Current Alzheimer Research - Volume 14, Issue 2, 2017

This review article aims at providing a state-of-the-art review of the role of fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging (FDG-PET) in the prediction of Alzheimer's dementia in subjects suffering mild cognitive impairment (MCI), with a particular focus on the predictive power of FDG-PET compared to structural magnetic resonance imaging (sMRI). We also address perfusion single photon emission computed tomography (SPECT) as a less costly and more accessible alternative to FDG-PET. A search in PubMed was performed, taking into consideration relevant scientific articles published in English within the last five years and limited to human studies. This recent literature confirms the effectiveness of FDG-PET and sMRI for prediction of AD dementia in MCI. However, there are discordant results regarding which image modality is superior. This could be explained by the high variability of metrics used to evaluate both imaging modalities and/or by sampling/population issues such as age, disease severity and conversion time. FDG-PET seems to outperform sMRI in rapidly converting early-onset MCI individuals, whereas sMRI may outperform FDG-PET in late-onset MCI subjects, in which case FDG PET might only provide a complementary role. Although FDG-PET performs better than perfusion SPECT, current evidence confirms perfusion SPECT as a valid alternative when FDG- PET is not available. Finally, possible future directions in the field are discussed.

As well known, the increase in life expectancy and the better physical condition of people in western countries will lead in the next 20 years to a dramatic development of neurodegenerative diseases, especially of dementia that could be considered one of the most important problems in clinical, social and economic fields for the future. Therefore, the differential diagnosis of the various types of dementia is a critical step for patients, clinicians and researchers since an accurate “in vivo” diagnosis can lead to a better patients management. Neuroimaging techniques and in particular the most diffuse and affordable single photon emission computed tomography (SPECT) have provided useful information about dementia disorders and these methods, on the basis of the recent advances, will have an increasingly important role in research and clinical practice. The purpose of this article is to analyze the different SPECT techniques now available which proved clinically useful in correctly formulating the differential diagnosis of dementia.

In the last decade, several radiolabeled compounds have been developed for the imaging in vivo of amyloid pathology by means of Positron Emission Tomography (PET). Among these, 18F Florbetaben appear to be one of the most reliable for its high affinity for amyloid plaques in brain and its radio-chemical properties that make it usable in common clinical routine. The aim of this review is to provide a general overview of the application in vivo of 18F Florbetaben, describing for first the physiopathological basis of amyloid pathology. Afterwards, the chemical characteristics of this radiolabeled compound will be described, with a particular attention to the synthesis process and the kinetic in vivo. An overview on the imaging protocols and image interpretation will be provided as well and, as a last aspect, the results of the main studies performed in subjects with advanced and early AD will be summarized.

Objective: Alzheimer’ disease (AD) is characterized by increase of cortical amyloid deposition in prodromal stage and subsequent decrease of cerebral glucose metabolism as disease progresses. The present study introduces the voxel-wise metabolism to amyloid deposits ratio (MAR) image and to evaluate its reliability for the diagnosis of AD. Methods: Consecutive one-hundred and forty-three subjects with AD and 181 normal subjects who underwent both 18F-FDG PET and 18F-florbetapir (AV-45) PET at baseline were included to this study from the database of Alzheimer's disease neuroimaging initiative (ADNI). After normalizing to a standard stereotactic space, the MAR image was created by dividing each FDG-PET image by corresponding AV-45 PET image using with voxel-wise inter-image computation. We examined voxel wise comparison in the MAR images between AD subjects and normal subjects and compared the diagnostic performances between the MAR image and FDG-PET and AV-45 image. Results: In the voxel wise comparison, the MAR images of AD subjects exhibited severe and extensive decrease compared with normal subjects in the affected region in both FDG-PET and AV-45, especially in the precuneus /posterior cingulate. The highest t-value was equivalent to FDG-PET and the voxel extent was much greater than the other images. In the ROI analysis, the diagnostic accuracies were 82.6% (sensitivity: 86.7%, specificity: 79.5%), 80.7% (sensitivity: 77%, specificity: 83.4%), and 78.8% (sensitivity: 75.2%, specificity: 81.5%) for the MAR image, FDG-PET, and AV-45, respectively. AUC for the MAR image was 0.904 (95%CI: 0.867-0.942), and was larger than those for FDG-PET (AUC: 0.884, 95%CI: 0.843-0.926), and AV-45 (AUC: 0.847, 95%CI: 0.798-0.897). Conclusion: MAR image reflected not only amyloid deposition but the cerebral glucose metabolisms and successfully classified the subjects with AD. These data suggest that the MAR image might be a more proper appropriate diagnostic marker for AD reflecting cerebral metabolisms and amyloid deposition.

