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1.  Perceived Misinterpretation Rates in Oncologic 18F-FDG PET/CT Studies: A Survey of Referring Physicians 
Because only pathologic examination can confirm the presence or absence of malignant disease in cancer patients, a certain rate of misinterpretation in any kind of imaging study is inevitable. For the accuracy of interpretation to be improved, determination of the nature, causes, and magnitude of this problem is needed. This study was designed to collect pertinent information from physicians referring patients for oncologic 18F-FDG PET/CT.
Methods
A total of 662 referring physicians completed an 11-question survey focused on their experience with the interpretation of oncologic 18F-FDG PET/CT studies. The participants were oncologists (36.1%; n = 239), hematologists (14.5%; n = 96), radiation oncologists (7.4%; n = 49), surgeons (33.8%; n = 224), and other physicians (8.2%; n = 54). Questions were aimed at determining the frequency, nature, and causes of scan misinterpretations as well as potential solutions to reduce the frequency of misinterpretations.
Results
Perceived misinterpretation rates ranged from 5% to 20%, according to most (59.3%) of the participants; 20.8% of respondents reported rates of less than 5%. Overinterpretation rather than underinterpretation was more frequently encountered (68.9% vs. 8.7%, respectively). Limited availability of a patient’s history and limited experience of interpreters were the major contributors to this phenomenon, according to 46.8% and 26.7% of the participants, respectively. The actions most commonly suggested to reduce misinterpretation rates (multiple suggestions were possible) were the institution of multidisciplinary meetings (59.8%), the provision of adequate history when ordering an examination (37.4%), and a discussion with imaging specialists when receiving the results of the examination (38.4%).
Conclusion
Overinterpretation rather than underinterpretation of oncologic 18F-FDG PET/CT studies prevails in clinical practice, according to referring physicians. Closer collaboration of imaging specialists with referring physicians through more multidisciplinary meetings, improved communication, and targeted training of interpreting physicians are actions suggested to reduce the rates of misinterpretation of oncologic 18F-FDG PET/CT studies.
doi:10.2967/jnumed.114.145607
PMCID: PMC4324619  PMID: 25453041
overinterpretation; false-positive results; false-negative results; accuracy; pitfall
2.  Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study 
Neurology  2014;82(1):70-76.
Objectives:
We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI).
Methods:
Participants included 448 CN individuals and 141 individuals with MCI from the Mayo Clinic Study of Aging who underwent Pittsburgh compound B (PiB)-PET, fluorodeoxyglucose-PET, and MRI. Head trauma was defined as a self-reported brain injury with at least momentary loss of consciousness or memory. Regression models examined whether head trauma was associated with each neuroimaging variable (assessed as continuous and dichotomous measures) in both CN and MCI participants, controlling for age and sex.
Results:
Among 448 CN individuals, 74 (17%) self-reported a head trauma. There was no difference in any neuroimaging measure between CN subjects with and without head trauma. Of 141 participants with MCI, 25 (18%) self-reported a head trauma. MCI participants with a head trauma had higher amyloid levels (by an average 0.36 standardized uptake value ratio units, p = 0.002).
Conclusions:
Among individuals with MCI, but not CN individuals, self-reported head trauma with at least momentary loss of consciousness or memory was associated with greater amyloid deposition, suggesting that head trauma may be associated with Alzheimer disease–related neuropathology. Differences between CN individuals and individuals with MCI raise questions about the relevance of head injury–PET abnormality findings in those with MCI.
doi:10.1212/01.wnl.0000438229.56094.54
PMCID: PMC3873622  PMID: 24371306
3.  Microbleeds in the logopenic variant of primary progressive aphasia 
Background
Microbleeds have been associated with Alzheimer’s disease (AD), although it is unclear whether they occur in atypical presentations of AD, such as the logopenic variant of primary progressive aphasia (lvPPA). We aimed to assess the presence and clinical correlates of microbleeds in lvPPA.
Methods
Thirteen lvPPA subjects underwent 3T T2*-weighted and fluid-attenuated inversion recovery MRI and Pittsburgh Compound B (PiB) PET imaging. Microbleeds were identified on manual review and assigned a regional location. Total and regional white matter hyperintensity (WMH) burden was measured.
