Clinical validation of 18F-AZD4694, an amyloid-ß-specific PET radioligand.

UNLABELLED: Pioneered with the invention of (11)C-Pittsburgh compound B, amyloid-ß imaging using PET has facilitated research in Alzheimer disease (AD). This imaging approach has promise for diagnostic purposes and evaluation of disease-modifying therapies. Broad clinical use requires an (18)F-labeled amyloid-ß radioligand with high specific and low nonspecific binding. The aim of the present PET study was to examine the radioligand (18)F-AZD4694 in human subjects. METHODS: Six control subjects and 10 clinically diagnosed AD patients underwent PET examination with (18)F-AZD4694 and a structural MRI scan. Of these, 4 controls and 4 patients underwent a second PET examination for test-retest analysis. Arterial sampling was done to derive a metabolite-corrected plasma input function for traditional compartment modeling. Besides, several simplified quantitative approaches were applied, including the reference Logan approach and simple ratio methods. RESULTS: After intravenous injection of (18)F-AZD4694, radioactivity appeared rapidly in brain. In patients, radioactivity was high in regions expected to contain amyloid-ß, whereas in controls, radioactivity was low and homogenously distributed. Binding in cerebellum, a reference region, was low and similar between the groups. Specific binding was reversible and peaked at about 27 min after injection in regions with high radioactivity. The time-activity curves could be described using the 2-tissue-compartment model. Distribution volume ratio estimates obtained using compartment models and simplified methods were highly correlated. Standardized uptake value ratios calculated at late times and distribution volume ratios estimated with the reference Logan approach were, in gray matter, significantly lower in control subjects (1.08 [11%] and 1.01 [6%], respectively) than in AD patients (2.15 [24%] and 1.62 [18%], respectively). Among noninvasive methods, the lowest test-retest variability was found with reference Logan, varying between 4% and 6% across brain regions. CONCLUSION: Noninvasive quantitative approaches provide valid estimates of amyloid-ß binding. Because of the radioisotope ((18)F) used for labeling, the radioligand has potential for wide clinical application. (18)F-AZD4694 satisfies the requirements for a promising amyloid-ß radioligand both for diagnostic use and for evaluation of disease-modifying therapies in AD.

CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.

CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184.

PURPOSE: Current positron emission tomography (PET) radioligands for detection of Abeta amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [(11)C]AZD2184 and report here the first clinical evaluation. METHODS: Eight AD patients and four younger control subjects underwent 93-min PET measurements with [(11)C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. RESULTS: Brain uptake of [(11)C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. CONCLUSION: [(11)C]AZD2184 is a promising radioligand for detailed mapping of Abeta amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.

Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study.

BACKGROUND: Dietary fish or fish oil rich in n-3 fatty acids (n-3 FAs), eg, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms. Whereas most studies have explored the effects of predominantly EPA-based n-3 FAs preparations, few have addressed the effects of n-3 FAs preparations with DHA as the main FA. OBJECTIVE: The objective was to determine the effects of 6 mo of dietary supplementation with an n-3 FAs preparation rich in DHA on release of cytokines and growth factors from peripheral blood mononuclear cells (PBMCs). DESIGN: In a randomized, double-blind, placebo-controlled trial, 174 Alzheimer disease (AD) patients received daily either 1.7 g DHA and 0.6 g EPA (n-3 FAs group) or placebo for 6 mo. In the present study blood samples were obtained from the 23 first randomized patients, and PBMCs were isolated before and after 6 mo of treatment. RESULTS: Plasma concentrations of DHA and EPA were significantly increased at 6 mo in the n-3 FAs group. This group also showed significant decreases of interleukin (IL)-6, IL-1beta, and granulocyte colony-stimulating factor secretion after stimulation of PBMCs with lipopolysaccharide. Changes in the DHA and EPA concentrations were negatively associated with changes in IL-1beta and IL-6 release for all subjects. Reductions of IL-1beta and IL-6 were also significantly correlated with each other. In contrast, this n-3 FA treatment for 6 mo did not decrease tumor necrosis factor-alpha, IotaL-8, IL-10, and granulocyte-macrophage colony-stimulating factor secretion. CONCLUSION: AD patients treated with DHA-rich n-3 FAs supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1beta, IL-6, and granulocyte colony-stimulating factor from PBMCs. This trial was registered at clinicaltrials.gov as NCT00211159.

The older patient's experience of encountering professional carers and close relatives during an acute confusional state: an interview study.

BACKGROUND: Acute confusional state (ACS) is a common and difficult condition among older patients with a variety of opinions about how to act when encountering patients with ACS. Few studies to our knowledge have been found exploring the encounter from the perspective of older patients and their experiences. OBJECTIVES: The aim of this study was to understand the experiences of older patients with ACS when encountering professional carers and close relatives. DESIGN: In order to understand older patients' experiences of encounters during their ACS a latent qualitative content analysis was used. SETTINGS: The data collection took place at two geriatric wards in an emergency hospital in a metropolitan area. PARTICIPANTS: The inclusion criteria included being aged 65 years or older and having suffered from ACS, according to the DSM-IV criteria, and having regained lucidity. Participants were being cared for at one of two geriatric wards. Patients diagnosed with dementia were excluded. About 150 patients were screened, 67 patients fulfilled the inclusion criteria and seven patients were included in the study, four females and three males, aged between 78 and 98 years. METHODS: Data were collected by interviews. RESULTS: Three themes were found, namely; 'Feeling lonely within the perceived reality of ACS', with three sub-themes: the unequal encounter, keeping a distance and being an outsider; 'striving towards understanding' with two sub-themes: searching for answers and it takes time to understand; and 'feelings of participation in the encounter' with two sub-themes: a mutual understanding and feeling safe and supported. CONCLUSIONS: Within the encounter the older patients with ACS are searching for answers to what is happening and why. The patients feel dependent on the persons they encounter and their willingness to understand and communicate. The patients also feel lonely, unnecessarily questioned and untrustworthy; but they can also feel safe, trusted and understood.

