Effectiveness of Florbetapir PET Imaging in Changing Patient Management.

AIMS: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study. METHODS: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months. RESULTS: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit. CONCLUSION: Knowledge of the amyloid status affects the diagnosis and alters patient management.

Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.

INTRODUCTION: Performance of the amyloid tracer [18F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [18F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [18F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria.

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

ABT-089, an α4ß2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Evaluating Response to High-Dose 13.3 mg/24 h Rivastigmine Patch in Patients with Severe Alzheimer's Disease.

AIMS: To identify factors predicting improvement/stabilization on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and investigate whether early treatment responses can predict long-term outcomes, during a trial of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Logistic regression was used to relate Week 24 ADCS-CGIC score to potential baseline predictors. Additional analyses based on receiver-operating characteristic curves were performed using Week 8/16 ADCS-CGIC scores to predict response (13.3 mg/24 h patch) at Week 24. ADCS-CGIC score of (1) 1-3 = "improvement," (2) 1-4 = "improvement or no change". RESULTS: "Treatment" (13.3 mg/24 h patch) and increased age were significant predictors of "improvement" (P = 0.01 and P = 0.003, respectively), and "treatment" (P = 0.001), increased age (P = 0.002), and prior AD treatment (P = 0.03) for "improvement or no change". At Week 8 and 16, ADCS-CGIC scores of 4 and 5 were optimal thresholds in predicting "improvement," and "improvement or no change," respectively, at Week 24. CONCLUSIONS: A significant therapeutic effect of high-dose rivastigmine patch on ADCS-CGIC response was observed. The 13.3 mg/24 h patch was identified as a predictor of "improvement" or "improvement or no change". Patients with minimal worsening/improvement/no change after treatment initiation may be more likely to respond following long-term therapy.

Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density.

IMPORTANCE: In vivo imaging of brain ß-amyloid, a hallmark of Alzheimer disease, may assist in the clinical assessment of suspected Alzheimer disease. OBJECTIVE: To determine the sensitivity and specificity of positron emission tomography imaging with flutemetamol injection labeled with radioactive fluorine 18 to detect ß-amyloid in the brain using neuropathologically determined neuritic plaque levels as the standard of truth. DESIGN, SETTING, AND PARTICIPANTS: Open-label multicenter imaging study that took place at dementia clinics, memory centers, and hospice centers in the United States and England from June 22, 2010, to November 23, 2011. Participants included terminally ill patients who were 55 years or older with a life expectancy of less than 1 year. INTERVENTIONS: Flutemetamol injection labeled with radioactive fluorine 18 (Vizamyl; GE Healthcare) administration followed by positron emission tomography imaging and subsequent brain donation. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of flutemetamol injection labeled with radioactive fluorine 18 positron emission tomography imaging for brain ß-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for ß-amyloid by 5 readers who were blind to patient information. In patients who died, neuropathologically determined neuritic plaque levels were used to confirm scan interpretations and determine sensitivity and specificity. RESULTS: Of 176 patients with evaluable images, 68 patients (38%) died during the study, were autopsied, and had neuritic plaque levels determined; 25 brains (37%) were ß-amyloid negative; and 43 brains (63%) were ß-amyloid positive. Imaging was performed a mean of 3.5 months (range, 0 to 13 months) before death. Sensitivity without computed tomography was 81% to 93% (median, 88%). Median specificity was 88%, with 4 of 5 of the readers having specificity greater than 80%. When scans were interpreted with computed tomography images, sensitivity and specificity improved for most readers but the differences were not significant. The area under the receiver operating curve was 0.90. There were no clinically meaningful findings in safety parameters. CONCLUSIONS AND RELEVANCE: This study showed that flutemetamol injection labeled with radioactive fluorine 18 was safe and had high sensitivity and specificity in an end-of-life population. In vivo detection of brain ß-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.

A clinical trial to validate event-related potential markers of Alzheimer's disease in outpatient settings.

INTRODUCTION: We investigated whether event-related potentials (ERP) collected in outpatient settings and analyzed with standardized methods can provide a sensitive and reliable measure of the cognitive deficits associated with early Alzheimer's disease (AD). METHODS: A total of 103 subjects with probable mild AD and 101 healthy controls were recruited at seven clinical study sites. Subjects were tested using an auditory oddball ERP paradigm. RESULTS: Subjects with mild AD showed lower amplitude and increased latency for ERP features associated with attention, working memory, and executive function. These subjects also had decreased accuracy and longer reaction time in the target detection task associated with the ERP test. DISCUSSION: Analysis of ERP data showed significant changes in subjects with mild AD that are consistent with the cognitive deficits found in this population. The use of an integrated hardware/software system for data acquisition and automated data analysis methods make administration of ERP tests practical in outpatient settings.