Results
Microbleeds were observed in four lvPPA subjects (31%); most common in frontal lobe. Subjects with microbleeds were older, more likely female, and had a greater burden of WMH than those without microbleeds. The regional distribution of microbleeds did not match the regional distribution of WMH. All cases were PiB-positive.
Conclusions
Microbleeds occur in approximately 1/3 subjects with lvPPA, with older women at the highest risk.
doi:10.1016/j.jalz.2013.01.006
PMCID: PMC3706560  PMID: 23562427
Logopenic variant of primary progressive aphasia; Alzheimer’s disease; microbleeds; white matter hyperintensities
4.  Remission of Disseminated Cancer After Systemic Oncolytic Virotherapy 
Mayo Clinic proceedings  2014;89(7):926-933.
MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 1011 TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.
doi:10.1016/j.mayocp.2014.04.003
PMCID: PMC4225126  PMID: 24835528
5.  MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies 
Neurology  2013;81(19):1681-1689.
Objective:
To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.
Methods:
Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.
Results:
pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.
Conclusion:
Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
doi:10.1212/01.wnl.0000435299.57153.f0
PMCID: PMC3812105  PMID: 24107861
6.  Diabetes and Elevated HbA1c levels are Associated with Brain Hypometabolism but not Amyloid Accumulation 
Dysfunctional insulin signaling may affect brain metabolism or amyloid deposition. We investigated the associations of type 2 diabetes with amyloid accumulation measured using 11C-Pittsburgh Compound B (PiB) and brain hypometabolism measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET).
Methods
We studied a sample of non-demented participants from the population-based Mayo Clinic Study of Aging. All subjects underwent MRI, amyloid PET and FDG PET. Alzheimer’s disease (AD) signature and region of interest (ROI) measures for PiB retention ratio and FDG ratio were measured. Diabetes was assessed from the Rochester Epidemiology Project medical records-linkage system.
Results
Among 749 participants (median age 79.0 years; 56.5% male, 81.0% cognitively normal; 20.6% diabetics), FDG hypometabolism (FDG ratio < 1.31) in the AD signature meta-ROI was more common in diabetics (48.1%) than in non-diabetics (28.9%; p <0.001). The median FDG ratio was lower in diabetics vs. non-diabetics in the AD signature meta-ROI (1.32 vs. 1.40, p < 0.001), and in the angular (1.40 vs. 1.48, p < 0.001) and posterior cingulate gyri ROIs (1.63 vs. 1.72, p < 0.001). The odds ratio (OR [95% confidence interval]) for abnormal AD signature FDG hypometabolism was elevated (OR, 2.28 [1.56, 3.33]) in diabetics vs. non-diabetics after adjustment for age, sex, and education, and after additional adjustment for Apolipoprotein ε4 allele, glycemic level, and cognitive status (OR, 1.69 [1.10, 2.60]). However, AD signature PiB retention ratio was similar in diabetics vs. non-diabetics (OR, 1.03 [0.71, 1.51]; p = 0.87). In post-hoc analyses in non-diabetics, a 1% increase in HBA1c was associated with greater AD signature hypometabolism in cognitively normal subjects (OR, 1.93 [1.03, 3.62; p = 0.04]) and in the total cohort (OR 1.59 [0.92, 2.75; p = 0.10).
Conclusion
Diabetes and poor glycemic control in non-diabetics may enhance glucose hypometabolism in AD signature regions. These factors should be investigated in longitudinal studies for their role in detecting onset of symptoms in AD.
