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

The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid positron emission tomography, and cognition in healthy older control (HC) subjects. Seventy-eight HC subjects were assessed with a brief cognitive test battery and positron emission tomography (PET) imaging with 18F-AV-45. A standard uptake value ratio was computed for mean data from 6 cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive or amyloid negative by 3 readers. Higher standard uptake value ratio correlated with lower immediate memory (r = −0.33; p = 0.003) and delayed recall scores (r = −0.25; p = 0.027). Performance on immediate recall was also lower in the visually rated amyloid positive compared with amyloid negative HC (p = 0.04), with a similar trend observed in delayed recall (p = 0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether 18F-AV-45 may also predict subsequent cognitive decline.

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

Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ-) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog (p0.01) and Clinical Dementia Rating-sum of boxes (CDR-SB) (p0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p0.01), CDR-SB (p0.03), a memory measure, DSS, and MMSE (p0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ- subjects (p0.10).Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.

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; t1 52 1.617, 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 test– retest 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.

The early detection and monitoring of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, dementia with Lewy bodies and other dementias, and movement disorders, represent a significant unmet medical need. Tools for accurate and early differential diagnosis are necessary to determine the appropriate treatment for patients and to minimize inappropriate use of potentially harmful treatments. Such diagnostic imaging tools are expected to permit monitoring of disease progression and will thus accelerate testing and development of disease-modifying drugs. The new imaging tests may be useful as prognostic tools by identifying humans with neurodegenerative diseases before the clinical manifestations become evident.

Metabolic heat rates of small insects which fit in 1 cm 3 ampoules can be measured readily using the Calorimetry Sciences Corporation 4100 DSC in the isothermal mode. The rapid thermal equilibration of the calorimeter on changing to a new isothermal temperature also permits the response of the metabolism to change in temperature to be determined quickly. By modifying the ampoules and measuring chamber lid for entry of silica capillaries to allow the headspace in the ampoules to be changed in situ, direct comparison can be made of metabolic heat rates in air and in controlled atmospheres. These results aid in assessing the effectiveness of controlled atmospheres, such as low oxygen and/or high carbon dioxide, as potential replacements of methyl bromide for fumigation of fresh produce. For a range of insects tested, including larval, pupal and adult stages, metabolic heat rates decrease to very close to zero under anoxic conditions. By analysis of the headspace of an ampoule containing an insect using ms, changes in metabolic heat rate can be related directly to compositional changes in the headspace, including those resulting from the insect’s metabolism. Important factors in the application of mass spectrometry to the more difficult task of measuring rates of oxygen consumption and carbon dioxide production associated with a metabolic heat rate are discussed.

Objective To evaluate the performance characteristics of florbetapir F18 positron emission tomography (PET) in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy control subjects (HCs). Methods Florbetapir PET was acquired in 184 subjects (45 AD patients, 60 MCI patients, and 79 HCs) within a multicenter phase 2 study. Amyloid burden was assessed visually and quantitatively, and was classified as positive or negative. Results Florbetapir PET was rated visually amyloid positive in 76% of AD patients, 38% of MCI patients, and 14% of HCs. Eighty-four percent of AD patients, 45% of MCI patients, and 23% of HCs were classified as amyloid positive using a quantitative threshold. Amyloid positivity and mean cortical amyloid burden were associated with age and apolipoprotein E e4 carrier status. Conclusions: The data are consistent with expected rates of amyloid positivity among individuals with clinical diagnoses of AD and MCI, and indicate the potential value of florbetapir F18 PET as an adjunct to clinical diagnosis.

Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD).Florbetapir F18 PET images were analyzed from 245 participants, 18-92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups.In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3-63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers.Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers.

We have developed a novel F-18 prosthetic ligand named fluoro-PEG-benzaldehyde (FPBA) 1 . [ 18 F]-FPBA 1 is formed in situ from its radiolabeled precursor [ 18 F] 6 . Compound 6 is efficiently synthesized in four steps starting from commercially available 6-bromo-3-pyridine carbaldehyde 2 . [ 18 F]-FPBA was evaluated as a prosthetic ligand to radiolabel three cyclic peptides bearing an aminooxy functional group at the N-terminus position. Acetal [ 18 F] 6 is purified by either solid-phase extraction (SPE) or reverse-phase HPLC with the overall radiochemical yields (RCY) and radiochemical purity (RCP) in very close agreement. The SPE purification process has the advantage of shorter reaction times (71–87 min for entire reaction sequence), while the use of the reverse-phase HPLC purification process allows the use of up to fifty times less of the expensive synthetic peptides (∼50 nmol) in the oxime coupling reaction. We have demonstrated an efficient methodology in the production of [ 18 F]-FPBA 1 and demonstrated its use as a prosthetic ligand for the labeling of peptides possessing an aminooxy functional group.

