Michael M. Witte

Comparison of neuroimaging modalities for the prediction of conversion from mild cognitive impairment to Alzheimer's dementia.

In this study we compared Pittsburgh compound-B (PIB) positron emission tomography (PET) amyloid imaging, fluorodeoxyglucose PET for metabolism, and magnetic resonance imaging (MRI) for structure to predict conversion from amnestic mild cognitive impairment (MCI) to Alzheimers dementia using data from the Alzheimers Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimers Disease Neuroimaging Initiative-funded laboratories for each neuroimaging modality along with apolipoprotein-E genotype (n = 29) were analyzed. Performance of these biomarkers for predicting conversion from MCI to Alzheimers dementia at 2 years was evaluated in 50 late amnestic MCI subjects, 20 of whom converted. Multivariate modeling found that among individual modalities, MRI had the highest predictive accuracy (67%) which increased by 9% to 76% when combined with PIB-PET, producing the highest accuracy among any biomarker combination. Individually, PIB-PET generated the best sensitivity, and fluorodeoxyglucose PET had the lowest. Among individual brain regions, the temporal cortex was found to be most predictive for MRI and PIB-PET.

Safety and Tolerability of Atomoxetine Over 3 to 4 Years in Children and Adolescents With ADHD

OBJECTIVE To assess the long-term safety and tolerability of atomoxetine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder treated for > or = 3 years. METHOD Data from 13 double-blind, placebo-controlled trials and 3 open-label extension studies were pooled. Outcome measures were patient-reported treatment-emergent adverse events (AEs); discontinuations due to AEs, serious AEs, and changes in body weight, height, vital signs, electrocardiogram, and hepatic function tests. RESULTS In total, 714 patients were treated with atomoxetine for > or = 3 years (mean follow-up 4.8 years [SD 1.1 years]), including a subset of 508 treated for > or = 4 years (mean follow-up 5.3 years [SD 0.8 years]). Most subjects were younger than 12 years at entry (73.8%), male (78.4%), and white (88.9%). The mean final daily dose of atomoxetine was 1.35 mg/kg (SD 0.37 mg/kg). No new or unexpected AEs were observed compared with acute-phase treatment. Less than 6% of patients exhibited aggressive/hostile behaviors, and less than 1.6% reported suicidal ideation/behavior. No clinically significant effects were seen on growth rate, vital signs, or electrocardiographic parameters, and < or = 2% of patients showed potentially clinically significant hepatic changes. CONCLUSION Atomoxetine was safe and well tolerated for children and adolescents with > or = 3 and/or > or = 4 years of treatment.

Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations

Until recently, estimation of β‐amyloid plaque density as a key element for identifying Alzheimers disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid‐positron emission tomography (amyloid‐PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid‐PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid‐PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid‐PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan.

Association Between Clinical Measures and Florbetapir F18 PET Neuroimaging in Mild or Moderate Alzheimer’s Disease Dementia

Clinical diagnosis of Alzheimers disease (AD) is challenging, with 20% or more of patients misdiagnosed, even by expert clinicians. The authors conducted a retrospective, cross-sectional analysis comparing baseline neuropsychiatric and other clinical characteristics in 199 expert-diagnosed mild and moderate AD dementia patients participating in industry-sponsored clinical trials of an investigational therapy, where 18% lacked florbetapir positron emission tomography (PET) evidence of AD neuropathology. Significant differences were found only for cognition and ApoE ε4 status, but the large degree of score overlap would preclude using these measures to predict AD misdiagnosis. This study highlights the value of amyloid PET when evaluating patients with seemingly typical AD.

