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Sperling R.A.,Harvard University | Johnson K.A.,Harvard University | Johnson K.A.,Massachusetts General Hospital | Doraiswamy P.M.,Duke University | And 15 more authors.
Neurobiology of Aging | Year: 2013

The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid positron emission tomography, and cognition in healthy older control (HC) subjects. Seventy-eight HC subjects were assessed with a brief cognitive test battery and positron emission tomography (PET) imaging with 18F-AV-45. A standard uptake value ratio was computed for mean data from 6 cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive or amyloid negative by 3 readers. Higher standard uptake value ratio correlated with lower immediate memory (r = 0.33; p = 0.003) and delayed recall scores (r = 0.25; p = 0.027). Performance on immediate recall was also lower in the visually rated amyloid positive compared with amyloid negative HC (p = 0.04), with a similar trend observed in delayed recall (p = 0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether 18F-AV-45 may also predict subsequent cognitive decline. © 2013 Elsevier Inc.

Sadowsky C.H.,Nova University | Farlow M.R.,Indiana University | Meng X.,Novartis | Olin J.T.,Novartis
International Journal of Clinical Practice | Year: 2010

Objectives: To compare the safety and tolerability of switching patients with mild-to-moderate Alzheimer's disease from donepezil to either rivastigmine capsule or transdermal patch. Methods: Three studies investigated the switch from donepezil to rivastigmine; study US13 was a 26-week, single-arm, immediate-switch study; US18 was a 26-week, sequential cohort study (both studies evaluated rivastigmine capsules 3-12 mg/day); study US38 was a 25-week, randomised, parallel-group, open-label study which investigated switch (immediate or after 7 days' withdrawal) from donepezil to rivastigmine transdermal patch (4.6 mg/24 hr). Safety outcomes included adverse events (AEs), discontinuations caused by AEs and serious AEs (SAEs). Results: Patient groups receiving rivastigmine patch (n = 261) or capsules (n = 331) had mean ± SD ages of 77.3 ± 8.0 and 78.1 ± 7.8 years, dementia durations of 3.9 ± 2.6 and 3.6 ± 2.2 years and Mini-Mental State Examination scores of 18.3 ± 4.00 and 17.9 ± 4.4 respectively. Overall, 184 (70.5%) and 276 (83.4%) patients experienced at least one AE, and 23 (8.8%) and 55 (16.6%) patients experienced an SAE with the rivastigmine patch and capsules respectively. Of the patients who experienced an AE, 10 (3.8%) and 109 (32.9%) experienced nausea, and 11 (4.2%) and 80 (24.1%) experienced vomiting with the rivastigmine patch and capsules respectively. Discontinuations because of AEs occurred in 64 (19.3%) patients receiving capsules and 38 (14.6%) patients in the transdermal patch group. The most common reasons for discontinuation with the transdermal patch were application site reaction and disease progression, and nausea and vomiting with the capsules. Conclusions: The rivastigmine transdermal patch appears to have better tolerability than rivastigmine capsules, with fewer gastrointestinal AEs and discontinuations because of these AEs. Simple daily rotation of patch location will likely reduce the frequency of skin reactions. This post hoc analysis was carried out by Novartis Pharmaceuticals Corporation. Data for the analysis were collected from the US13 study (CENA713B US13), the US18 study (CENA713B US18) and the US38 study (CENA713D US38). © 2009 Blackwell Publishing Ltd.

Fleisher A.S.,Banner Alzheimers Institute | Fleisher A.S.,University of California at San Diego | Chen K.,Banner Alzheimers Institute | Chen K.,Arizona State University | And 23 more authors.
Neurobiology of Aging | Year: 2013

Objectives: Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD). Methods: Florbetapir F18 PET images were analyzed from 245 participants, 18-92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups. Results: In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3-63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers. Interpretation: Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers. © 2013 Elsevier Inc.

Doraiswamy P.M.,Duke University | Sperling R.A.,Harvard University | Coleman R.E.,Duke University | Johnson K.A.,Harvard University | And 15 more authors.
Neurology | Year: 2012

Objectives: Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline. Methods: A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ-) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline. Results: In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating-sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ- subjects (p < 0.10). Conclusions: Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline. © 2012 by AAN Enterprises, Inc.

Weiner M.W.,University of California at San Francisco | Sadowsky C.,Nova University | Saxton J.,University of Pittsburgh | Hofbauer R.K.,Forest Research Institute | And 7 more authors.
Alzheimer's and Dementia | Year: 2011

Background: This study was designed to assess changes in brain volume and cognitive abilities in memantine-treated patients with Alzheimer's disease (AD) by using an exploratory, single-arm, delayed-start design. Methods: Cholinesterase inhibitor-treated patients with AD (N = 47; Mini-Mental State Examination score range: 15-23) were enrolled in an observational lead-in period (weeks: 1-24), followed by an open-label period of add-on memantine treatment (weeks: 25-48). The patients underwent magnetic resonance imaging at weeks 0 (baseline), 24 (immediately before memantine initiation), and 48 (endpoint), and a battery of neuropsychological tests at weeks 0, 24, 28, 36, and 48. The primary outcome measure was the annualized rate of change (%) in total brain volume (TBV) between the two study periods. Data were analyzed using paired t-tests. Results: There were no statistically significant differences in the rates of change in TBV, ventricular volume, or left hippocampal volume between the study periods; however, the memantine treatment period was associated with a significantly slower right hippocampal atrophy (-5.5% ± 12.0% vs -10.8% ± 7.2%; P =.038). Memantine treatment was also associated with superior performances on the Boston Naming Test (P =.034) and the Trail Making Test, Part B (P =.001), but also with a higher number of errors (i.e., repetitions and intrusions) on the California Verbal Learning Test. Memantine was found to be safe and well tolerated. Conclusions: In this study, no difference in the rates of TBV change between the two periods was observed; however, memantine treatment was found to be associated with slowing of right hippocampal atrophy, and with improvement on one test of executive functioning as well as a test of confrontation naming ability. Trials using structural magnetic resonance imaging and a delayed-start design may be a feasible option for the assessment of treatments for AD. © 2011 The Alzheimer's Association. All rights reserved.

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