doi:10.2967/jnumed.113.132647
PMCID: PMC4011952  PMID: 24652830
Diabetes; cerebral glucose metabolism; FDG- and PiB-PET imaging; hemoglobin A1c; amyloid accumulation
7.  3D registration of micro-PET-CT for measurable correlates of dyspeptic symptoms in mice 
Patients with chronic calorie insufficiency commonly suffer from upper gastrointestinal dysfunction and consequent dyspeptic symptoms, which may interfere with their nutritional rehabilitation. To investigate the relationship between gastric dysfunction and feeding behavior, we exposed mice to chronic caloric restriction and demonstrated gastric motor abnormalities in them. Gastric dysmotility is typically associated with dyspeptic symptoms but sensations cannot be directly assessed in animal models. Therefore, as an initial step toward establishing measurable correlates of postprandial symptoms in small animals, we have attempted to characterize central responses to food intake by positron emission tomography—computerized microtomography (PET-CT) in normal and calorically restricted mice. Animals consumed a standard test meal after an overnight fast before receiving 2-deoxy-2[18F]fluoro-D-glucose tracer. The same mice were also scanned in the fasting state on a separate day. We were able to bring the fed and fasting PET volume images into spatial registration with each other and with an MR-derived atlas of the mouse brain, so that the differences in uptake between the two states could be mapped quantitatively against the neuroanatomic regions of the atlas. Our approach is suitable for studying the effects of gastric dysmotilities on central responses to feeding.
doi:10.1117/12.811408
PMCID: PMC4188375  PMID: 25301990
registration; micro-PET; micro-CT; caloric restriction; dyspepsia; anorexia nervosa; bulimia nervosa
8.  Biopsy validation of 18F-DOPA PET and biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a prospective pilot study 
Neuro-Oncology  2013;15(8):1058-1067.
Background
Delineation of glioma extent for surgical or radiotherapy planning is routinely based on MRI. There is increasing awareness that contrast enhancement on T1-weighted images (T1-CE) may not reflect the entire extent of disease. The amino acid tracer 18F-DOPA (3,4-dihydroxy-6-[18F] fluoro-l-phenylalanine) has a high tumor-to-background signal and high sensitivity for glioma imaging. This study compares 18F-DOPA PET against conventional MRI for neurosurgical biopsy targeting, resection planning, and radiotherapy target volume delineation.
Methods
Conventional MR and 18F-DOPA PET/CT images were acquired in 10 patients with suspected malignant brain tumors. One to 3 biopsy locations per patient were chosen in regions of concordant and discordant 18F-DOPA uptake and MR contrast enhancement. Histopathology was reviewed on 23 biopsies. 18F-DOPA PET was quantified using standardized uptake values (SUV) and tumor-to-normal hemispheric tissue (T/N) ratios.
Results
Pathologic review confirmed glioma in 22 of 23 biopsy specimens. Thirteen of 16 high-grade biopsy specimens were obtained from regions of elevated 18F-DOPA uptake, while T1-CE was present in only 6 of those 16 samples. Optimal 18F-DOPA PET thresholds corresponding to high-grade disease based on histopathology were calculated as T/N > 2.0. In every patient, 18F-DOPA uptake regions with T/N > 2.0 extended beyond T1-CE up to a maximum of 3.5 cm. SUV was found to correlate with grade and cellularity.
Conclusions
18F-DOPA PET SUVmax may more accurately identify regions of higher-grade/higher-density disease in patients with astrocytomas and will have utility in guiding stereotactic biopsy selection. Using SUV-based thresholds to define high-grade portions of disease may be valuable in delineating radiotherapy boost volumes.
doi:10.1093/neuonc/not002
PMCID: PMC3714146  PMID: 23460322
18F-DOPA PET; glioma target delineation; image-guided biopsy planning; image-guided radiation therapy; PET-MRI image registration
9.  Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology 
Brain  2013;136(8):2510-2526.
Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer’s pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer’s pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer’s pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer’s changes (‘mismatches’), and demented Alzheimer’s cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer’s cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species—monomers, dimers and higher molecular weight oligomers—in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer’s pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer’s pathological changes.
doi:10.1093/brain/awt171
PMCID: PMC3722351  PMID: 23824488
Alzheimers disease; amyloid pathology; tau pathology; resilience; astrocytes; microglia
10.  Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA 
Neurology  2013;81(4):337-345.
Objective:
We assessed whether clinical and imaging features of subjects with apraxia of speech (AOS) more severe than aphasia (dominant AOS) are more similar to agrammatic primary progressive aphasia (agPPA) or to primary progressive AOS (PPAOS).
