 0 and with 2 epsilon4 allele copies. An exploratory analysis of multiple cortical structures suggested that this asymmetry extended to additional regions (superior temporal) and to combined association cortex. CONCLUSIONS: Greater parietal rCBF asymmetry is involved in epsilon4- AD than in epsilon4+ AD. Lack of the epsilon4 allele may be associated with other (as yet undiscovered) genetic or environmental risk factors, which confer greater neuropathological asymmetry.

The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task.

Research indicates that norepinephrine enhances the working memory functions of the prefrontal cortex (PFC) through actions at post-synaptic, alpha-2A adrenoceptors. The current study examined the effects of the alpha-2A adrenoreceptor agonist, guanfacine (0.7 mg/kg, i.m.), compared to saline on SPECT measures of regional cerebral blood flow (rCBF) in monkeys performing a spatial working memory task. Animals were infused with the SPECT blood flow tracer, Tcm-99m ECD, through an indwelling intravenous catheter while performing the working memory task. Guanfacine treatment significantly improved cognitive performance of the working memory task, and significantly increased rCBF values in the dorsolateral PFC, the brain region most tightly associated with performance of spatial working memory tasks. In contrast, guanfacine had no significant effect on rCBF in the superior temporal cortex, an auditory association area unrelated to task performance. These data are consistent with the hypothesis that alpha-2A adrenoceptor stimulation preferentially enhances functioning of the PFC.

The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans.

A 40 base polymorphism of a variable number of tandem repeats (VNTR) has been described in the 3' untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT). Despite being located in the untranslated region of the gene, this polymorphism has been associated with clinical phenotypes associated with dysregulation of dopamine transmission, such as attention deficit hyperactivity disorder and cocaine-induced paranoia. To examine the neurochemical phenotype associated with this polymorphism, we compared amphetamine-induced dopamine release (measured as displacement of the radiotracer [123I]IBZM) and DAT expression (measured with [123I]beta-CIT) in the striatum with Single Photon Computerized Emission Tomography (SPECT). Our sample included 59 subjects, 31 healthy controls and 29 patients with schizophrenia. No significant association was found between VNTR polymorphism and amphetamine-induced dopamine release or DAT density in the total sample, nor when each diagnostic group was considered separately. Thus, we did not replicate the findings of two previous studies, which had suggested that the 9 repeat allele was associated with either an increased or decreased DAT expression, albeit in different patient populations.

Iodine-123-beta-CIT and iodine-123-FPCIT SPECT measurement of dopamine transporters in healthy subjects and Parkinson's patients.

UNLABELLED: Iodine-123-beta-carbomethoxy-3 beta-(4-iodophenyltropane) (CIT) has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. This tracer has a protracted period of striatal uptake enabling imaging 14-24 hr postinjection for stable quantitative measures of dopamine transporters, and it binds with nanomolar affinity to the serotonin transporter. Iodine-123 fluoropropyl (FP)CIT is an analog of [123I]-beta-CIT and has been shown to achieve peak tracer uptake in the brain within hours postinjection and to provide greater selectivity for the dopamine transporter. The purpose of the present study was to compare [123I]-beta-CIT with [123I]-FPCIT in a within-subject design. METHODS: Six Parkinson's disease patients and five healthy control subjects participated in one [123I]-beta-CIT and one [123I]-FPCIT SPECT scan separated by 7-21 days. Controls were imaged at 24 hr postinjection 222 MBq (6 mCi) [123I]-beta-CIT and serially from 1-6 hr postinjection 333 MBq (9 mCi) [123I]-FPCIT. Two imaging outcome measures were evaluated: (a) the ratio of specific striatal activity to nondisplaceable uptake, also designated V"3, at each imaging time point; and (b) the rate of striatal washout of radiotracer expressed as a percent reduction per hr for [123I]-FPCIT. In addition, venous plasma was obtained from the five control subjects after the [123I]-FPCIT injection for analysis of radiometabolites. RESULTS: Both [123I]-FPCIT and [123I]-beta-CIT demonstrated decreased striatal uptake in Parkinson's disease patients compared with the controls with a mean of V"3=3.5 and 6.7 for [123I]-beta-CIT (Parkinson's disease and controls, respectively) and a mean of V"3=1.34 and 3.70 for [123I]-FPCIT (Parkinson's disease and controls, respectively). For [123I]-beta-CIT, the mean Parkinson's disease values represented 52% of the control uptake, while the mean [123I]-FPCIT value for Parkinson's disease patients was 37% of the control values. Analysis of [123I]-FPCIT time-activity curves for specific striatal counts showed washout rates of 8.2%/hr for Parkinson's disease and 4.9%/hr for controls. CONCLUSION: These data suggest that SPECT imaging with [123I]-FPCIT visually demonstrates reductions in striatal uptake similar to [123I]-beta-CIT. iodine-123-FPCIT washed out from striatal tissue 15-20 times faster than [123I]-beta-CIT, and estimates of dopamine transporter loss in Parkinson's disease patients were higher for [123I]-FPCIT than for [123I]-beta-CIT. This was most likely due to the faster rate of striatal washout and establishment of transient equilibrium binding conditions at the dopamine transporter, which the modeling theory suggests produces an overestimation of dopamine transporter density with relatively greater overestimates in healthy control subjects by [123I]-FPCIT.

