High Contrast PET Imaging of Subcortical and Allocortical Amyloid-ß in Early Alzheimer's Disease Using [11C]AZD2184.

Background: Deposits of amyloid-ß (Aß) appear early in Alzheimer's disease (AD). Objective: The aim of the present study was to compare the presence of cortical and subcortical Aß in early AD using positron emission tomography (PET). Methods: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184. A data driven cut-point for Aß positivity was defined by Gaussian mixture model of isocortex binding potential (BPND) values. Results: Sixteen subjects (3 CU, 5 MCI and 8 AD) were Aß-positive. BPND was lower in subcortical and allocortical regions compared to isocortex. Fifteen of the 16 Aß-positive subjects displayed Aß binding in striatum, 14 in thalamus and 10 in allocortical regions. Conclusions: Aß deposits appear to be widespread in early AD. It cannot be excluded that deposits appear simultaneously throughout the whole brain which has implications for improved diagnostics and disease monitoring.

Decreased 5-HT1A binding in mild Alzheimer's disease-A positron emission tomography study.

Decreased 5-HT1A receptor binding has been associated with Alzheimer's disease (AD) and interpreted as a consequence of neuron loss. The purpose of the present study was to compare [11 C]WAY100635 binding to the 5-HT1A receptor in the hippocampus, entorhinal cortex, amygdala and pericalcarine cortex in mild AD patients and elderly controls. AD patients (n = 7) and elderly control subjects (n = 8) were examined with positron emission tomography (PET) and [11 C]WAY100635. PET data acquisition was performed with an ECAT EXACT HR system. Wavelet-aided parametric images of nondisplaceable binding potential (BPND ) were generated using Logan's graphical analysis with cerebellum as the reference region. Correction for partial volume effects was performed with the Müller-Gärtner method. Regions of interest (ROIs) were applied to the individual parametric images, and the regional BPND was calculated as the average parametric voxel value within each ROI. In addition to comparisons between subject groups, correlations between BPND values and scores on the Mini-Mental State Examination, Disability Assessment for Dementia (DAD), and Neuropsychiatric Inventory were expressed by Pearson correlation coefficients. Mean regional BPND was lower in AD patients than in control subjects, and the difference was statistically significant for the hippocampus, entorhinal cortex, and amygdala. A statistically significant correlation was obtained between hippocampal BPND values and DAD scores. The results of the present study corroborate and extend previous findings of decreased 5-HT1A binding in AD and strengthen the support for 5-HT1A receptor PET as a tool for the assessment of neurodegenerative changes in mild AD.

High Early Suicide Risk in Elderly Patients After Self-Poisoning.

This article reports the findings of a follow-up study of suicide mortality in elderly patients after an index episode of self-poisoning. A total of 222 consecutive patients (143 female) aged 65 years or older (mean age 76.5 years; range 65-100) presenting at the emergency department of the Karolinska University Hospital after self-poisoning during 1994-2000, were followed up for the cause of death by January 1, 2006. Survival analysis was applied to study suicide and death risk. Of the 15 suicides, 13 (87%) occurred during the first year after the index episode of self-poisoning (cumulative suicide risk 6.2%). The risk of dying of all causes during the first year was increased fourfold. Self-poisoning in both elderly men and women is associated with high early suicide risk.

ß-Amyloid binding in elderly subjects with declining or stable episodic memory function measured with PET and [¹¹C]AZD2184.

PURPOSE: Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and ß-amyloid using positron emission tomography (PET) and [(11)C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits. METHODS: Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [(11)C]AZD2184. The binding potential BP ND was calculated using linear graphical analysis with the cerebellum as reference region. RESULTS: The binding of [(11)C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP ND was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BP ND were ApoE ε4 allele carriers. CONCLUSIONS: We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits.

In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer's disease patients.

PURPOSE: Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer's disease (AD). ((R)-1-(2-chlorophenyl)-N-[(11)C]-methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([(11)C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to-nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoroethyl-5-methoxybenzyl)acetamide ([(18)F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [(18)F]FEDAA1106 to TSPO in control subjects and AD patients. METHODS: Seven controls (five men, two women, age 68±3 years, MMSE score 29±1) and nine AD patients (six men, three women, age 69±4 years, MMSE score 25±3) were studied with [(18)F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V T) and binding potential (BP(ND)=k3/k4). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V(ND 1-15 min)). Binding potential (BP(ND)) was also calculated as: V(T)/V(ND 1-15 min) - 1. RESULTS: No statistically significant differences in V(T), k3/k4 or BP(ND) were observed between controls and AD patients. CONCLUSION: This study suggests that TSPO imaging with [(18)F]FEDAA1106 does not enable the detection of microglial activation in AD.

Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine.

BACKGROUNDS AND PURPOSE: The main objectives of the present study were (i) to measure density changes of activated microglia and the peripheral benzodiazepine receptor/translocator protein (TSPO) system during normal ageing in the human brain with positron emission tomography (PET) using the TSPO molecular imaging biomarker [(11)C]vinpocetine and (ii) to compare the level and pattern of TSPO in Alzheimer (AD) patients with age matched healthy subjects, in order to assess the biomarker's usefulness as a diagnostic imaging marker in normal (ageing) and pathological (AD) up-regulation of microglia. METHODS AND SUBJECTS: PET measurements were made in healthy volunteers, aged between 25 and 78 years, and AD patients, aged between 67 and 82 years, using [(11)C]vinpocetine as the tracer. Global and regional quantitative parameters of tracer uptake and binding, including time activity curves (TAC) of standard uptake values (%SUV), binding affinity parameters, intensity spectrum and homogeneity of the uptake distribution were measured and analysed. RESULTS: Both %SUV and binding values increased with age linearly in the whole brain and in all brain regions. There were no significant differences between the %SUV values of the AD patients and age matched control subjects. There were, however, significant differences in %SUV values in a large number of brain regions between young subjects and old subjects, as well as young subjects and AD patients. The intensity spectrum analysis and homogeneity analysis of the voxel data show that the homogeneity of the %SUV values decreases with ageing and during the disease, whereas the centre of the intensity spectrum is shifted to higher %SUV values. These data indicate an inhomogeneous up-regulation of the TSPO system during ageing and AD. These changes were significant between the group of young subjects and old subjects, as well as young subjects and AD patients, but not between old subjects and AD patients. CONCLUSIONS: The present data indicate that [(11)C]vinpocetine may serve as a molecular imaging biomarker of the activity of the TSPO system and, consequently, of the up-regulation of microglia during ageing and in neuroinflammatory diseases. However, the global and regional brain %SUV values between AD patients and age matched controls are not different from each other. The disease specific changes, measured with [(11)C]vinpocetine in AD, are significantly different from those measured in age matched controls only if the inhomogeneities in the uptake pattern are explored with advanced mathematical techniques. For this reason, PET studies using [(11)C]vinpocetine, as molecular imaging biomarker, can efficiently visualise the activation of microglia and the up-regulation of TSPO during ageing and in diseased brains with the help of an appropriate inhomogeneity analysis of the radioligand's brain uptake pattern.