Methods:
Sixty-seven subjects (PPAOS = 18, dominant AOS = 10, agPPA = 9, age-matched controls = 30) who all had volumetric MRI, diffusion tensor imaging, F18-fluorodeoxyglucose and C11-labeled Pittsburgh compound B (PiB)-PET scanning, as well as neurologic and speech and language assessments, were included in this case-control study. AOS was classified as either type 1, predominated by sound distortions and distorted sound substitutions, or type 2, predominated by syllabically segmented prosodic speech patterns.
Results:
The dominant AOS subjects most often had AOS type 2, similar to PPAOS. In contrast, agPPA subjects most often had type 1 (p = 0.01). Both dominant AOS and PPAOS showed focal imaging abnormalities in premotor cortex, whereas agPPA showed widespread involvement affecting premotor, prefrontal, temporal and parietal lobes, caudate, and insula. Only the dominant AOS and PPAOS groups showed midbrain atrophy compared with controls. No differences were observed in PiB binding across all 3 groups, with the majority being PiB negative.
Conclusion:
These results suggest that dominant AOS is more similar to PPAOS than agPPA, with dominant AOS and PPAOS exhibiting a clinically distinguishable subtype of progressive AOS compared with agPPA.
doi:10.1212/WNL.0b013e31829c5ed5
PMCID: PMC3772832  PMID: 23803320
11.  Application of the National Institute on Aging–Alzheimer’s Association AD criteria to ADNI 
Neurology  2013;80(23):2130-2137.
Objective:
We describe the operationalization of the National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroup diagnostic guidelines pertaining to Alzheimer disease (AD) dementia in a large multicenter group of subjects with AD dementia.
Methods:
Subjects with AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with at least 1 amyloid biomarker (n = 211) were included in this report. Biomarker data from CSF Aβ42, amyloid PET, fluorodeoxyglucose-PET, and MRI were examined. The biomarker results were assessed on a per-patient basis and the subject categorization as defined in the NIA-AA workgroup guidelines was determined.
Results:
When using a requirement that subjects have a positive amyloid biomarker and single neuronal injury marker having an AD pattern, 87% (48% for both neuronal injury biomarkers) of the subjects could be categorized as “high probability” for AD. Amyloid status of the combined Pittsburgh compound B–PET and CSF results showed an amyloid-negative rate of 10% in the AD group. In the ADNI AD group, 5 of 92 subjects fit the category “dementia unlikely due to AD” when at least one neuronal injury marker was negative.
Conclusions:
A large proportion of subjects with AD dementia in ADNI may be categorized more definitively as high-probability AD using the proposed biomarker scheme in the NIA-AA criteria. A minority of subjects may be excluded from the diagnosis of AD by using biomarkers in clinically categorized AD subjects. In a well-defined AD dementia population, significant biomarker inconsistency can be seen on a per-patient basis.
doi:10.1212/WNL.0b013e318295d6cf
PMCID: PMC3716359  PMID: 23645596
12.  Distinct regional anatomic and functional correlates of neurodegenerative apraxia of speech and aphasia: an MRI and FDG-PET study 
Brain and language  2013;125(3):245-252.
Progressive apraxia of speech (AOS) can result from neurodegenerative disease and can occur in isolation or in the presence of agrammatic aphasia. We aimed to determine the neuroanatomical and metabolic correlates of progressive AOS and aphasia. Thirty-six prospectively recruited subjects with progressive AOS or agrammatic aphasia, or both, underwent the Western Aphasia Battery (WAB) and Token Test to assess aphasia, an AOS rating scale (ASRS), 3T MRI and 18-F fluorodeoxyglucose (FDG) PET. Correlations between clinical measures and imaging were assessed. The only region that correlated to ASRS was left superior premotor volume. In contrast, WAB and Token Test correlated with hypometabolism and volume of a network of left hemisphere regions, including pars triangularis, pars opercularis, pars orbitalis, middle frontal gyrus, superior temporal gyrus, precentral gyrus and inferior parietal lobe. Progressive agrammatic aphasia and AOS have non-overlapping regional correlations, suggesting that these are dissociable clinical features that have different neuroanatomical underpinnings.
doi:10.1016/j.bandl.2013.02.005
PMCID: PMC3660445  PMID: 23542727
apraxia of speech; aphasia; atrophy; Broca’s area; premotor cortex; hypometabolism
13.  Peptide Carrier-Mediated Non-Covalent Delivery of Unmodified Cisplatin, Methotrexate and Other Agents via Intravenous Route to the Brain 
PLoS ONE  2014;9(5):e97655.
