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ABSTRACTBACKGROUND AND PURPOSEGlutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1H‐MRS) protocol composed of semi‐localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment.METHODSParticipants with amnestic mild cognitive impairment (n= 14; median age = 80) and age‐ and sex‐matched clinically normal controls (n= 32; median age = 79) from the population‐based Mayo Clinic Study of Aging were recruited prospectively to the 3T single‐voxel1H‐MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β‐amyloid load on [11C] Pittsburgh Compound B (PiB)‐PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β‐amyloid load (SUVr ≥ 1.42).RESULTSGlutamate concentration and the glutamate/myo‐inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P< .05). Higher global cortical PiB‐PET SUVr correlated with lower glutamate/myo‐inositol (r= –.3,P= .04).CONCLUSIONSThe advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced1H‐MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment.

Impaired brain clearance of amyloid-beta peptides (Aβ) 40 and 42 across the blood–brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer’s disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase Aβ accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect Aβ accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and Aβ transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of Aβ40 increased, but Aβ42 clearance reduced; the plasma-to-brain influx of Aβ40 increased, and that of Aβ42 reduced; and the clearance of intracerebrally injected Aβ40 decreased, whereas Aβ42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of Aβ40 increased and that of Aβ42 reduced; the abluminal-to-luminal permeability of Aβ40 decreased, whereas Aβ42 permeability increased. Moreover, Aβ cellular trafficking machinery was altered. In summary, Aβ40 and Aβ42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology.

Objective There is a need for inexpensive noninvasive tests to identify older healthy persons at risk for Alzheimer disease (AD) for enrollment in AD prevention trials. Our objective was to examine whether abnormalities in neuroimaging measures of amyloid and neurodegeneration are correlated with odor identification (OI) in the population‐based Mayo Clinic Study of Aging. Methods Cognitively normal (CN) participants had olfactory function assessed using the Brief Smell Identification Test (B‐SIT), underwent magnetic resonance imaging (n = 829) to assess a composite AD signature cortical thickness and hippocampal volume (HVa), and underwent 11 C‐Pittsburgh compound B (n = 306) and 18 fluorodeoxyglucose (n = 305) positron emission tomography scanning to assess amyloid accumulation and brain hypometabolism, respectively. The association of neuroimaging biomarkers with OI was examined using multinomial logistic regression and simple linear regression models adjusted for potential confounders. Results Among 829 CN participants (mean age = 79.2 years; 51.5% men), 248 (29.9%) were normosmic and 78 (9.4%) had anosmia (B‐SIT score < 6). Abnormal AD signature cortical thickness and reduced HVa were associated with decreased OI as a continuous measure (slope = −0.43, 95% confidence interval [CI] = −0.76 to −0.09, p = 0.01 and slope = −0.72, 95% CI = −1.15 to −0.28, p < 0.01, respectively). Reduced HVa, decreased AD signature cortical thickness, and increased amyloid accumulation were significantly associated with increased odds of anosmia. Interpretation Our findings suggest that OI may be a noninvasive, inexpensive marker for risk stratification, for identifying participants at the preclinical stage of AD who may be at risk for cognitive impairment and eligible for inclusion in AD prevention clinical trials. These cross‐sectional findings remain to be validated prospectively. Ann Neurol 2017;81:871–882

Background: There is growing interest in white matter (WM) imaging with positron emission tomography (PET). Objectives: We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding. Methods: In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences. Results: MS patients had lower memory ( p = 0.03) and language ( p = 0.02) performance; smaller thalamic volumes ( p = 0.003); and thinner temporal ( p = 0.001) and frontal ( p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls ( p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS ( p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities ( r = 0.65; p = 0.02) and NAWM ( r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS. Conclusion: PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures’ integrity such as those involved in visuospatial performance.

AbstractQuantitative measurement of β‐amyloid from amyloid PET scans typically relies on localizing target and reference regions by image registration to MRI. In this work, we present a series of simulations where 50 small random perturbations of starting location and orientation were applied to each subject's PET scan, and rigid registration usingspm_coregwas performed between each perturbed PET scan and its corresponding MRI. We then measured variation in the output PET‐MRI registrations and how this variation affected the resulting SUVR measurements. We performed these experiments using scans of 1196 participants, half using 18F florbetapir and half using 11C PiB. From these experiments, we measured the magnitude of the imprecision in the rigid registration steps used to localize measurement regions, and how this contributes to the overall imprecision in SUVR measurements. Unexpectedly, we found for both tracers that the imprecision in these measurements depends on the degree of amyloid tracer uptake, and thus also indirectly on Alzheimer's disease clinical status. We then examined common choices of reference regions, and we show that SUVR measurements using supratentorial white matter references are relatively resistant to this source of error. We also show that the use of partial volume correction further magnifies the effects of registration imprecision on SUVR measurements. Together, these results suggest that this rigid registration step is an attractive target for future work in improving measurement techniques.Hum Brain Mapp 38:3323–3336, 2017. ©2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III–IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I–II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68–6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94–93.31%), specificity (90%, 95% CI=88.56–91.56%), and negative predictive value (99%, 95% CI=98.46–99.52%). However, the positive predictive value was only 37% (95% CI=31.32–43.68%). In patients with resected stage III–IV melanoma, surveillance PET/CT detected a large proportion of clinically occult recurrences amenable to curative-intent salvage treatment. Despite a high rate of second relapse, curative-intent salvage treatment was associated with superior overall survival. Even though PET/CT had high sensitivity, specificity, and negative predictive value, positive predictive value was poor, highlighting the need for histologic confirmation of PET/CT-detected abnormalities.

243 Background: Cbz/pred extends survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase I trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) of the combination of Cbz, Mito, and Pred. Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD of CAMP; secondary objectives included assessing PSA and objective response rates and duration of response. Starting dose of Cbz was 25 mg/m2 (the currently approved single-agent dose) and Mito 4 mg/m2, administered on day 1 of a 21-day cycle. Mito was escalated by 2 mg/m2 per dose level. Pred 5 mg BID and pegfilgrastim were administered with each cycle. Results: 9 pts were enrolled (dose level I, N = 1; dose level II, N = 1; dose level III, N = 3; dose level IV N = 4). The median age was 67 (range 55-81) and the median baseline PSA was 82.3 (range 20.4-791.2). There were 2 DLTs observed at dose level IV (Cbz 25 mg/m2 + mito 10 mg/m2), both grade 4 sepsis. The most common grade 3 adverse events were hematologic (neutropenia, n = 5; febrile neutropenia, n = 2, thrombocytopenia, n = 2). 6 of 9 pts remain on study (range 2.2 - 10.5+ months). Maximal PSA declines from baseline > 50% have been observed in 4/7 (57%) evaluable pts to date. 2 of 4 pts with measurable disease have experienced partial responses and a third has had a minor response after 4 cycles of chemo. The median progression-free survival and duration of response have not been reached. Conclusions: The approved single-agent dosage of Mito (12 mg/m2) could not be safely reached in combination with Cbz 25 mg/m2. Pre-planned evaluation of an alternate dosing strategy combining Mito with Cbz 20 mg/m2, which has demonstrated activity in mCRPC and potentially less hematologic toxicity, is underway. Preliminary efficacy data are encouraging but additional follow-up and further study of the treatment combination is required. Clinical trial information: NCT01594918.