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1.  Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease 
Neurology  2011;77(1):39-47.
Objective:
This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD).
Methods:
Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1–42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging–Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage.
Results:
Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology.
Conclusions:
Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
doi:10.1212/WNL.0b013e3182231419
PMCID: PMC3127332  PMID: 21700583
2.  Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB 
Neurology  2010;74(10):807-815.
Objective:
To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Aβ) deposition in vivo in individuals without dementia.
Method:
[11C]PiB images were obtained to measure fibrillar Aβ burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [11C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations.
Results:
[11C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions.
Conclusions:
Higher Aβ deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Aβ deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.
GLOSSARY
= Alzheimer disease;
= Baltimore Longitudinal Study of Aging;
= Benton Visual Retention Test;
= Clinical Dementia Rating;
= California Verbal Learning Test;
= distribution volume ratio;
= mild cognitive impairment;
= Mini-Mental State Examination;
= regions of interest.
doi:10.1212/WNL.0b013e3181d3e3e9
PMCID: PMC2839197  PMID: 20147655
3.  Quantitative In Vivo Magnetic Resonance Spectroscopy Using Synthetic Signal Injection 
PLoS ONE  2010;5(12):e15166.
Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment.
doi:10.1371/journal.pone.0015166
PMCID: PMC3010995  PMID: 21203385
4.  Relationships between biomarkers in aging and dementia 
Neurology  2009;73(15):1193-1199.
Background:
PET imaging using [18F]fluorodeoxyglucose (FDG) and [11C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid β-amyloid protein (Aβ1-42) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.
Methods:
Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Aβ1-42, t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as “positive” or “negative” for AD based on cutoffs established in patients with AD and controls from other cohorts.
Results:
Dichotomous categorization showed substantial agreement between PIB-PET and CSF Aβ1-42 measures (91% agreement, κ = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, κ = 0.50), and minimal agreement for other comparisons (κ <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Aβ1-42. Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Aβ1-42, t-tau, and p-tau181p, whereas FDG-PET was correlated only with Aβ1-42.
Conclusions:
PET and CSF biomarkers of Aβ agree with one another but are not related to cognitive impairment. [18F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.
GLOSSARY
β1-42 = 42 amino acid β-amyloid protein;
= Alzheimer disease;
= Alzheimer’s Disease Neuroimaging Initiative;
= Clinical Dementia Rating;
= confidence interval;
= [18F]fluorodeoxyglucose;
= mild cognitive impairment;
= Mini-Mental State Examination;
= magnetic resonance;
= [11C]Pittsburgh compound B;
= phosphorylated tau;
= receiver operating characteristic;
= region of interest;
= standardized uptake value ratio;
= total tau;
= Wechsler Memory Scale–Revised.
doi:10.1212/WNL.0b013e3181bc010c
PMCID: PMC2764726  PMID: 19822868
5.  Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia 
Aim
To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson's disease (PD) and parkinsonian dementia (PDem).
Methods
Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [11C]methyl‐4‐piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD).
Results
Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = −0.5, p = 0.007. This correlation remained significant after controlling for Mini‐Mental State Examination scores.
Conclusion
Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.
doi:10.1136/jnnp.2006.100073
PMCID: PMC2077949  PMID: 17507447
6.  Episodic memory loss is related to hippocampal-mediated β-amyloid deposition in elderly subjects 
Brain  2008;132(5):1310-1323.
Although β-amyloid (Aβ) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via ‘Pittsburgh Compound-B’ (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Aβ and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Aβ deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Aβ deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Aβ-induced hippocampus atrophy.
doi:10.1093/brain/awn320
PMCID: PMC2677792  PMID: 19042931
Pittsburgh Compound-B; magnetic resonance imaging; β-amyloid; hippocampus; preclinical Alzheimer's disease
7.  Anti-Amyloid Effects of Small Molecule Aβ-Binding Agents in PS1/APP Mice 
Aims
One promising approach for treatment of Alzheimer’s disease (AD) is use of anti-amyloid therapies, based on the hypothesis that increases in amyloid-beta (Aβ) deposits in brain are a major cause of AD. Several groups have focused on Aβ immunotherapy with some success. Small molecules derivatives of Congo red have been shown to inhibit Aβ aggregation and protect against Aβ neurotoxicity in vitro. The agents described here are all small molecule Aβ-binding agents (SMAβBA’s) derivatives of Congo red.
Main Methods
Here, we have explored the anti-amyloid properties of these SMAβBA’s in mice doubly transgenic for human prensenilin-1 (PS1) and APP gene mutations that cause early-onset AD. Mice were treated with either methoxy-X04, X:EE:B34 and X:034-3-OMe1. After treatment, brains were examined for Aβ-deposition, using histochemistry, and soluble and insoluble Aβ levels were determined using ELISA.
Key Findings
A range of anti-amyloid activity was observed with these three compounds. PS1/APP mice treated with methoxy-X04 and X:EE:B34 showed decrease in total Aβ load, a decrease in Aβ fibril load, and a decrease in average plaque size. Treatment with methoxy-X04 also resulted in a decrease in insoluble Aβ levels. The structurally similar compound, X:034:3-OMe1, showed no significant effect on any of these measures. The effectiveness of the SMAβBA’s may be related to a combination of binding affinity for Aβ and entry into brain, but other factors appear to apply as well.