Background
Rapid pre-clinical evaluation of chemotherapeutic agents against brain cancers and other neurological disorders remains largely unattained due to the presence of the blood-brain barrier (BBB), which limits transport of most therapeutic compounds to the brain. A synthetic peptide carrier, K16ApoE, was previously developed that enabled transport of target proteins to the brain by mimicking a ligand-receptor system. The peptide carrier was found to generate transient BBB permeability, which was utilized for non-covalent delivery of cisplatin, methotrexate and other compounds to the brain.
Approach
Brain delivery of the chemotherapeutics and other agents was achieved either by injecting the carrier peptide and the drugs separately or as a mixture, to the femoral vein. A modification of the method comprised injection of K16ApoE pre-mixed with cetuximab, followed by injection of a ‘small-molecule’ drug.
Principal findings
Seven-of-seven different small molecules were successfully delivered to the brain via K16ApoE. Depending on the method, brain uptake with K16ApoE was 0.72–1.1% for cisplatin and 0.58–0.92% for methotrexate (34-50-fold and 54–92 fold greater for cisplatin and methotrexate, respectively, with K16ApoE than without). Visually intense brain-uptake of Evans Blue, Light Green SF and Crocein scarlet was also achieved. Direct intracranial injection of EB show locally restricted distribution of the dye in the brain, whereas K16ApoE-mediated intravenous injection of EB resulted in the distribution of the dye throughout the brain. Experiments with insulin suggest that ligand-receptor signaling intrinsic to the BBB provides a natural means for passive transport of some molecules across the BBB.
Significance
The results suggest that the carrier peptide can non-covalently transport various chemotherapeutic agents to the brain. Thus, the method offers an avenue for pre-clinical evaluation of various small and large therapeutic molecules against brain tumors and other neurological disorders.
doi:10.1371/journal.pone.0097655
PMCID: PMC4029735  PMID: 24847943
14.  Traffic Jam at the Blood Brain Barrier Promotes Greater Accumulation of Alzheimer’s Disease Amyloid-β Proteins in the Cerebral Vasculature 
Molecular pharmaceutics  2013;10(5):1557-1565.
Amyloid-β (Aβ) deposition in the brain vasculature results in cerebral amyloid angiopathy (CAA), which occurs in about 80% of Alzheimer’s disease (AD) patients. While Aβ42 predominates parenchymal amyloid plaques in AD brain, Aβ40 is prevalent in the cerebrovascular amyloid. Dutch mutation of Aβ40 (E22Q) promotes aggressive cerebrovascular accumulation and leads to severe CAA in the mutation carriers; knowledge of how DutchAβ40 drives this process more efficiently than Aβ40 could reveal various pathophysiological events that promote CAA. In this study we have demonstrated that DutchAβ40 show preferential accumulation in the blood-brain-barrier (BBB) endothelial cells due to its inefficient blood-to-brain transcytosis. Consequently, DutchAβ40 establishes a permeation barrier in the BBB endothelium, prevents its own clearance from the brain and promotes the formation of amyloid deposits in the cerebral microvessels. The BBB endothelial accumulation of native Aβ40 is not robust enough to exercise such a significant impact on its brain clearance. Hence, the cerebrovascular accumulation of Aβ40 is slow and may require other co-pathologies to precipitate into CAA. In conclusion, the magnitude of Aβ accumulation in the BBB endothelial cells is a critical factor that promotes CAA; hence, clearing vascular endothelium of Aβ proteins may halt or even reverse CAA.
doi:10.1021/mp300352c
PMCID: PMC3756545  PMID: 23249146
Amyloid beta proteins; blood-brain barrier; cerebral amyloid angiopathy; Alzheimer’s disease; transcytosis
15.  Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration 
Neurology  2014;82(18):1605-1612.
Objective:
To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample.
Methods:
A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A−) and baseline hippocampal volume (N+ or N−). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups.
Results:
At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A−N−), 29 (12%) amyloid negative and neurodegeneration positive (A−N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N−), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+.
