ment of Alzheimer disease (AD) are hampered by the lack of noninvasive biomarkers of the underlying pathology. Between 10% and 20% of patients clinically diagnosed with AD lack AD pathology at autopsy, 1-3 and community physicians may not diagnose AD in 33% of patients with mild signs and symptoms. 4 Thus, a diagnostic biomarker may help clinicians separate patients who have AD pathology from those who do not. See also pp 261 and 304.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

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ObjectivesTo compare the efficacy, safety and tolerability of a novel rivastigmine transdermal patch with conventional rivastigmine capsules and placebo in patients with Alzheimer's disease (AD).MethodsIn this 24‐week, multicenter, double‐blind, double‐dummy, placebo‐ and active‐controlled trial, patients with probable AD were randomized to one of four treatment groups: 12 mg/day rivastigmine capsules; 10 cm2 (9.5 mg/24 h) rivastigmine patch; 20 cm2 (17.4 mg/24 h) rivastigmine patch; or placebo. Primary efficacy measures were the Alzheimer's Disease Assessment Scale—Cognitive subscale (ADAS‐Cog) and Alzheimer's Disease Cooperative Study––Clinical Global Impression of Change (ADCS‐CGIC).ResultsOne thousand one hundred and ninety five AD patients from 21 countries participated in the study. Treatment differences (vs placebo) on the ADAS‐Cog at Week 24 in 10 cm2 patch, 20 cm2 patch and capsule groups were 1.6 (p = 0.005), 2.6 (p < 0.001) and 1.6 (p = 0.003). Treatment differences on the ADCS‐CGIC were 0.3 (p = 0.01), 0.2 (p = 0.054) and 0.3 (p = 0.009). Comparison between the 10 cm2 patch and the capsule revealed non‐inferiority. Rates of nausea in the 10 cm2 patch and capsule groups were 7.2% and 23.1%, respectively; rates of vomiting were 6.2% and 17.0%, respectively. Moderate or severe skin irritation occurred in ≤10% patients across the four patch sizes (5, 10, 15 and 20 cm2).ConclusionsThe target dose of 10 cm2 rivastigmine patch provides efficacy similar to the highest doses of capsules with a superior tolerability profile. The transdermal patch with rivastigmine may offer convenience important to many caregivers and patients. Copyright © 2007 John Wiley & Sons, Ltd.

The objectives of this study were to examine the effective dose range and the test-retest reliability of florbetapir F 18 using, first, visual assessment by independent raters masked to clinical information and, second, semiautomated quantitative measures of cortical target area to cerebellum standardized uptake value ratios (SUVr) as primary outcome measures. Visual ratings of PET image quality and tracer retention or b-amyloid (Ab) binding expressed as SUVrs were compared after intravenous administration of either 111 MBq (3 mCi) or 370 MBq (10 mCi) of florbetapir F 18 in patients with Alzheimer's disease (AD) (n 5 9) and younger healthy controls (YHCs) (n 5 11). In a separate set of subjects (AD, n 5 10; YHCs, n 5 10), test-retest reliability was evaluated by comparing intrasubject visual read ratings and SUVrs for 2 PET images acquired within 4 wk of each other. Results: There were no meaningful differences between the 111-MBq (3-mCi) and 370-MBq (10-mCi) dose in the visual rating or SUVr. The difference in the visual quality across 111 and 370 MBq showed a trend toward lower image quality, but no statistical significance was achieved (t test; t 1 5 21.617, P 5 0.12) in this relatively small sample of subjects. At both dose levels, visual ratings of amyloid burden identified 100% of AD subjects as Ab-positive and 100% of YHCs as Ab-negative. Mean intrasubject test-retest variability for cortical average SUVrs with the cerebellum as a reference over the 50-to 70-min period was 2.4% 6 1.41% for AD subjects and 1.5% 6 0.84% for controls. The overall SUVr test-retest correlation coefficient was 0.99. The overall k-statistic for test-retest agreement for Ab classification of the masked reads was 0.89 (95% confidence interval, 0.69-1.0). Conclusion: Florbetapir F 18 appears to have a wide effective dose range and a high testretest reliability for both quantitative (SUVr) values and visual assessment of the ligand. These imaging performance properties provide important technical information on the use of florbetapir F 18 and PET to detect cerebral amyloid aggregates.

In vivo imaging of brain β-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 β-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 β-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for β-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 β-amyloid negative; and 43 brains (63%) were β-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 β-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.