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease.

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Detection of Amyloid ß Signature in the Lens and Its Correlation in the Brain to Aid in the Diagnosis of Alzheimer's Disease.

We report the findings from a clinical trial in which a group of patients clinically diagnosed with probable Alzheimer's disease (AD) were discriminated from an age-matched group of healthy volunteers (HVs) with statistical significance (P<.001). The results from 20 patients with AD and 20 HVs were obtained by a Fluorescent Ligand Eye Scanning (FLES) technique that measures a fluorescent signature specific to an exogenous ligand bound to amyloid-ß in the lens of the eye. Sensitivity and specificity of 85% and 95%, respectively, have been achieved in predicting clinical diagnosis. Additionally, amyloid brain imaging using florbetapir F18 positron emission tomography shows significant correlation with the results obtained in the eye. Results of the study demonstrate the safety of the FLES system.

Neuropathologic heterogeneity does not impair florbetapir-positron emission tomography postmortem correlates.

Neuropathologic heterogeneity is often present among Alzheimer disease (AD) patients. We sought to determine whether amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinically and pathologically defined AD and 17 nondemented patients with quantitative florbetapir F-18 (F-AV-45) positron emission tomography (PET) imaging during life and postmortem histological ß-amyloid quantification and neuropathologic examination were assessed. AD patients were divided on the basis of concurrent pathologies, including those with Lewy bodies (LBs) (n = 21), white matter rarefaction (n = 27), severe cerebral amyloid angiopathy (n = 11), argyrophilic grains (n = 5), and TAR DNA binding protein-43 inclusions (n = 18). Many patients exhibited more than 1 type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical ß-amyloid load were analyzed in 6 cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological ß-amyloid measures (p µ 0.001). All AD subgroups had significantly greater amyloid measures versus nondemented patients, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with LBs had significantly lower SUVr measures versus AD cases without LBs (p = 0.002); there were no other paired comparison differences. These findings indicate that florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.

Rivastigmine from capsules to patch: therapeutic advances in the management of Alzheimer's disease and Parkinson's disease dementia.

OBJECTIVE: To discuss the pharmacology, mechanism of action, and chemical properties of the cholinesterase inhibitor (ChEI) rivastigmine; to provide a rationale for transdermal delivery and supportive clinical data, along with practical guidance on rivastigmine patch use in Alzheimer's disease and Parkinson's disease dementia. DATA SOURCES: Pivotal studies of rivastigmine capsules and patch were identified using PubMed and the rivastigmine US prescribing information. PubMed searches were performed in 2013 using rivastigmine as a keyword. STUDY SELECTION: English-language articles related to rivastigmine considered of relevance to primary care physicians were included. DATA SYNTHESIS: Pharmacologic differences exist between rivastigmine and ChEIs. Clinical studies demonstrate symptomatic efficacy of oral rivastigmine across all stages of Alzheimer's disease and mild-to-moderate Parkinson's disease dementia. However, gastrointestinal adverse events limit access to optimal therapeutic doses. Strategies that lower maximum plasma concentrations (Cmax) and prolong time to Cmax, ie, transdermal delivery, may improve tolerability. Clinical registration studies have demonstrated improved tolerability of rivastigmine 9.5-mg/24-h patch versus 6-mg twice-daily capsules in mild-to-moderate Alzheimer's disease, and a positive benefit-risk profile of 13.3-mg/24-h versus 9.5-mg/24-h patch in patients needing enhanced efficacy. Clinical data comparing 13.3-mg/24-h versus 4.6-mg/24-h patch in severe Alzheimer's disease demonstrated efficacy on cognition and activities of daily living. These data led to approval of rivastigmine patch in severe Alzheimer's disease. Transdermal delivery also has practical advantages, including simple, once-daily administration and a visual indicator of compliance. Potential application site reactions can be minimized and need not be a barrier to treatment. CONCLUSIONS: In addition to practical advantages, rivastigmine patch may improve clinical outcomes throughout the course of Alzheimer's disease by providing access to high-dose efficacy without compromising tolerability.

The S-Connect study: results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer's disease.