Conclusions:
We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging–Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.
doi:10.1212/WNL.0000000000000386
PMCID: PMC4013810  PMID: 24706010
16.  A Hand-Held Beta Imaging Probe for FDG 
Annals of nuclear medicine  2012;27(3):203-208.
Objectives
Advances in radiopharmaceuticals and clinical understanding have escalated the use of intraoperative gamma probes in surgery. However, most probes on the market are non-imaging gamma probes that suffer from the lack of ancillary information of the surveyed tissue area. We have developed a novel, hand-held digital Imaging Beta Probe™ (IBP™) to be used in surgery in conjunction with beta-emitting radiopharmaceuticals such as 18FDG, 131I and 32P for real-time imaging of a surveyed area with higher spatial resolution and sensitivity and greater convenience than existing instruments.
Methods
We describe the design and validation of a hand-held beta probe intended to be used as a visual mapping device to locate and confirm excision of 18FDG-avid primary tumors and metastases in an animal model.
Results
We have demonstrated a device which can generate beta images from 18FDG avid lesions in an animal model.
Conclusions
It is feasible to image beta irradiation in animal models of cancer given 18FDG. This technology may be applied to clinical mapping of tumors and/or their metastases in the operating room. Visual image depiction of malignancy may aid the surgeon in localization and excision of lesions of interest.
doi:10.1007/s12149-012-0672-6
PMCID: PMC3622128  PMID: 23229110
18FDG; PET; 131I; Imaging; Beta Probe
17.  Brain Injury Biomarkers Are Not Dependent on β-amyloid in Normal Elderly 
Annals of neurology  2013;73(4):472-480.
Background
The new criteria for preclinical Alzheimer’s Disease (AD) proposed 3 stages: abnormal levels of β-amyloid (stage 1); stage 1 plus evidence of brain injury (stage 2); and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β-amyloid biomarkers have evidence of brain injury; we labeled them as “suspected non-Alzheimer pathway” (sNAP) group. The characteristics of the sNAP group are poorly understood.
Methods
Using the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain MR, 18fluorodeoxyglucose (FDG) and Pittsburgh compound B (PiB) positron emission tomography (PET) were evaluated with FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity (WMH) volume and number of infarcts. We examined cross-sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.
Results
The sNAP group had a lower proportion (14%) with APOE ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α-synucleinopathy or physical findings of parkinsonism.
Conclusions
Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β-amyloid, were indistinguishable on a variety of imaging markers, clinical features and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β-amyloidosis.
doi:10.1002/ana.23816
PMCID: PMC3660408  PMID: 23424032
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
18.  Multimodal Nanoprobes to target cerebrovascular amyloid in Alzheimer’s disease brain 
Biomaterials  2013;35(6):1967-1976.
Cerebral amyloid angiopathy (CAA) results from the accumulation of Aβ proteins primarily within the media and adventitia of small arteries and capillaries of the cortex and leptomeninges. CAA affects a majority of Alzheimer’s disease (AD) patients and is associated with a rapid decline in cognitive reserve. Unfortunately, there is no pre-mortem diagnosis available for CAA. Furthermore, treatment options are few and relatively ineffective. To combat this issue, we have designed nanovehicles (nanoparticles-IgG4.1) capable of targeting cerebrovascular amyloid (CVA) and serving as early diagnostic and therapeutic agents. These nanovehicles were loaded with Gadolinium (Gd) based (Magnevist®) magnetic resonance imaging contrast agents or single photon emission computed tomography (SPECT) agents, such as 125I. In addition, the nanovehicles carry either anti-inflammatory and anti-amyloidogenic agents such as curcumin or immunosuppressants such as dexamethasone, which were previously shown to reduce cerebrovascular inflammation. Owing to the anti-amyloid antibody (IgG4.1) grafted on the surface, the nanovehicles are capable of specifically targeting CVA deposits. The nanovehicles effectively marginate from the blood flow to the vascular wall as determined by using quartz crystal microbalance with dissipation monitoring (QCM-D) technology. They demonstrate excellent distribution to the brain vasculature and target CVA, thus providing MRI and SPECT contrast specific to the CVA in the brain. In addition, they also display the potential to carry therapeutic agents to reduce cerebrovascular inflammation associated with CAA, which is believed to trigger hemorrhage in CAA patients.
doi:10.1016/j.biomaterials.2013.10.075
PMCID: PMC3970424  PMID: 24331706
Cerebrovascular amyloid (CVA); Brain targeting; Alzheimer’s disease (AD); Nanovehicles; Magnetic resonance imaging (MRI); Single photon emission computed; tomography (SPECT)
19.  Brain β-amyloid load approaches a plateau 
Neurology  2013;80(10):890-896.