Paratya curvirostris (Heller, 1862) (Decapoda: Atyidae) is the first member of its family found to be protandrous. Reappraisal of published information on Atya bisulcata, Atya serrata and Caridina richtersi indicates that they are also protandrous. The occurrence and biology of protandry in the Decapoda is reviewed. Analysis of available data suggests that protandry has no adaptive value and its frequency in these Crus:tacea is a result of the ease with which decapod reproductive physiology can be modified to produce the phenomenon.

Using a 200 g per litre solution of magnesium sulphate (specific gravity 1.08) in a metal cylinder it is possible to sample porina eggs cheaply and efficiently in pasture by direct flotation. When a known number of eggs were spread on a given area of pasture and then sampled, 60–80% recovery was achieved. This efficiency was not affected by the time interval between flotation and counting the eggs, but it did decline linearly with time elapsed between egg deposition and sampling.

The life history of the endemic New Zealand freshwater shrimp Paratya curvirostris (Heller, 1862) (Decapoda: Atyidae) in 3 streams in North Canterbury is described. Each female carried on average 2000(±634) eggs and incubation took about 28 days at 14–18°C. Mixohaline planktonic larvae were found in the Ashley Estuary and in small numbers in fresh water. Post‐larvae had a carapace length of 0.5–1.5 mm, and most developed into males which occurred in freshwater streams. At a carapace length of 5.0–6.0 mm males developed into females which could be ovigerous at any time of year and could bear several successive broods. Estimated growth rate was greatest from late winter to early summer with a maximum weekly rate of 1.5 mm carapace length calculated in spring. The behaviour of a female during egg hatching is described in detail.

Fourteen different synthetic engine sounds were mixed with five different synthetic cavitation sounds at realistically difficult signal‐to noise ratios. Eighty one Royal Navy ratings, divided into eight training groups, were asked to identify the 14 engine sounds. Training procedures were varied among groups to answer some questions pertinent for programming a teaching machine. It was found that (1) verbal descriptions of the actual physical characteristics of the sounds give better results than those supplied by experienced listeners, (2) the order in which training items are presented is important. The most useful order involved changing one relevant quality per item, (3) “good” high engine‐to‐cavitation ratio) recordings may be an advantage if alternated with realistically “bad” ones, (4) feedback (knowledge‐of‐results) procedures should be concentrated more at the end of a training program and recordings should be extended temporally to overlap with the feedback, (5) a large population of engine noises is desirable for but probably not essential to, a good program.

Naval ratings were given the task of identifying the sounds of three lorry diesel engines at running speeds of 1000, 2000 and 3000 rev/min. The physical signal was varied by adding thermal noise and by multiplying all frequencies by factors of 1, 2, 4 and 8. The experimental variables were knowledge of results, amount of cueing, and the meaningfulness of the identifying names. Meaningfulness consisted either of code names or of the real names plus a description of the physical characteristics of the engine. Where real names were in use, identification was more accurate even with frequency multiplication. Engine types were identified better than engine rev/min. The accuracy of engine identification decreased as the noise masking increased and as the frequency multiplications changed from × 1 to ×2 to ×8 to ×4. However, when noise masking was absent, engine identification at the ×8 speedup yielded scores equal to ×1 and ×2. The rev/min identifications were all equivalent except at ×4 in noise, which always gave the lowest score.

Experiments are described which suggest that, for human perception, the information concerning the location of a formantlike complex sound is contained in the two most prominent harmonics. This result is limited to the condition where adjacent harmonics are more widely separated than the width of a critical band.

Five vowel sounds, each produced in five different ways, were presented to subjects with widely differing experience of tasks of this type for identification. The vowels were the last five of the standard set of eight cardinal vowels, and were presented to subjects with no experience of phonetics as belonging to the words bat, bart, bought, boat and boot. Each vowel was (a) spoken by a phonetician, (b) synthesized by adding individual harmonics in direct imitation of the spoken sounds, (c) represented by two pure tone components only, (d) synthesized by a talking machine (P.A.T.) and (e) imitated by selecting harmonics with a low-pass filter. All these sounds were categorised more or less “correctly” by skilled subjects; and, although there were wide and systematic differences in accuracy with untrained subjects, these performed consistently better than chance. The experiment showed (a) that the selection of harmonics according to formant theory is not the only, and perhaps not always the best means of synthesizing isolated vowels, (b) that even sounds which are poor representations of vowels can still be categorised with some consistency even by untrained subjects and (c) that a simple “percent correct” score is less sensitive than other measures.

