Adrian Ivanoiu

18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.

The most widely studied positron emission tomography ligand for in vivo β‐amyloid imaging is 11C‐Pittsburgh compound B (11C‐PIB). Its availability, however, is limited by the need for an on‐site cyclotron. Validation of the 18F‐labeled PIB derivative 18F‐flutemetamol could significantly enhance access to this novel technology.

Memory evaluation with a new cued recall test in patients with mild cognitive impairment and Alzheimer’s disease

Free delayed recall is considered the memory measure with the greatest sensitivity for the early diagnosis of dementia. However, its specificity for dementia could be lower, as deficits other than those of pure memory might account for poor performance in this difficult and effortful task. Cued recall is supposed to allow a better distinction between poor memory due to concurrent factors and impairments related to the neurodegenerative process. The available cued recall tests suffer from a ceiling effect. This is a prospective, longitudinal study aiming to assess the utility of a new memory test based on cued recall that avoids the ceiling effect in the early diagnosis of Alzheimer’s disease (AD). Twenty-five patients with mild cognitive impairment (MCI), 22 probable AD patients (NINCDS-ADRDA) at a mild stage, 22 elderly patients with subjective memory complaints (SMC) and 38 normal age-matched controls took part in the study. The patients underwent a thorough cognitive evaluation and the recommended screening procedure for the diagnosis of dementia. All patients were re-examined 12–18 months later. A newly devised delayed cued recall test using semantic cues (The RI48 Test) was compared with three established memory tests: the Ten Word-List Recall from CERAD, the “Doors” and the “Shapes” Tests from “The Doors and People Test Battery”. Forty-four % of the MCI patients fulfilled criteria for probable AD at follow-up. The RI48 Test classified correctly 88% of the MCI and SMC participants and was the best predictor of the status of MCI and mild AD as well as the outcome of the MCI patients. Poor visual memory was the second best predictor of those MCI patients who evolved to AD. A cued recall test which avoids the ceiling effect is at least as good as the delayed free recall tests in the early detection of AD.

Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging

The regional cerebral blood flow (rCBF) and metabolic rate for glucose (rCMRGlc) are associated with functional activity of the neural cells. The present work reports a comparison study between rCBF and rCMRGlc in a normal population as a function of age. 10 young (25.9+/-5.6 years) and 10 old (65.4+/-6.1 years) volunteers were similarly studied at rest. In each subject, rCBF and rCMRGlc were measured in sequence, during the same session. Both rCBF and rCMRGlc values were found to decrease from young (mean rCBF=43.7 ml/100 g per min; mean rCMRGlc=40.6 micromol/100 g per min) to old age (mean rCBF=37.3 ml/100 g per min; mean rCMRGlc=35.2 micromol/100 g per min), resulting in a drop over 40 years of 14.8% (0.37%/year) and 13.3% (0.34%/year), respectively. On a regional basis, the frontal and the visual cortices were observed to have, respectively, the highest and the lowest reduction in rCBF, while, for rCMRGlc, these extremes were observed in striatum and cerebellum. Despite these differences, the ratio of rCBF to rCMRGlc was found to have a similar behavior in all brain regions for young and old subjects as shown by a correlation coefficient of 88%. This comparative study indicates a decline in rCBF and rCMRGlc values and a coupling between CBF and CMRGlc as a function of age.

Semantic memory in Alzheimer's disease and the frontotemporal dementias: A longitudinal study of 236 patients

Using semantic dementia (SD) as a reference point, the authors assessed semantic memory in four other neurodegenerative disorders: progressive nonfluent aphasia (PNFA), frontal variant frontotemporal dementia (fvFTD), Alzheimers disease (AD), and posterior cortical atrophy (PCA). Individuals with SD were more impaired than other groups on semantic measures and showed a characteristic pattern across tasks: category fluency (CF) worse than letter fluency (LF), naming worse than comprehension, and visual and verbal comprehension equally affected, suggesting disruption to an amodal semantic system. Individuals with AD demonstrated a similar pattern to a milder degree. Although PNFA, fvFTD, and PCA groups had abnormal scores (relative to controls) on most semantic measures, their differing patterns across measures indicate that the apparent semantic impairment in these conditions is largely secondary to other factors.

Patterns of impairment in autobiographical memory in the degenerative dementias constrain models of memory

Detailed study of the autobiographical memory (ABM) impairments seen in different forms of degenerative dementia, in particular Alzheimers disease (AD) and semantic dementia (SD) can inform neuropsychological models of memory. A modified ABM questionnaire which allowed more detailed analysis of episodic and semantic ABM was used to study the pattern of deficits in patients with minimal to mild Alzheimers disease (AD) and in two patients with mild and moderate semantic dementia (SD). The questionnaire tested both cued and free recall. A group of healthy elderly was also tested. AD patients differed from controls in all measures. There was no clear temporal gradient for episodic ABM, but a modest gradient was observed for semantic ABM. The mild SD patient performed at control level for episodic ABM but showed a deficit within the range of the AD patients for semantic ABM except for the most recent life period. In contrast the moderate SD patient was impaired within the range of the AD patients for both episodic and semantic ABM. The evidence for differential impairment of episodic and semantic ABM retrieval in AD and SD is interpreted as supporting the multiple trace model of memory.

Cerebrospinal fluid TAU protein and amyloid beta42 in mild cognitive impairment: prediction of progression to Alzheimer's disease and correlation with the neuropsychological examination.