Objective:
To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging.
Methods:
Participants, aged 70–92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association.
Results:
Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined—reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5–2.5 is approximately 15 years.
Conclusion:
This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.
doi:10.1212/WNL.0b013e3182840bbe
PMCID: PMC3653215  PMID: 23446680
20.  USING FLUORODEOXYTHYMIDINE TO MONITOR ANTI-EGFR INHIBITOR THERAPY IN SQUAMOUS CELL CARCINOMA XENOGRAFTS 
Head & neck  2008;30(6):790-799.
Background
3′-18F-fluoro-3′-deoxy-fluorothymidine (18F-FLT), a nucleoside analog, could monitor effects of molecularly targeted therapeutics on tumor proliferation.
Methods
We tested whether 18F-FLT positron emission tomography (PET) uptake changes are associated with antitumor effects of erlotinib in A431 xenografts or cetuximab in SCC1 xenografts.
Results
Compared with pretreatment FLT PET scans, 3 days of erlotinib in A431 reduced the standardized uptake value (SUV) by 18%, whereas placebo increased SUV by 1% (p = .005). One week of cetuximab in SCC1 reduced SUV by 62%, whereas placebo reduced SUV by 16% (p = .005). FLT uptake suppression following anti–epidermal growth factor receptor (EGFR) treatment was associated with reduced tumor thymidine kinase-1 (TK1) activity. In vitro TK1 knockdown studies confirmed the importance of TK1 activity on intracellular FLT accumulation suppression.
Conclusions
18F-FLT PET imaging detects tumor responses to EGFR-inhibitors within days of starting therapy. This technique may identify patients likely to benefit from EGFR-inhibitors early in their treatment course.
doi:10.1002/hed.20770
PMCID: PMC3942889  PMID: 18286491
fluorodeoxythymidine (FLT); anti-EGFR inhibitor therapy; squamous cell carcinoma xenografts; cetuximab; erlotinib
21.  Elevated occipital β-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia 
Background
Most subjects with logopenic primary progressive aphasia (lvPPA) have beta-amyloid (Aβ) deposition on Pittsburgh Compound B PET (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement.
Objectives
To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.
Methods
Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line-plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on F18-fluorodeoxyglucose PET, and presence and distribution of microbleeds and white matter hyperintensities (WMH) were assessed.
Results
Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions, and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low.
Conclusions
Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA, and suggest that Aβ influences severity of overall cognitive impairment but not aphasia.
doi:10.1136/jnnp-2013-305628
PMCID: PMC3920541  PMID: 23946416
22.  Selective Worsening of Brain Injury Biomarker Abnormalities in Cognitively Normal Elderly with β-amyloidosis 
JAMA neurology  2013;70(8):10.1001/jamaneurol.2013.182.
Importance
The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer’s disease (AD), but their interaction is poorly understood.
Objective
To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration.
Design
Longitudinal Cohort Study
Setting
Population-based Mayo Clinic Study of Aging.
Participants
191 CN persons (median age 77, range 71–93) in the Mayo Clinic Study of Aging who underwent MR, FDG PET and PiB PET imaging at least twice 15 months apart. Subjects were grouped according to the recommendations of the NIA-AA Preclinical AD criteria, based on the presence of β-amyloidosis, defined as a PiB PET SUVr >1.5, alone (Stage 1) or with brain injury (stage 2+3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of MCI (n=17) and dementia (n=9) patients from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had had comparable imaging and who all had PiB PET SUVr >1.5.
Main Outcome Measures
Rate of change of cortical volume on volumetric MR scans and rate of change of glucose metabolism on FDG PET scans.