An experiment is described in which synthetic sounds were identified by untrained subjects as vowels. The sounds were constructed by adding together harmonics selected from a buzz source in the same relative amplitudes as were found in corresponding natural vowels. This work is the first step in an attempt to identify those qualities of a complex sound which determine its perception as a particular vowel, irrespective of theories based upon the mechanism by which speech sounds are produced.

Complex sounds were manufactured by passing the output of a buzz source through band-pass filter networks. The resulting stimuli were played both to phoneticians and to phonetically naive subjects who were asked to judge the vowel colour of the sounds. The responses showed that complex sounds are categorised consistently with regard to their vowel colour in spite of the absence of formant peaks. The following additional conclusions can be drawn: (1) The judgement of vowel colour is relatively unaffected by such features of the stimulus as variability in length between 300 and 700 msec. and the temporal qualities of the on-off transitions. (2) Vowel sounds of the back group can be simulated with a low-pass filter; and increasing the cut-off frequency shifts judgement in the direction from “high” to “low”, i.e. from /u/ to /α/, and then /a/.

Series of buzz tones with up to 24 harmonics were presented to five groups of listeners for identification. Nine tones in which different harmonics were emphasized were presented to Group I who could easily tell them apart and could identify them with 33% accuracy. The remaining groups heard three of the tones in various conditions of noise, filtering, fundamental frequency, and emphasized to nonemphasized harmonic intensity differentials. The most difficult task was to identify the tones with differing harmonic structure when the fundamental frequency was not the same for every complex tone. It was also difficult to pick out complexes with the same harmonic structure and basic frequency when noise‐masked, filtered, and in‐quiet items were intermixed at random in the same test. The distinguishing differences in the meaningless buzz complexes were in harmonics six and above.

Four adult specimens of the pycnogonid Ammothea magniceps were observed swimming at the sea surface at night at Kaikoura. Even after capture the animals continued to swim at the surface of the water for over an hour. Such swimming behaviour is considered important in explaining the presence of “benthic” animals in plankton samples.

The aim of this study was to determine the relative importance of source parameters (fundamental frequency and waveform) versus formant parameters (resonant frequency and number) in identifying meaningless complex sounds. Sixteen sounds were generated differing on four dimensions, each having two values. These were the source waveform, containing either all harmonics or odd harmonics only; the fundamental frequency, either 90 or 142 Hz, ratio=1.6; the number of formants, one or two; and the frequency of the formant(s) either low (600 Hz, or 600 and 1550 Hz) or high (940 Hz, or 940 and 2440 Hz) high/low ratio = 1.6. Twenty‐four listeners were trained to identify these sounds. The results show that fewer confusions were made between pairs of sounds (1) as the number of dimensions on which they differed increased, and (2) as the dimension (single or in combination) changed, from formant number to formant frequency region, to fundamental frequency, to source waveform. Listeners appear to make a generalized classification along a single dimension which seems to vary systematically with waveform complexity and periodicity.

Background Florbetapir is one of several 18F-labeled amyloid plaque imaging tracers for positron emission tomography (PET). As the bio-distribution and radiation dose of PET tracers in human research are important for estimating the relative risks and benefits, a study was conducted to obtain this information on florbetapir. Methods Nine cognitively normal subjects (six females and three males, age 58 ± 10 years, weight 81 ± 17 kg) received an intravenous bolus injection of 395 ± 27.9 MBq of florbetapir, and whole-body emission scans were performed over approximately 6 h. Computed tomography scans were acquired for attenuation correction. Volumes of interest (VOIs) for source organs including the brain, liver, lung, heart wall, and vertebrae were defined on the PET images. The VOIs of the gallbladder, urinary bladder, and large and small intestines were also defined. Using reference man organ volumes (ICRP 30), total activity was calculated per organ for each time point. The resultant time-activity curves (TACs) were fitted with constrained exponentials. Kinetic data were entered into OLINDA/EXM software to calculate dose estimates; the dynamic urinary bladder and ICRP 30 GI tract models were employed. The effective dose (ED) for each subject was estimated from the acquired data using the adult model. Results The mean ED determined for nine healthy volunteers was 18.60 ± 4.26 μSv/MBq or 6.88 mSv for a 370-MBq dose. The organs that received the highest radiation absorbed doses were the gallbladder, upper large intestine, small intestine, liver, and urinary bladder at 143.0 ± 80.20, 74.50 ± 34.20, 65.50 ± 29.60, 64.40 ± 22.10, and 27.10 ± 11.70 μSv/MBq, respectively. Conclusions The ED for florbetapir has been calculated for nine healthy volunteers. At a dose of 370 MBq florbetapir, the total average ED is approximately 6.88 mSv.