阿尔茨海默病的PET分子影像学研究进展

阿尔茨海默病（AD）是一种好发于老年人的神经退行性疾病,是痴呆最常见的原因,发病隐匿且临床表现缺乏特异性,早期诊断困难。目前,基于生物标志物的AT（N）诊断框架使AD诊断的准确性明显提高。随着学科交叉融合的广泛推进,分子影像学展现出巨大潜力,是未来医学影像发展的趋势。PET显像可以在细胞和分子水平对活体内AD的病理过程进行定位和定量,是诊断AD重要的影像学手段,针对AD葡萄糖代谢和病理机制的多种示踪剂的研发有助于更好地研究AD的发病本质。本综述将对以淀粉样蛋白、Tau蛋白、葡萄糖、神经炎症、突触密度、神经递质为靶标的PET显像在AD诊断中的研究进展进行归纳阐述。     

The neural basis of social tactics: An fMRI study

One of the most powerful ways of succeeding in complex social interactions is to read the minds of companions and stay a step ahead of them. In order to assess neural responses to reciprocal mind reading in socially strained human relationships, we used a 3-T scanner to perform an event-related functional magnetic resonance imaging study in 16 healthy subjects who participated in the game of Chicken. Statistical parametric mapping showed that the counterpart effect (human minus computer) exclusively activated the medial frontal area corresponding to the anterior paracingulate cortex (PCC) and the supramarginal gyrus neighboring the posterior superior temporal sulcus (STS). Furthermore, when we analyzed the data to evaluate whether the subjects made risky/aggressive or safe/reconciliatory choices, the posterior STS showed that the counterpart had a reliable effect regardless of risky or safe decisions. In contrast, a significant opponent x selection interaction was revealed in the anterior PCC. Based on our findings, it could be inferred that the posterior STS and the anterior PCC play differential roles in mentalizing; the former serves as a general mechanism for mentalizing, while the latter is exclusively involved in socially risky decisions.     

The neural basis for category-specific knowledge: an fMRI study

Functional neuroimaging studies of healthy adults have associated different categories of knowledge with distinct activation patterns. The basis for these recruitment patterns has been controversial, due in part to the limited range of categories that has been studied. We used fMRI to monitor regional cortical recruitment patterns while subjects were exposed to printed names of Animals, Implements, and Abstract nouns. Both Implements and Abstract nouns were related to recruitment of left posterolateral temporal cortex and left prefrontal cortex, and Abstract nouns additionally recruited posterolateral temporal and prefrontal regions of the right hemisphere. Animals were associated with activation of ventral-medial occipital cortex in the left hemisphere at a level that approaches significance. These findings are not consistent with the "sensory-motor" model proposed to explain the neural representation of word knowledge. We suggest instead a neural model of semantic memory that reflects the processes common to understanding Implements and Abstract nouns and a selective sensitivity, possibly evolving from adaptive pressures, to the overlapping, intercorrelated visual characteristics of Animals.     

Familial Alzheimer's disease: a study of HLA markers

We have studied HLA markers in family with 2 "Probable" and 2 "possible" cases of Alzheimer disease over 3 generations. Three of them (two brothers and the father) present A29 C-B12 DR2 haplotype. It seems that it exists an association between HLA system and Alzheimer disease but we cannot define the character of this genetic linkage; the study of many families and sporadic cases will allow to define it.     

Hippocampal shape analysis in Alzheimer's disease: a population-based study

BACKGROUND: Hippocampal atrophy--particularly of the CA1 region--may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n=24: age=82.5+/-4.6) or were not demented (n=102: age=83.0+/-5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. RESULTS: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903+/-857 mm(3) vs. 5540+/-805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and non-demented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region.     

The neural correlates of spatial language in English and American Sign Language: a PET study with hearing bilinguals

Rather than specifying spatial relations with a closed-class set of prepositions, American Sign Language (ASL) encodes spatial relations using space itself via classifier constructions. In these constructions, handshape morphemes specify object type, and the position of the hands in signing space schematically represents the spatial relation between objects. A [15O]water PET study was conducted to investigate the neural regions engaged during the production of English prepositions and ASL locative classifier constructions in hearing subjects with deaf parents (ASL-English bilinguals). Ten subjects viewed line drawings depicting a spatial relation between two objects and were asked to produce either an ASL locative classifier construction or an English preposition that described the spatial relation. The comparison task was to name the figure object (colored red) in either ASL or in English. Describing spatial relations in either ASL or English engaged parietal cortex bilaterally. However, an interaction analysis revealed that right superior parietal cortex was engaged to a greater extent for ASL than for English. We propose that right parietal cortex is involved in the visual-motoric transformation required for ASL. The production of both English prepositions and ASL nouns engaged Broca's area to a greater extent than ASL classifier constructions. We suggest that Broca's area is not engaged because these constructions do not involve retrieval of the name of an object or the name of a spatial relation. Finally, under the same task conditions, only left parietal activation was observed for monolingual English speakers producing spatial prepositions (H. Damasio et al., 2001, NeuroImage, 13). We conclude that the right hemisphere activation observed for ASL-English bilinguals was due to their life-long experience with spatial language in ASL.     

Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease

Recently developed positron emission tomography (PET) tracers, such as PIB and FDDNP, help to visualize amyloid plaques and neurofibrillary tangles in living subjects. FDDNP binds to both amyloid plaques and tangles, whereas PIB selectively labels amyloid plaques. Therefore, it will be interesting to see a direct comparison of the regional binding of the two radiotracers for plaques (PIB) and plaques and tangles (FDDNP) using multitracer PET imaging for both PIB and FDDNP in the same subjects with and without Alzheimer's disease. Here we report that multitracer PET images of PIB and FDDNP in the same Alzheimer subjects show negligible PIB but strong FDDNP binding in the medial temporal cortex (hippocampus, amygdala, and parahippocampal gyrus), whereas there are significant quantities of both PIB and FDDNP binding in neocortical areas. These results suggest that tangles rather than amyloid plaques are the dominant pathology in the medial temporal cortex of living Alzheimer patients. In nondemented elderly normal subjects, PIB binding shows a significant increase in the posterior cingulate cortex compared with other brain regions, whereas in the same normal subjects we found significant FDDNP binding in the medial temporal cortex. Interestingly, the medial temporal FDDNP uptake values in normal elderly subjects were inversely correlated with long delay recall scores in the California Verbal Learning Test, a measure of episodic memory performance. We conclude that multitracer PET imaging of amyloid plaques and tangles using FDDNP and PIB in both nondemented and demented subjects provides important insight into these complicated pathological processes in living subjects.     

The neural basis of individual differences in working memory capacity: an fMRI study

Using fMRI, neural substrates of verbal working memory were investigated with respect to differences in working memory capacity. Listening-span test (LST), Listen, and Remember conditions were performed. Two subjects groups were selected: those who had large working memory capacities, labeled high-span subjects (HSS) according to the working memory span test, and those who had small working memory capacities, labeled low-span subjects (LSS). Significant activation was found mainly in three regions in comparison with resting control: left prefrontal cortex (PFC), anterior cingulate cortex (ACC) and temporal language area. For both groups, fMRI signal intensity increased in PFC during the LST condition compared to the Listen condition. A group difference was found in the ACC region; specifically, a significant increase in signal intensity was observed in ACC only for the HSS group and not for the LSS group. Behavioral data also showed that the performance was better in HSS than in LSS. These results indicate that the attention controlling system, supported by ACC, is more effective in HSS compared to that of LSS.     

The neural correlates of cross-modal interaction in speech perception during a semantic decision task on sentences: a PET study

Speech perception in face-to-face conversation involves processing of speech sounds (auditory) and speech-associated mouth/lip movements (visual) from a speaker. Using PET where no scanner noise was present, brain regions involved in speech cue processing were investigated with the normal hearing subjects with no previous lip-reading training (N = 17) carrying out a semantic plausibility decision on spoken sentences delivered in a movie file. Multimodality was ensured at the sensory level in all four conditions. Sensory-specific speech cue of one sensory modality, i.e., auditory speech (A condition) or mouth movement (V condition), was delivered with a control stimulus of the other modality whereas speech cues of both sensory modalities (AV condition) were delivered during bimodal condition. In comparison to the control condition, extensive activations in the superior temporal regions were observed bilaterally during the A condition but these activations were reduced in extent and left lateralized during the AV condition. Polymodal region such as left posterior superior temporal sulcus (pSTS) involved in cross-modal interaction/integration of audiovisual speech was found to be activated during the A and more so during the AV conditions but not during the V condition. Activations were observed in Broca's (BA 44), medial frontal (BA 8), and anterior ventrolateral prefrontal (BA 47) regions in the left during the V condition, where lip-reading performance was less successful. Results indicated that the speech-associated lip movements (visual speech cue) rendered suppression on the activity in the right auditory temporal regions. Overadditivity (AV > A + V) observed in the right postcentral region during the bimodal condition relative to the sum of unimodal speech conditions was also associated with reduced activity during the V condition. These findings suggested that visual speech cue could exert an inhibitory modulatory effect on the brain activities in the right hemisphere during the cross-modal interaction of audiovisual speech perception.     

Health utilities in Alzheimer's disease: a cross-sectional study of patients and caregivers.