Effects of olanzapine long-acting injection on levels of functioning among acutely ill patients with schizophrenia

Abstract Objective: To assess the effects of olanzapine long-acting injection (olanzapine-LAI) on levels of functioning in acutely ill patients with schizophrenia. Research design and methods: During this 8-week randomized, double-blind, placebo-controlled trial, 404 inpatients were randomized to four treatment arms (olanzapine-LAI 210 mg/2 weeks = 106; olanzapine-LAI 300 mg/2 weeks = 100; olanzapine-LAI 405 mg/4 weeks = 100; placebo = 98). Also, data from the three active dosing arms were combined and compared to placebo data. Clinical trial registration: NCT00088478 Main outcome measures: The treatment group comparison of mean change from baseline to endpoint in the total score and four subdomains of the Heinrichs–Carpenter Quality of Life Scale (QLS) and in the 2 summary scores and 8 subscale scores of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were assessed using an ANOVA model. Results: All three olanzapine-LAI treatment groups and the combined olanzapine-LAI group were superior to placebo on the QLS total score (all p-values < 0.01) and the Intrapsychic Foundations subdomain (all p-values < 0.02). Olanzapine-LAI 210 mg/2 weeks (p < 0.001), 300 mg/2 weeks (p = 0.006), and the combined olanzapine-LAI group (p = 0.003) were superior to placebo on the Interpersonal Relations subdomain. The 300 mg/2 weeks group (p = 0.027) and the combined olanzapine-LAI group (p = 0.014) were also superior to placebo on the Instrumental Role subdomain. For the SF-36, the 300 mg/2 weeks and 405 mg/4 weeks olanzapine-LAI groups and the combined olanzapine-LAI group were superior to placebo on the Mental component score (all p-values < 0.05). Each olanzapine-LAI group and the combined group were superior on the Mental Health scale (all p-values < 0.05). Significant negative correlations between PANSS scores and measures of functioning indicate that as symptoms decreased, functioning increased. Conclusion: These results suggest that olanzapine-LAI may improve level of functioning in acutely ill patients with schizophrenia within 8 weeks of initiating treatment.

Relationship of Hippocampal Volume to Amyloid Burden across Diagnostic Stages of Alzheimer's Disease.

Aims: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimers disease (AD) and its relevance to patient care. Methods: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimers Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. Results: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. Conclusion: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum.

Effect of atomoxetine on Tanner stage sexual development in children and adolescents with attention deficit/hyperactivity disorder: 18-month results from a double-blind, placebo-controlled trial

Abstract Objective: To determine the effects of long-term atomoxetine treatment on sexual development in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as compared with placebo and with a national US survey in non-Hispanic white children and adolescents. Methods: This double-blind, placebo-controlled, relapse prevention, multicenter trial was conducted in pediatric patients (6–15 years) with DSM-IV diagnosed ADHD and lasting for ∼18 months. All patients received 10 weeks of open-label atomoxetine treatment (0.5–1.8 mg/kg/day). Patients responding in the last 2 weeks of treatment were randomized to double-blind treatment with either placebo or atomoxetine for up to 9 months, after which atomoxetine patients were re-randomized to either continued atomoxetine treatment or to placebo for up to another 6 months. Patients randomized to placebo at first randomization remained on placebo. The Tanner stage was assessed by the investigator at baseline and at approximately 6, 12, and 18 months, and the rate of sexual development (change in the Tanner stage) was compared between treatment groups. Results: No statistically significant differences were observed between treatment groups either in sexual development (mean time, in days, to the first Tanner stage change: atomoxetine, 464.3 ± 23.0; placebo, 433.1 ± 14.4; p = 0.33) or in the duration of treatment exposure (atomoxetine, 315.3 days; placebo, 315.1 days; p = 0.90). Similar proportions of patients had at least one Tanner stage increase (atomoxetine: 27.1%; placebo: 31.9%; p = 0.39). Proportions of patients in each baseline Tanner stage group moving to higher stages were not statistically significantly different (p = 0.88, p = 0.18, p > 0.99, p = 0.68 for baseline Tanner stages 1–4, respectively). The puberty onset age was similar across treatment groups and consistent with US normative data. Conclusions: Long-term atomoxetine treatment was not associated with any appreciable impact on or delay in sexual maturation in children with ADHD compared with US normative data. Limitations: Study limitations include the relatively short duration of exposure to atomoxetine treatment, and the fact that half of the patients had been previously treated with stimulants. In addition, the Tanner stage data were collected as a secondary measure. Clinical trial registration: Trial was completed prior to the requirement to post trials at initiation and therefore does not have a registration number.