Cerebrospinal fluid (CSF) TAU protein and Amyloid β42 were able to distinguish between 28 mild cognitive impairment (MCI) patients and both 38 normal aged and 17 anxious and depressed elderly patients, with good sensitivity/specificity when the two measures were combined. These biological markers are independent predictors of the presence of Alzheimer disease (AD), in addition to memory performance. Low Amyloid β42 level was predictor of a fast progression of MCI patients to full blown dementia. The TAU protein level tended to correlate with memory performance, presumably in relation with the extent of the bilateral medio-temporal damage in early AD. We are indebted to Marie-Paule Van Antwerpen and Adriana Fuentes Polanco for helping us with the biomarker assessment. We would like to thank Dr. Eric Constant for the psychiatric evaluation of anxio-depressed patients. We thank Dr. Annalena Venneri for her amendments to the English and for her help in improving the style. In addition, we are grateful to Innogenetics for useful advices on technical issues.

Optimization of encoding specificity for the diagnosis of early AD : the RI-48 task.

The aim of this study was to evaluate the discriminant validity of the RI-48 test, a shorter French version of the Category Cued Recall portion of the Double Memory Test developed initially by Buschke and colleagues (1997), in the diagnosis of mild and very mild Alzheimer disease (AD). The distinctive feature of the RI-48 task is that encoding specificity was increased by adding an immediate cued recall stage at the encoding phase. The results show that the RI-48 task seems to be well adapted to the clinical context and to have good psychometric properties, in particular a lack of a ceiling effect. Moreover, this task appears to be especially well suited for the diagnosis of both mild and very mild AD (sensitivity of 93% and 83.8%). From a more theoretical point of view, this study confirms the importance of optimizing the encoding specificity for the diagnosis of very mild AD, since the more encoding specificity is accentuated, the more discriminating power is increased for the diagnosis of very mild AD.

Cholinergic Neurotransmission Has Different Effects on Cerebral Glucose Consumption and Blood Flow in Young Normals, Aged Normals, and Alzheimer's Disease Patients

Cerebral blood flow (CBF) and glucose consumption (GC) are both tracers of brain metabolic activity used to image the human brain in vivo. To know if both tracers reacted in the same manner when brain cholinergic neurotransmission was activated, CBF and GC were measured in young normals (YN), aged normals (AN), and Alzheimers Disease patients (AD) using positron emission tomography (PET), H2 15O, and 18F-FDG. Each subject was studied twice, under placebo and physostigmine, in randomized order and blind fashion using the maximal tolerated dose of physostigmine individually determined. Under physostigmine CBF increased significantly (P = 0.0007) in posterior regions of the cerebral cortex and in the subcortical structures. Inversely, GC was decreased significantly in most regions. The largest decrease was seen in the prefrontal region of the cerebral cortex (P < 0.0001). Significant regional decreases were registered in all three groups of subjects, but were larger in AD than in controls. Looking at the absolute values of prefrontal cortex metabolism we found no correlation (r = 0.04) between the responses of CBF and GC. After normalization of the regional values for the mean we found a significant positive correlation between the responses of CBF and GC (r = 0.71, P < 0.0001). These findings suggest two components in the CBF response to physostigmine: one metabolic, depressive, and regional which follows the GC response; and one vascular, larger, diffuse, and opposite in direction to the metabolic component. These results have implications for the interpretation of CBF values as tracer of brain metabolic activity when brain cholinergic neurotransmission is manipulated.

Binary classification of 18F-flutemetamol PET using machine learning: Comparison with visual reads and structural MRI

(18)F-flutemetamol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as normal versus Alzheimer-like, is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how (18)F-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed (18)F-flutemetamol scans and volumetric MRI scans from 72 cases from the (18)F-flutemetamol phase 2 study (27 clinically probable Alzheimers disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the (18)F-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The (18)F-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the (18)F-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the (18)F-flutemetamol- and the gray matter volume-based classifiers were identical (85.2%), albeit with discordant classification in three cases. Specificity of the (18)F-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI group, the (18)F-flutemetamol based classifier distinguished more reliably between converters and non-converters than the gray matter-based classifier. The visual read-based binary classification of (18)F-flutemetamol scans can be replicated using SVM. In this sample the specificity of (18)F-flutemetamol based SVM for distinguishing AD from controls is higher than that of gray matter volume-based SVM.

Associative encoding deficits in amnestic mild cognitive impairment : a volumetric and functional MRI study.

BACKGROUNDnPrevious functional MRI studies have shown increased hippocampus activation in response to item encoding in amnestic mild cognitive impairment (aMCI). Recent behavioral studies suggested that associative memory could be more impaired than item memory in aMCI. So far, associative encoding has not been evaluated separately from item encoding in functional MRI studies.nnnMETHODSnWe conducted a volumetric and functional MRI study investigating associative encoding in 16 aMCI and 16 elderly controls while controlling for item encoding.nnnRESULTSnWe confirmed the presence of associative memory impairment in aMCI even after controlling for item memory differences between groups. Associative memory but not item memory correlated with hippocampus volume in aMCI. Such a correlation was not observed in elderly controls. The left anterior hippocampus activation in response to successful associative encoding was decreased in aMCI, even after correction for hippocampus atrophy.nnnCONCLUSIONnAssociative memory impairment in aMCI appears to be related to hippocampus atrophy and left anterior hippocampus hypoactivation.