OBJECTIVES: Although the broad impacts of Alzheimer's disease (AD) are increasingly recognized, little work has focused on the overall health-related quality of life experienced by Alzheimer's disease patients and their caregivers. The study had two main objectives: (1) to test the feasibility of measuring health utilities in Alzheimer's disease with a generic preference-weighted instrument using proxy respondents and (2) to assess the utility scores of Alzheimer's disease patients (and their caregivers) in different disease stages and care setting. METHODS: A cross-sectional study of 679 Alzheimer's disease patient/caregiver pairs was conducted at 13 sites in the United States: four academic medical centers, four managed care plans, two assisted living facilities, and three nursing homes. The Health Utilities Index Mark II (HUI:2) questionnaire was administered to caregivers of patients who responded both as proxies for patients and for themselves. Responses to the questionnaire were converted into a global utility score, between 0 and 1, using the HUI:2 multi-attribute utility function. RESULTS: Global utility scores varied considerably across patients' Alzheimer's disease stage: for the six stages assessed (questionable, mild, moderate, severe, profound, and terminal), mean utility scores were 0.73, 0.69, 0.53, 0.38, 0.27, and 0.14, respectively. In multiple regression analyses, Alzheimer's disease stage was a negative and significant predictor of utility scores for patients; setting did not exert an independent effect. Utility scores for the caregivers were insensitive to patients' Alzheimer's disease stage and setting. CONCLUSIONS: Patients' Alzheimer's disease stage had a substantial influence on health utilities, as measured by the HUI:2. More research is needed to assess the validity of using proxy respondents.     

Convolutional neural networks for classification of Alzheimer's disease: Overview and reproducible evaluation

Numerous machine learning (ML) approaches have been proposed for automatic classification of Alzheimer's disease (AD) from brain imaging data. In particular, over 30 papers have proposed to use convolutional neural networks (CNN) for AD classification from anatomical MRI. However, the classification performance is difficult to compare across studies due to variations in components such as participant selection, image preprocessing or validation procedure. Moreover, these studies are hardly reproducible because their frameworks are not publicly accessible and because implementation details are lacking. Lastly, some of these papers may report a biased performance due to inadequate or unclear validation or model selection procedures. In the present work, we aim to address these limitations through three main contributions. First, we performed a systematic literature review. We identified four main types of approaches: i) 2D slice-level, ii) 3D patch-level, iii) ROI-based and iv) 3D subject-level CNN. Moreover, we found that more than half of the surveyed papers may have suffered from data leakage and thus reported biased performance. Our second contribution is the extension of our open-source framework for classification of AD using CNN and T1-weighted MRI. The framework comprises previously developed tools to automatically convert ADNI, AIBL and OASIS data into the BIDS standard, and a modular set of image preprocessing procedures, classification architectures and evaluation procedures dedicated to deep learning. Finally, we used this framework to rigorously compare different CNN architectures. The data was split into training/validation/test sets at the very beginning and only the training/validation sets were used for model selection. To avoid any overfitting, the test sets were left untouched until the end of the peer-review process. Overall, the different 3D approaches (3D-subject, 3D-ROI, 3D-patch) achieved similar performances while that of the 2D slice approach was lower. Of note, the different CNN approaches did not perform better than a SVM with voxel-based features. The different approaches generalized well to similar populations but not to datasets with different inclusion criteria or demographical characteristics. All the code of the framework and the experiments is publicly available: general-purpose tools have been integrated into the Clinica software (www.clinica.run) and the paper-specific code is available at: https://github.com/aramis-lab/AD-DL.     

Activation of human hippocampal formation reflects success in both encoding and cued recall of paired associates

Contemporary theories of hippocampal function suggest that both encoding and retrieval of episodic memories may be accomplished by neural circuitry embedded within the same anatomical structures, but neuroimaging support for this hypothesis has been ambiguous. Recent studies suggest that the best available indicators of hippocampal encoding and retrieval operations are selective activations due to novelty, encoding success, and recall success in a paired associate learning paradigm. In the current study, both encoding and cued recall of paired associate words were conducted during a single session of fMRI scanning. Bilateral activation in the medial temporal lobe was detected for encoding word pairs vs. a fixation baseline and for encoding novel word pairs vs. repeated word pairs. These activations were stronger in subjects who successfully memorized more word pairs. In cued recall, greater responses were seen in higher performing subjects. In lower performing subjects, responses were greater to cue words whose paired associate was correctly recalled than to cue words whose correct associate had been forgotten (or not encoded). The difference between correct and incorrect trials was more pronounced on repeated presentations of the same cue words, but not apparent on their first presentation alone. Overlap of encoding and retrieval effects was maximal in the middle of the longitudinal extent of the right hippocampus, with one additional locus of overlap outside the MTL, in left occipitotemporal cortex. The conjunction of these effects suggests that it is correct to view both encoding and recall of associative memories as functions of an integrated hippocampal system.