Results
There were 25 CN subjects with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (Preclinical AD stages 2+3). On follow-up scans, the Preclinical AD stages 2+3 subjects had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared to other CN groups. The changes were similar to the cognitively impaired participants. Extra-temporal regions did not show similar changes.
Conclusions
Higher rates of medial temporal neurodegeneration occurred in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers.
doi:10.1001/jamaneurol.2013.182
PMCID: PMC3884555  PMID: 23797806
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
23.  The role of LAT1 in 18F-DOPA uptake in malignant gliomas 
Journal of neuro-oncology  2012;111(1):11-18.
Positron emission tomography (PET) imaging with the amino acid tracer 6-18F-fluoro-l-3,4-dihydroxy-phenylalanine (18F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The l-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and 18F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Uptake of 18F-DOPA was approximated in vitro using 3H-l-DOPA as an analog. Uptake of 3H-l-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA and compared to non-targeted (NT) control shRNA or siRNA sequences, respectively. To demonstrate the clinical relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of 18F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of 3H-l-DOPA uptake was positively correlated with endogenous LAT1 expression. Stable shRNA-mediated LAT1 knockdown in T98 and GBM28 reduced 3H-l-DOPA uptake relative to NT shRNA by 57 (P < 0.0001) and 52 % (P < 0.001), respectively. Transient siRNA-mediated LAT1 knockdown in T98 reduced 3H-l-DOPA uptake relative to NT siRNA up to 68 % (P < 0.01). In clinical samples, LAT1 expression positively correlated with 18F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly associated with 3H-l-DOPA uptake in vitro and 18F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of 18F-DOPA accumulation in GBM.
doi:10.1007/s11060-012-0986-1
PMCID: PMC3907171  PMID: 23086431
18F-DOPA PET/CT; Glioma; Glioblastoma; Amino acid transport
24.  Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography 
The cholangiopathies are a diverse group of biliary tract disorders, many of which lack effective treatment. Murine models are an important tool for studying their pathogenesis, but existing noninvasive methods for assessing biliary disease in vivo are not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop a technique for live-mouse cholangiography. Using mdr2 knockout (mdr2KO, a model for primary sclerosing cholangitis (PSC)), bile duct-ligated (BDL), and normal mice, we performed in vivo: (1) microCT on a Siemens Inveon PET/CT scanner and (2) MR on a Bruker Avance 16.4 T spectrometer, using Turbo Rapid Acquisition with Relaxation Enhancement, IntraGate Fast Low Angle Shot, and Half-Fourier Acquisition Single-shot Turbo Spin Echo methods. Anesthesia was with 1.5–2.5% isoflurane. Scans were performed with and without contrast agents (iodipamide meglumine (microCT), gadoxetate disodium (MR)). Dissection and liver histology were performed for validation. With microCT, only the gallbladder and extrahepatic bile ducts were visualized despite attempts to optimize timing, route, and dose of contrast. With MR, the gallbladder, extra-, and intrahepatic bile ducts were well-visualized in mdr2KO mice; the cholangiographic appearance was similar to that of PSC (eg, multifocal strictures) and could be improved with contrast administration. In BDL mice, MR revealed cholangiographically distinct progressive dilation of the biliary tree without ductal irregularity. In normal mice, MR allowed visualization of the gallbladder and extrahepatic ducts, but only marginal visualization of the diminutive intrahepatic ducts. One mouse died during microCT and MR imaging, respectively. Both microCT and MR scans could be obtained in ≤ 20min. We, therefore, demonstrate that MR cholangiography can be a useful tool for longitudinal studies of the biliary tree in live mice, whereas microCT yields suboptimal duct visualization despite requiring contrast administration. These findings support further development and application of MR cholangiography to the study of mouse models of PSC and other cholangiopathies.
doi:10.1038/labinvest.2013.52
PMCID: PMC3875307  PMID: 23588707
animal models; biliary tract diseases; live-animal imaging; magnetic resonance cholangiopancreatography; primary sclerosing cholangitis; strictures
25.  Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity 
Neurology  2013;81(20):1732-1740.
Objective:
To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.
Methods:
Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison.
Results:
Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline.
Conclusions:
The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist.
doi:10.1212/01.wnl.0000435556.21319.e4
PMCID: PMC3821718  PMID: 24132377

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