Clinical classifications of neurodegenerative disorders are often based on neuropathology. The term proteinopathies“ includes disorders that have in common abnormal proteins as a hallmark, e.g. amyloidoses, tauopathies, synucleopathies, ubiquitinopathies. Different proteins can also co-exist in the same disease. To further complicate the pathophysiology scenario, not only different proteins, but also cells are believed to play an active role in neurodegeneration, in particular those participating in neuroinflammatory processes in the brain, such as activated microglia and astrocytes. In clinical practice, differentiating pathophysiology from clinical symptoms to allow accurate clinical classification of these disorders during life, becomes difficult in absence of biomarkers for these pathology hallmarks. PET imaging can be a useful tool in this context. Using PET tracers targeting misfolded proteins it will be possible to identify the presence or absence of the target, to depict the cerebral distribution and to quantify the protein load in different cerebral regions, as well as to monitor changes over time. Beta-amyloid is one of the proteins involved in neurodegenerative disorders, which is currently suitable to be imaged by means of PET. Research efforts are currently ongoing in order to identify new PET tracers targeting non-amyloid PET tracers for neurodegeneration. This article will focus on the investigational PET tracers targeting tau and alpha-synuclein as misfolded proteins, and activated microglia and astrocytes as cellular targets for neuroinflammation. An overview of target characteristics, development challenges, clinical relevance and current status of human PET imaging is provided.

Alzheimer’s disease is the most common form of dementia among older people. Misfolding and aggregation of proteins (amyloid-β and tau) in the brain is the primary cause of neurodegeneration in the disease. Non-invasive detection of amyloid-β deposition can be realized using positron emission tomography probes, but a proportion of Aβ-positive subjects do not present with cognitive dysfunction, suggesting limitations in assessment using this method. Non-invasive detection of tau deposits in the brain can be used to diagnose, monitor, and predict Alzheimer’s disease progression. Tau positron emission tomography radiolabelled probes such as T807, THK-5117, and PBB3 can image the pathology of the disease in vivo. The 18F-labeled tau imaging agents 18F-THK-5351, 18F-T807 (18F-AV-1451), and 18F-RO6958948 are presently under evaluation in clinical studies and clinical trials worldwide. This imaging methodology could be applied to enable preclinical diagnoses and disease-modifying drugs for Alzheimer’s disease. In this review, we provide an overview of the pathology and potential imaging of tau in Alzheimer’s disease, development of a THK series among tau tracers, and the chemical, radiochemical, biological, and clinical features of tau probes.

PET/MRI tomographs represent the latest development in hybrid molecular imaging, opening new perspectives for clinical and research applications and attracting a large interest among the medical community. This new hybrid modality is expected to play a pivotal role in a number of clinical applications and among these the assessment of neurodegenerative disorders. PET and MRI, acquired separately, are already the imaging biomarkers of choice for a comprehensive assessment of the changes occurring in dementias (major cognitive disorders) as well as in their prodromal phase. In this paper we review the current evidence on the use of integrated PET/MRI scanners to investigate patients with neurodegenerative conditions, and in particular major neurocognitive disorders. The number of studies performed is still limited and shows that the use of PET/MRI gives results overall comparable to PET/CT and MRI acquired independently. We also address the challenges for quantitative aspects in PET/MRI, namely attenuation, partial volume and motion correction and the use of semi-quantitative approaches for FDG PET image analysis in this framework. The recent development of PET tracers for the in vivo differential diagnosis of dementias, able to visualize amyloid and tau deposits, suggests that in the future PET/MRI might represent the investigation of choice for a single session evaluation of morphological, functional and molecular markers.