INTRODUCTION: Souvenaid® containing Fortasyn® Connect is a medical food designed to support synapse synthesis in persons with Alzheimer's disease (AD). Fortasyn Connect includes precursors (uridine monophosphate; choline; phospholipids; eicosapentaenoic acid; docosahexaenoic acid) and cofactors (vitamins E, C, B12, and B6; folic acid; selenium) for the formation of neuronal membranes. Whether Souvenaid slows cognitive decline in treated persons with mild-to-moderate AD has not been addressed. METHODS: In a 24-week, double-masked clinical trial at 48 clinical centers, 527 participants taking AD medications [52% women, mean age 76.7 years (Standard Deviation, SD = 8.2), and mean Mini-Mental State Examination score 19.5 (SD = 3.1, range 14-24)] were randomized 1:1 to daily, 125-mL (125 kcal), oral intake of the active product (Souvenaid) or an iso-caloric control. The primary outcome of cognition was assessed by the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog). Compliance was calculated from daily diary recordings of product intake. Statistical analyses were performed using mixed models for repeated measures. RESULTS: Cognitive performance as assessed by ADAS-cog showed decline over time in both control and active study groups, with no significant difference between study groups (difference =0.37 points, Standard Error, SE = 0.57, p = 0.513). No group differences in adverse event rates were found and no clinically relevant differences in blood safety parameters were noted. Overall compliance was high (94.1% [active] and 94.5% [control]), which was confirmed by significant changes in blood (nutritional) biomarkers. CONCLUSIONS: Add-on intake of Souvenaid during 24 weeks did not slow cognitive decline in persons treated for mild-to-moderate AD. Souvenaid was well tolerated in combination with standard care AD medications. TRIAL REGISTRATION: DUTCH TRIAL REGISTER NUMBER: NTR1683.

A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer's dementia.

AIMS: The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Patients had probable AD and Mini-Mental State Examination scores ≥3-≤12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. RESULTS: Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P < 0.0001 and P = 0.049, respectively) and 24 (primary endpoint; P < 0.0001 and P = 0.025). Significant between-group differences (Week 24) were observed on the ADCS-CGIC (P = 0.0023), not NPI-12 (P = 0.1437). A similar proportion of the 13.3 mg/24 h and 4.6 mg/24 h patch groups reported adverse events (AEs; 74.6% and 73.3%, respectively) and serious AEs (14.9% and 13.6%). CONCLUSIONS: The 13.3 mg/24 h patch demonstrated superior efficacy to 4.6 mg/24 h patch on SIB and ADCS-ADL-SIV, without marked increase in AEs, suggesting higher-dose patch has a favorable benefit-to-risk profile in severe AD.

Alzheimer's disease diagnosis by detecting exogenous fluorescent signal of ligand bound to Beta amyloid in the lens of human eye: an exploratory study.

We report results of a clinical exploratory human trial involving 10 participants using a combination of a fluorescent ligand and a laser scanning device, SAPPHIRE System, as an aid in the diagnosis of Probable Alzheimer's disease (AD). To the best of our knowledge, this is the first time that such a technique has been used in vivo of a human lens. The primary goal of the clinical trial, in addition to safety assessment, was to evaluate efficacy of the system. By detecting specific fluorescent signature of ligand bound beta amyloid in the supranucleus (SN) region of the human lens, a twofold differentiation factor between AD patients and Control groups is achieved. Data from our studies indicates that deeper regions of the SN provide the highest measures of ligand bound fluorescence signal from both controls and patients with AD. In addition, we present preclinical studies that were performed to investigate the binding affinity of the ligand to beta amyloid and evaluate the pharmacokinetics of the ligand in rabbit eyes. Further studies are underway involving a larger population for statistical evaluation of the method.

Florbetapir (F18-AV-45) PET to assess amyloid burden in Alzheimer's disease dementia, mild cognitive impairment, and normal aging.

OBJECTIVE: To evaluate the performance characteristics of florbetapir F18 positron emission tomography (PET) in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy control subjects (HCs). METHODS: Florbetapir PET was acquired in 184 subjects (45 AD patients, 60 MCI patients, and 79 HCs) within a multicenter phase 2 study. Amyloid burden was assessed visually and quantitatively, and was classified as positive or negative. RESULTS: Florbetapir PET was rated visually amyloid positive in 76% of AD patients, 38% of MCI patients, and 14% of HCs. Eighty-four percent of AD patients, 45% of MCI patients, and 23% of HCs were classified as amyloid positive using a quantitative threshold. Amyloid positivity and mean cortical amyloid burden were associated with age and apolipoprotein E ε4 carrier status. CONCLUSIONS: : The data are consistent with expected rates of amyloid positivity among individuals with clinical diagnoses of AD and MCI, and indicate the potential value of florbetapir F18 PET as an adjunct to clinical diagnosis.

Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease.

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.

Amyloid deposition detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance in clinically normal older individuals.

The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 ((18)F-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 (18)F-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 (18)F-AV-45 may also predict subsequent cognitive decline.

Potential impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline.

Florbetapir F18 has been approved by the Food and Drug Administration for in vivo assessment of amyloid pathology in patients undergoing evaluation for Alzheimer disease (AD). The aim of this study was to determine the impact of amyloid imaging on the diagnoses and management of patients undergoing evaluation for cognitive decline. Patients were recruited to participate at 19 clinical sites. The site physician provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plan for diagnostic evaluation and management both before and after receiving the results from amyloid imaging with florbetapir F18. Analyses compared the frequency of AD and non-AD diagnoses, plans for ancillary testing, and intended patient management before and after florbetapir imaging. A total of 229 patients participated in the trial (113 amyloid positive, 116 amyloid negative). After receiving the results of the florbetapir scan, diagnosis changed in 125/229, or 54.6% [95% confidence intervals (CI), 48.1%-60.9%], of cases, and diagnostic confidence increased by an average of 21.6% (95% CI, 18.3%-24.8%). A total of 199/229 or 86.9% (95% CI, 81.9%-90.7%) of cases had at least 1 change in their management plan. Intended cholinesterase inhibitor or memantine treatment increased by 17.7% (95% CI, 11.8%-25.8%) of all cases with positive scans and decreased by 23.3% (95% CI, 16.5%-31.8%) of all those with negative scans. Among subjects who had not yet undergone a completed work up, planned brain structural imaging (computed tomographic/magnetic resonance imaging) decreased by 24.4% (95% CI, 17.5%-32.8%) and planned neuropsychological testing decreased by 32.8% (95% CI, 25.0%-41.6%). In summary, amyloid imaging results altered physician's diagnostic thinking, intended testing, and management of patients undergoing evaluation for cognitive decline.

Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-ß plaques: a prospective cohort study.

BACKGROUND: Results of previous studies have shown associations between PET imaging of amyloid plaques and amyloid-ß pathology measured at autopsy. However, these studies were small and not designed to prospectively measure sensitivity or specificity of amyloid PET imaging against a reference standard. We therefore prospectively compared the sensitivity and specificity of amyloid PET imaging with neuropathology at autopsy. METHODS: This study was an extension of our previous imaging-to-autopsy study of participants recruited at 22 centres in the USA who had a life expectancy of less than 6 months at enrolment. Participants had autopsy within 2 years of PET imaging with florbetapir ((18)F). For one of the primary analyses, the interpretation of the florbetapir scans (majority interpretation of five nuclear medicine physicians, who classified each scan as amyloid positive or amyloid negative) was compared with amyloid pathology (assessed according to the Consortium to Establish a Registry for Alzheimer's Disease standards, and classed as amyloid positive for moderate or frequent plaques or amyloid negative for no or sparse plaques); correlation of the image analysis results with amyloid burden was tested as a coprimary endpoint. Correlation, sensitivity, and specificity analyses were also done in the subset of participants who had autopsy within 1 year of imaging as secondary endpoints. The study is registered with ClinicalTrials.gov, number NCT 01447719 (original study NCT 00857415). FINDINGS: We included 59 participants (aged 47-103 years; cognitive status ranging from normal to advanced dementia). The sensitivity and specificity of florbetapir PET imaging for detection of moderate to frequent plaques were 92% (36 of 39; 95% CI 78-98) and 100% (20 of 20; 80-100%), respectively, in people who had autopsy within 2 years of PET imaging, and 96% (27 of 28; 80-100%) and 100% (18 of 18; 78-100%), respectively, for those who had autopsy within 1 year. Amyloid assessed semiquantitatively with florbetapir PET was correlated with the post-mortem amyloid burden in the participants who had an autopsy within 2 years (Spearman ρ=0·76; p<0·0001) and within 12 months between imaging and autopsy (0·79; p<0·0001). INTERPRETATION: The results of this study validate the binary visual reading method approved in the USA for clinical use with florbetapir and suggest that florbetapir could be used to distinguish individuals with no or sparse amyloid plaques from those with moderate to frequent plaques. Additional research is needed to understand the prognostic implications of moderate to frequent plaque density. FUNDING: Avid Radiopharmaceuticals.

Amyloid-ß assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study.