Significance
These data suggest that SMAβBA’s may significantly decrease amyloid burden in brain during the pathogenesis of AD and could be useful therapeutics alone, or in combination with immunotherapy.
doi:10.2174/157018009789057526
PMCID: PMC2812908  PMID: 20119496
Alzheimer’s Disease; amyloid β; Congo Red; Methoxy-X04; transgenic mice
8.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
9.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
10.  Impact of Amyloid Imaging on Drug Development in Alzheimer’s Disease 
Nuclear medicine and biology  2007;34(7):809-822.
Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer’s disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([11C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.
doi:10.1016/j.nucmedbio.2007.06.015
PMCID: PMC2078205  PMID: 17921032
Amyloid imaging; amyloid-beta; Aβ; PiB; Alzheimer’s disease; anti-amyloid therapy
11.  Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease 
Objectives: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy.
Methods: Cognitive and N-[11C]methyl-piperidin-4-yl propionate ([11C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy.
Results: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = –7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = –14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R2 = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = –2.7; p<0.05).
Conclusions: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.
doi:10.1136/jnnp.2004.038729
PMCID: PMC1739536  PMID: 15716518
12.  "Bone bruises" of the knee: a review. 
The Iowa Orthopaedic Journal  1998;18:112-117.
Magnetic resonance (MR) imaging is often used to assess the location and degree of ligamentous or cartilage damage in the knee following acute traumatic injury. Occasionally, these studies will also document abnormal signal within the adjacent subchondral bone. These "bone bruises" are considered incidental findings by some, while others suggest possible clinical significance. The purpose of this paper is to review the literature and consolidate current thinking on the radiographic characteristics, classification, histopathology and natural history of bone bruises.
Images
PMCID: PMC2378166  PMID: 9807716
13.  Food and water intake as functions of resource consumption costs in a closed economy. 
In two experiments, rats living in a closed economy were offered continuous, concurrent access to four resources: food, water, a nest, and a running wheel. Costs of consuming food and water were imposed with bar-press requirements, and the price of either one or both resources was raised. As the consumption cost increased, less was consumed in each bout of resource use. Bout frequency increased, but not sufficiently to compensate for the fall in bout size, and total intake fell. Food and water tended to be complementary resources, in that as intake of one fell with its price, intake of the other also decreased. This interaction was accounted for by the defense of the ratio of body water to lean body mass. As amount consumed decreased, increases in feed efficiency (weight gain per unit of food ingested) and the use of stored calories compensated for the reduced energy intake. There was evidence of competition between feeding and drinking at the higher costs: When both commodities were expensive, the decline in the intake of each one was greater than when only one commodity was expensive. Although the time spent nesting, running, and in unmonitored activity was adjusted when feeding or drinking took more of the rat's day, there was no particular activity that was sacrificed.
doi:10.1901/jeab.1996.65-527
PMCID: PMC1349950  PMID: 8636661
14.  Procurement time as a determinant of meal frequency and meal duration. 
Foraging involves the expenditure of both time and effort in the acquisition of food; animals typically modify their meal patterns so as to reduce these expenditures or costs. The contribution of time, as compared with effort, to the overall cost perceived by an animal is not known. We investigated the effect of foraging time as a cost independent of effort by measuring the meal patterns of rats living in a laboratory foraging simulation in which they earned all their daily intake. They pressed a bar once to initiate an interval (procurement interval) leading to the presentation of a large cup of food from which they could eat a meal of any size. As the length of the interval increased from 1 s to 46 hr, meal frequency decreased regularly. Meal size increased in a compensatory fashion, and total daily intake was conserved through an interval of 23 hr. The changes in meal frequency occurred because of changes in the rat's latency to bar press after each meal. The functions relating meal frequency and size to the procurement interval were of the same shape as those seen when cost is the completion of a bar-press requirement, which entails the expenditure of both effort and time. When the bar-press requirement was increased to 10, meal frequency was reduced, but time and effort did not appear to simply add together in the rat's perception of cost. These data reveal that time is preceived to be a cost by rats foraging in this laboratory environment. These results suggest that the time parameters of foraging are different from those of consumption.
doi:10.1901/jeab.1995.63-295
PMCID: PMC1334447  PMID: 7751834
15.  Drinking in a patchy environment: the effect of the price of water. 
Rats in a laboratory foraging paradigm searched for sequential opportunities to drink in two water patches that differed in the bar-press price of each "sip" (20 licks) of water within a bout of drinking (Experiment 1) or the price and size (10, 20, or 40 licks) of each sip (Experiment 2). Total daily water intake was not affected by these variables. The rats responded faster at the patch where water was more costly. However, they accepted fewer opportunities to drink, and thus had fewer drinking bouts, and drinking bouts were smaller at the more costly patch than at the other patch. This resulted in the rats consuming a smaller proportion of their daily water from the more costly patch. The size of the differences in bout frequency and size between the patches appears to be based on the relative cost of water at the patches. The profitability of each patch was calculated in terms of the return (in milliliters) on either effort (bar presses) or time spent there. Although both measures were correlated with the relative total intake, bout size, and acceptance of opportunities at each patch, the time-based profitability was the better predictor of these intake measures. The rats did not minimize bar-press output; however, their choice between the patches and their bout sizes within patches varied in a way that reduced costs compared to what would have been expended drinking randomly. These data accord well with similar findings for choices among patches of food, suggesting that foraging for water and food occurs on the basis of comparable benefit-cost functions: In each case, the amount consumed is related to the time spent consuming.
doi:10.1901/jeab.1994.62-169
PMCID: PMC1334456  PMID: 7964364

Results 1-15 (15)