IS FLORBETAPIR-PET OCCIPITAL SUVR A LATE BIOMARKER IN MILD OR MODERATE AD DEMENTIA AS COMPARED TO HIPPOCAMPAL VOLUME?

P4-311 IS FLORBETAPIR-PET OCCIPITAL SUVR A LATE BIOMARKER IN MILD OR MODERATE AD DEMENTIA AS COMPARED TO HIPPOCAMPAL VOLUME? Michael Witte, Peng Yu, Shufang Wang, Peter Castelluccio, Helen Hochstetler, Abhinay Joshi, Grazia Dell’Agnello, David Henley, Elisabeth Degenhardt, Sara Kollack Walker, Michael D. Devous, Sr,, Adam Devous, Sr., Paula Trzepacz, Eli Lilly and Company, Indianapolis, Indiana, United States; Eli Lilly and Company, Indianapolis, Indiana, United States; Bucher & Christian Consulting, Inc., Philadelphia, Pennsylvania, United States; Avid Radiopharmaceuticals, Philadelphia, Pennsylvania, United States; Eli Lilly Italia, Sesto Fiorentino, Italy; Eli Lilly and Company, Indianapolis, Indiana, United States; Avid Radiopharmaceuticals, Inc., Philadelphia, Pennsylvania, United States. Contact e-mail: witte_michael_m@lilly.com

Comparison of 11C-PiB-PET, FDG-PET and MRI modalities for the prediction of conversion from mild cognitive impairment to Alzheimer's dementia

will provide additional information about level of tracer uptake and may also help enable consistency in image assessment over time and across different centers. In this study, we investigate the performance of a fully automated quantification method by calculating sensitivity and specificity against histopathology and by comparing scan categorization using quantification and visual evaluation, respectively. Methods: [18 F]Flutemetamol images from 10 prior studies were used. A total of 276 scans were used from 172 AD, MCI and healthy volunteer (HV) subjects, 36 normal pressure hydrocephalus (NPH) subjects, and 68 end-of-life subjects from an autopsy trial, where a histopathology standard of truth (SOT) was available. Five visual readers, trained with an electronic training program, categorized all scans. A fully automated PET-only, MNI-space, quantification method was used to compute SUVR values for a composite neocortical region using pons as reference. An SUVR threshold was derived by ranking the PET scans from the autopsy cohort based on the composite SUVR and comparing data with SOT, a dichotomous Bielschowsky silver stain assessment of neuritic plaques based on CERAD criteria. The derived threshold was used to categorize all 276 scans into normal and abnormal. For the 68 scans from end-of-life subjects, sensitivity and specificity against SOT were computed. For all 276 scans quantification results were compared to categorization using visual assessment. Results: In the autopsy cohort, classification by quantification gave three false-positive and four false-negative scans, yielding 91% sensitivity and 88% specificity. All three false-positive cases were either borderline normal by SOT or had moderate to heavy cortical diffuse plaque burden. There was concordance between quantitative and visual read categorization for 268 of the 276 scans (97.1%). After excluding the autopsy scans, many of which were atypical with gross atrophy making both visual assessment and quantification difficult, quantitative and visual read categorization agreed in 206 of 208 remaining scans (99.0%). Conclusions: Categorization of [18 F]flutemetamol amyloid imaging data using an automated PET-only quantification method showed good agreement with histopathological classification of neuritic plaque density, and there was a strong concordance with visual read results.

Comparison of florbetapir positron emission tomography scans with cerebrospinal fluid biomarkers in healthy individuals and people with mild cognitive impairment or Alzheimer's disease dementia

differences between CNAband Ab+ subjects in themetabolic ROIs, but not in four volumetric and ten cortical thickness ROIs. Moreover, receiver operating characteristics analyses revealed significant differences between the areas under the curve for metabolic vs. structural ROIs, indicating larger metabolic than structural changes in CN Ab+ subjects. Conclusions: Our findings largely agreewith the proposed temporo-anatomical model of hypometabolic and atrophic changes in AD, supporting the notion that amyloid load may affect synaptic activity leading to synaptic loss.