OBJECTIVES: Florbetapir F 18 PET can image amyloid-ß (Aß) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aß 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 (Aß+) or negative (Aß-) for pathologic levels of ß-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 Aß+ 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 Aß+ 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). Aß+ MCI tended to convert to AD dementia at a higher rate than Aß- subjects (p < 0.10). CONCLUSIONS: Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.

Concurrent onabotulinumtoxinA treatment of cervical dystonia and concomitant migraine.

OBJECTIVE: The objective of this study was to assess the clinical benefits of onabotulinumtoxinA (BOTOX®) treatment on the symptoms of cervical dystonia and the frequency, severity, and associated symptoms of migraine in patients with cervical dystonia and concurrent migraine. BACKGROUND: Botulinum toxin is established as first-line treatment of cervical dystonia. Recent clinical trials have shown onabotulinumtoxinA to be an effective prophylactic therapy for patients with chronic migraine, and onabotulinumtoxinA has been approved for use in this patient population by the Food and Drug Administration. Patients with headache associated with cervical dystonia have been identified as a specific subpopulation of patients in whom botulinum toxin treatment may be effective for controlling the symptoms of both conditions. METHODS: An open-label pilot study was conducted for 7.5 months in patients at least 18 years old with primary cervical dystonia of moderate severity (baseline rating of at least 20 on the Toronto Western Spasmodic Torticollis Rating Scale) complicated by migraine headache meeting the International Classification of Headache Disorders-II criteria for migraines with or without aura. Each patient received 2 cycles of treatment at Visit 3 (baseline) and Visit 6 (Day 90). For cervical dystonia, each patient was injected with a maximum of 175 units. At the same visit, a maximum of 125 units was also injected for migraine using a fixed-site, fixed-dose injection paradigm, with additional cervical dystonia injection-site treatment to a maximum dose of 300 units. Patients were assessed following onabotulinumtoxinA injection and at follow-up on Visit 4 (Day 30), Visit 5 (Day 60), Visit 6 (Day 90), and at Visits 7, 8, and 9 (Days 120, 150, and 180). The primary outcome measures for this study were change in Toronto Western Spasmodic Torticollis Rating Scale total score for cervical dystonia and frequency of headache episodes per 28-day period. Migraine episodes were defined as at least 4 hours of sustained pain with no upper limit. An episode was considered new if the patient was pain free for at least 24 hours. Secondary study end points included number of headache days per month, headache intensity, headache disability (assessed using Headache Impact Test-6 and the Migraine Disability Assessment score scales), acute headache medication use, resource utilization, and allodynia pain. Adverse events were reported. RESULTS: A total of 25 patients (24 women, mean age 50.5 years; mean age of disease onset 21.9 years) were enrolled in the study. Patients experienced improvement in cervical dystonia symptoms with significant reductions from baseline in Toronto Western Spasmodic Torticollis Rating Scale scores at 30, 60, 90, 120, 150, and 180 days (-9.84 ± 8.49, -12.67 ± 8.22, -13.63 ± 7.27, -14.92 ± 7.05, -14.76 ± 6.97, -14.49 ± 6.14, respectively, P < .0001 at all time points from a baseline of 31.03 ± 3.61). Changes from baseline were assessed using the t-test. Reductions in the number of headache episodes from baseline on concurrent onabotulinumtoxinA treatment for coexistent chronic migraine did not attain significance. However, patients experienced significant reductions from baseline in the number of headache days at 90, 120, and 180 days (-3.39 ± 6.78, P = .0289; -4.29 ± 7.94, P = .0194; -4.38 ± 7.99, P = .0178, respectively, from a baseline of 15.33 ± 6.76). Changes from baseline were assessed using the t-test. The change from baseline in Headache Impact Test-6 total scores was significant at 30, 60, 90, 150, and 180 days (3.21 ± 4.14, P = .0009; -3.04 ± 4.04, P = .0012; -2.41 ± 2.79, P = .0006; -2.59 ± 3.87, P = .0050; -3.09 ± 3.80, respectively, from a baseline of 22.68 ± 3.20). Changes from baseline were assessed using the t-test. The change from baseline in Migraine Disability Assessment was significant at 120, 150, and 180 days (-38.09 ± 47.87, P < .0001, Wilcoxon signed rank test; -16.91 ± 62.69, P = .0358, Wilcoxon signed rank test; -23.73 ± 40.57, P = .0122, t-test, respectively, from a baseline of 56.68 ± 50.41). There were no serious adverse events or treatment-related discontinuations. CONCLUSIONS: Concurrent treatment with onabotulinumtoxinA is effective and well tolerated in controlling the symptoms of cervical dystonia complicated by concurrent migraine.