Encountering the older confused patient: professional carers' experiences.

UNLABELLED: THE STUDY'S RATIONALE: Confusion is a common condition among older patients and often a fearful experience. Opinions vary as to how to communicate with and care for confused patients and professional carers often find the patients' situation almost as distressing as the patients' themselves do. AIMS AND OBJECTIVES: The aim of this study was to describe professional carers' experiences of their encounters with older confused patients. METHODOLOGICAL DESIGN AND JUSTIFICATION: Data was collected from interviews with 10 professional carers working on a ward specializing in the care of older confused patients. A descriptive phenomenological research approach was used to gather knowledge of professional carers' experiences of encounters with older confused patients. ETHICAL ISSUES AND APPROVAL: A Regional Board of Research Ethics granted ethical permission for the study. The appropriate ethical principles were followed. The participants were contacted personally and received a letter providing information on the study. Written consent was requested before the interview. If needed, the participants were able to get in contact with the staff health service for a follow-up after the interview. Names or places have been changed in order to ensure confidentiality. RESULTS: The encounter with the confused patient is experienced as an encounter with an unfamiliar person, where the patients' actions and words are unforeseeable and with a lack of immediate trust. The essential meaning is further illuminated by the meaning constituents: the unforeseeable encounter, always being on guard and using oneself as a tool. RELEVANCE TO CLINICAL PRACTICE: This paper focuses on the importance of encouraging professional carers to pay attention to the complexity of the encounter with the confused patient, reflecting upon their own behaviour within these encounters and the importance of knowledge of the patient's preferred senses and life stories. Caring for confused patients involves a great responsibility where both the professional carers and the patients are vulnerable and exposed.

Patient- and proxy-reported utility in Alzheimer disease using the EuroQoL.

This study aims to compare patient- and proxy-rated utilities and health-related quality of life from individuals in different stages of Alzheimer disease (AD). Two hundred seventy-two patients and their primary caregivers were enrolled in a prospective observational study and underwent three consecutive interviews, 6 months apart. Average Mini-Mental State Examination (MMSE) scores were 19.3, 18.0, and 16.4 at the three interviews; scores ranged from 0 to 30. Using the EuroQoL EQ-5D instrument, patient-rated health utilities were on average 0.833 with little variation across MMSE-based severity levels. Proxy-rated health utilities were 0.69 (MMSE >25), 0.64 (MMSE 21-25), 0.50 (MMSE 15-20), 0.49 (MMSE 10-14), and 0.33 (MMSE <10). Proxy-rated utilities, as well as changes in utilities over time, were significantly related to MMSE scores and inversely related to scores on a brief version of the neuropsychiatric inventory (NPI) and institutionalization. Utilities were highly correlated with the disease-specific quality of life instrument QoL-AD. The study shows that the EuroQoL can be used to rate utilities in Alzheimer disease, but there are important differences between patient- and proxy-ratings.

Determination of isoprostanes in urine samples from Alzheimer patients using porous graphitic carbon liquid chromatography-tandem mass spectrometry.

F2-isoprostanes (F2-iPs) comprise four classes of isomers produced non-enzymatically by free radical attack on arachidonic acid, a component of the cell membrane. This paper describes a new method for the quantification of F2-isoprostanes in urine samples from thoroughly diagnosed Alzheimer's disease (AD) patients. The sample pretreatment consisted of liquid extraction of 900 microl urine with diethyl ether, its subsequent evaporation, and finally, reconstitution in 50 microl water. Of this, 20 microl was injected into a HPLC system with a 15 mm x 1 mm porous graphitic carbon column coupled to a triple quadrupole mass spectrometer running in negative electrospray ionization mode. The F2-isoprostanes were separated in 15 min using a linear solvent gradient comprising water, methanol, acetonitrile and ammonium hydroxide at a pH of 9.5. The average recovery obtained was approximately 75%. The limit of detection (3S/N) was calculated for iPF2alpha-III to be 0.7 pg injected on column, corresponding to 0.1 nM. The average level of iPF2alpha was 241 +/- 163 pg/mg creatinine in the urine samples from AD patients (average +/- standard deviation). The corresponding control values were 216 +/- 101 pg/mg creatinine, i.e. no statistically significant difference was noticed. No correlation pattern specific to Alzheimer's disease was revealed by principal component analysis of the isoprostane peaks obtained either. The results from this study support earlier findings that levels of peripheral isoprostanes are not increased in patients with Alzheimer's disease.

Mild cognitive impairment: experience from a memory clinic.

Mild cognitive impairment (MCI) is sometimes a transition between normal aging and dementia. We investigated the occurrence of MCI in a population referred to a memory clinic. The criteria used to diagnose the state were similar to those used by Petersen et al. in many previous publications. A clinical evaluation after approximately 3 years was also performed. In a subsample of 43 subjects, we found that, during 1 year, 37% (136/402) of all investigated subjects were patients with MCI. After a mean follow-up time of 3 years, 11% (5/43) showed cognitive improvement, while 53% (23/43) were stable and showed no cognitive decline or improvement. Fifteen out of 42 patients (35%) deteriorated and were diagnosed as demented during the same time. We conclude that MCI is a heterogeneous concept and that the outcome at follow-up is dependent on which population is studied and how MCI has been defined.