Artificial Intelligence (AI) is a very active Computer Science research field aiming to develop systems that mimic human intelligence and is helpful in many human activities, including Medicine. In this review we presented some examples of the exploiting of AI techniques, in particular automatic classifiers such as Artificial Neural Network (ANN), Support Vector Machine (SVM), Classification Tree (ClT) and ensemble methods like Random Forest (RF), able to analyze findings obtained by positron emission tomography (PET) or single-photon emission tomography (SPECT) scans of patients with Neurodegenerative Diseases, in particular Alzheimer’s Disease. We also focused our attention on techniques applied in order to preprocess data and reduce their dimensionality via feature selection or projection in a more representative domain (Principal Component Analysis – PCA – or Partial Least Squares – PLS – are examples of such methods); this is a crucial step while dealing with medical data, since it is necessary to compress patient information and retain only the most useful in order to discriminate subjects into normal and pathological classes. Main literature papers on the application of these techniques to classify patients with neurodegenerative disease extracting data from molecular imaging modalities are reported, showing that the increasing development of computer aided diagnosis systems is very promising to contribute to the diagnostic process.

Alzheimer’s disease (AD) is one of the most common causes of dementia. Despite several decades of research in AD, there is no standard disease- modifying therapy available and currentlyapproved drugs provide only symptomatic relief. Stem cells hold immense potential to regenerate damaged tissues and are currently tested in some brain-related disorders, such as AD, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). We review stem cell transplantation studies using preclinical and clinical tools. We describe different sources of stem cells used in various animal models and explaining the putative molecular mechanisms that can rescue neurodegenerative disorders. The clinical studies suggest safety, efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies, but no unifying hypothesis can convincingly explain the underlying mechanism. Some studies have reported paracrine effects exerted by these stem cells via the release of neurotrophic factors, while other studies describe the immunomodulatory effects exerted by the transplanted cells. There are also reports which indicate that stem cell transplantation might result in endogenous cell proliferation or replacement of diseased cells. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins.

Background: Alzheimer’s disease (AD), the most common cause of dementia among older people, could not be prevented, halted, or reversed up till now. A large body of pharmacological study has revealed that Liuwei Dihuang decoction (LW), a classical traditional Chinese medicinal prescription, possesses potential therapeutic effects on AD. LW-AFC is key fractions from LW. Method: Cognition ability was evaluated by behavioral experiments. Using multiplex bead analysis, radioimmunoassay, immunochemiluminometry and ELISA to determine levels of cytokines and hormones. The splenocyte proliferation and peripheral lymphocyte subsets was investigated by 3H-thymidine incorporation and flow cytometric analysis, respectively. Results: This study showed the treatment of LW-AFC slowed the aging process of senescence-accelerated mouse prone 8 strain (SAMP8), a robust model sporadic AD or late-onset/age-related AD. LW-AFC had ameliorative effects on spontaneous locomotor activity, object recognition memory, spatial learning and memory, passive and active avoidance impairment in SAMP8 mice. Administration of LW-AFC restored the imbalance of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis, enhanced the proliferation of splenocytes, corrected the disorder of lymphocyte subsets, and regulated the abnormal production of cytokine in SAMP8 mice. Effects of LW-AFC on pharmacodynamics and neuroendocrine immunomodulation network in SAMP8 mice were better than memantine and donepezil. Conclusion: This data indicated LW-AFC may be a promising therapeutic medicine for AD.