Reproducibility of iodine-123-beta-CIT SPECT brain measurement of dopamine transporters.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of monoamine transporters in human and nonhuman primates utilizing SPECT. To assess the utility of this tracer for measurement of striatal dopamine (DA) transporters in human disease, we studied the test/retest variability and reliability of SPECT measures obtained after bolus injection of [123I]beta-CIT 0-7 hr (Day 1) and 18-24 hr (Day 2) after administration. METHODS: For the Day 2 study, seven healthy humans (4 men, 3 women; aged 19-74 yr) participated in two [123I]beta-CIT SPECT scans separated by 7-14 days. Subjects were imaged at 18, 21 and 24 hr postinjection of 370 MBq (10 mCi) [123I]beta-CIT. Two outcome measures were evaluated: (a) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V"3 and (b) the total, specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. Test/retest variability associated with V"3 and total specific striatal uptakes were compared for scans acquired at 18, 21 and 24 hr with 24 hr only postinjection scans. For the Day 1 study, three of the subjects participated in two kinetic studies of [123I]beta-CIT uptake. A three-compartment model was used for determination of konBmax and binding potential (BP = Bmax/Kd) and the reproducibility of the measures assessed. RESULTS: In the Day 2 study, both outcome measures demonstrated excellent test/retest reproducibility with variability of V"3 = 6.8 +/- 6.8% and percent striatal uptake = 6.6 +/- 4.3% using data acquired from all time points. There were no significant differences in variability for the two outcome measures obtained. The intraclass correlation coefficient rho was 0.96 and 0.98 for V"3 and %SSU, respectively. Considering the 24 hr postinjection scans only, there was a nonsignificant trend toward lower test/retest variability for %SSU compared to V"3 (6.6 +/- 4.2% and 12.8 +/- 9.0%, respectively). The test/retest variability for the Day 1 kinetic modeling data showed marked differences depending on the fitting strategy and assumptions about the reversibility of [123I]beta-CIT in striatum. Using a model that assumed a low, fixed value for reversible striatal binding (k4) produced low variability (12 +/- 9%). CONCLUSION: These data suggest that SPECT imaging performed at either 0-7 hr or 18-24 hr after [123I]beta-CIT injection permits calculation of reliable and reproducible measures of dopamine transporters and supports the feasibility of using [123I]beta-CIT in serial evaluation of human neuropsychiatric disease.

Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopamine transporters in Parkinson's patients.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. We studied the test/retest reproducibility of SPECT measures in Parkinson's disease patients and healthy controls obtained after injection of [123I])beta-CIT in part to assess the utility of this tracer for longitudinal evaluation of striatal dopamine transporters as a marker of disease progression. METHODS: Seven Parkinson's disease patients and seven healthy control subjects participated in two [123I]beta-CIT SPECT scans separated by 7-21 days. Subjects were imaged at 24 hr post injection of 360 MBq (9.7 mCi) of [123I]beta-CIT. Two outcome measures were evaluated; 1) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V3," and 2) the total specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. For both measures, test/retest variability was calculated as the absolute difference of test minus retest divided by the mean of test/retest and expressed as a percent. In addition, the reproducibility of left and right striatal asymmetry and putamen:caudate ratios were determined. RESULTS: The two outcome measures demonstrated excellent test/retest reproducibility for both the Parkinson's disease and healthy subject groups with variability of striatal V3" = 16.8 +/- 13.3% and percent striatal uptake = 6.8 +/- 3.4% for Parkinson's disease patients and V3" = 12.8 +/- 8.9% and %SSU = 7.0 +/- 3.9% for control subjects. There were no statistically significant differences in test/retest variability between control subjects and Parkinson's disease patients for either outcome measure. The reproducibility of left/right asymmetry indices and putamen-to-caudate ratios showed no patient versus control subject differences. The asymmetry index had greater test/retest variability than the other outcome measures. CONCLUSION: These data suggest that SPECT imaging performed at 24 hr postinjection of [123I]beta-CIT permits calculation of reliable and reproducible measures of dopamine transporters in both Parkinson's disease patients and control subjects and supports the feasibility of using [123I]beta-CIT in the evaluation of disease progression in Parkinson's disease.

Comparison of technetium-99m-HMPAO and technetium-99m-ECD cerebral SPECT images in Alzheimer's disease.

UNLABELLED: SPECT has shown increasing promise as a diagnostic tool in Alzheimer's disease (AD). Recently, a new SPECT brain perfusion agent, 99mTc-ethyl cysteinate dimer (99mTc-ECD) has emerged with purported advantages in image quality over the established tracer, 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO). This research aimed to compare cerebral images for 99mTc-HMPAO and 99mTc-ECD in discriminating patients with AD from control subjects. METHODS: Twenty-four AD patients (mean age +/- s.d. = 68.9 +/- 8.2 yr) and 13 healthy subjects (68.4 +/- 8.0 yr) were scanned sequentially with 20 mCi of each tracer using the CERASPECT system within 1 mo. Scanning began on average 11.5 +/- 2.8 min after 99mTc-HMPAO injection and 41.8 +/- 10.1 min after 99mTc-ECD. A ratio, R, was derived of count densities in "typically affected" brain structures (parietal and temporal association cortices) to "unaffected" structures (cerebellum, basal ganglia, thalamus, occipital cortex, and sensorimotor cortex). RESULTS: Analysis of variance revealed significant interaction between diagnostic group and radiopharmaceutical (F = 4.71; df = 1.35; p = 0.04), with 99mTc-ECD demonstrating better separation of R values between AD patients and control subjects than 99mTc-HMPAO. Receiver operating characteristic (ROC) analysis, revealed no significant difference in the ability of the two tracers to correctly classify AD patients and control subjects. Both tracers showed high diagnostic accuracy (99mTc-ECD: sensitivity = 100%, specificity = 92%; 99mTc-HMPAO: sensitivity = 100%, specificity = 85%). CONCLUSION: Technetium-99m-ECD shows greater contrast than 99mTc-HMPAO between affected and unaffected brain structures in AD when patients are compared to age-matched control subjects. Both tracers perform equally well in correctly classifying patients and control subjects.