Amyloid plaque imaging in vivo: current achievement and future prospects. Eur J Nucl Med Mol Imaging 35(Suppl 1):S46-S50

Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska University Hospital Huddinge, Novum 5th floor, Stockholm, Sweden.
European journal of nuclear medicine and molecular imaging (Impact Factor: 5.38). 04/2008; 35 Suppl 1(S1):S46-50. DOI: 10.1007/s00259-007-0700-2
Source: PubMed


Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment.
The rapid development of molecular imaging techniques now allows imaging of amyloid plaques in vivo in Alzheimer patients by PET amyloid ligands such as Pittsburgh compound B (PIB). Studies so far have revealed high (11)C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by (11)C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes.
In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD.

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Available from: Agneta Nordberg
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    • "Investigation into amyloid-imaging ligands for the diagnosis of AD and the evaluation of anti-amyloid therapy started more than 10 years ago [20-24]. Fibrillar amyloid-binding dyes such as Congo red, chrysamine G, and thioflavins were investigated as ligands for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of amyloid deposits in AD patients. "
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    ABSTRACT: Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [11C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired. We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible. To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.
    Full-text · Article · Dec 2011 · Molecular Neurodegeneration
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    • "Interestingly, the increase in 11 C- PIB retention observed in mild AD patients relative to agematched healthy controls was larger than the decrease in 18 F- FDG uptake in AD patients relative to controls [47]. Figure 2 illustrates cerebral glucose metabolism as assessed by 18 F- FDG PET and amyloid plaque burden as assessed by 11 C-PIB PET in two AD patients and a healthy control [43]. The memory predominant subtype, amnestic mild cognitive impairment (MCI), has been suggested to constitute a transitional stage between normal aging and AD [34]. "
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    ABSTRACT: Neuropsychiatric disorders are becoming a major socioeconomic burden to modern society. In recent years, a dramatic expansion of tools has facilitated the study of the molecular basis of neuropsychiatric disorders. Molecular imaging has enabled the noninvasive characterization and quantification of biological processes at the cellular, tissue, and organism levels in intact living subjects. This technology has revolutionized the practice of medicine and has become critical to quality health care. New advances in research on molecular imaging hold promise for personalized medicine in neuropsychiatric disorders, with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, early diagnosis, and personal health planning. In this paper, we discuss the development of radiotracers for imaging dopaminergic, serotonergic, and noradrenergic systems and β-amyloid plaques. We will underline the role of molecular imaging technologies in various neuropsychiatric disorders, describe their unique strengths and limitations, and suggest future directions in the diagnosis and management of neuropsychiatric disorders.
    Full-text · Article · Mar 2011 · BioMed Research International
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    • "When searching for a biological marker of AD amyloid imaging could hopefully replace invasive procedures such as lumbar puncture. There is very active research investigating molecules labelled with radioactive isotopes that might enter the brain, bind selectively to ␤-amyloid, be visualised with PET scanners and analysed with PET imaging tools, enabling in vivo quantification of beta-amyloid plaque load in AD [133] [134]. "
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    ABSTRACT: Older persons with Mild Cognitive Impairment (MCI) feature neurobiological Alzheimer's Disease (AD) in 50% to 70% of the cases and develop dementia within the next 5 to 7 years. Current evidence suggests that biochemical, neuroimaging, electrophysiological, and neuropsychological markers can track the disease over time since the MCI stage (also called prodromal AD). The amount of evidence supporting their validity is of variable strength. We have reviewed the current literature and categorized evidence of validity into three classes: Class A, availability of multiple serial studies; Class B a single serial study or multiple cross sectional studies of patients with increasing disease severity from MCI to probable AD; and class C, multiple cross sectional studies of patients in the dementia stage, not including the MCI stage. Several Class A studies suggest that episodic memory and semantic fluency are the most reliable neuropsychological markers of progression. Hippocampal atrophy, ventricular volume and whole brain atrophy are structural MRI markers with class A evidence. Resting-state fMRI and connectivity, and diffusion MR markers in the medial temporal white matter (parahippocampus and posterior cingulum) and hippocampus are promising but require further validation. Change in amyloid load in MCI patients warrant further investigations, e.g. over longer period of time, to assess its value as marker of disease progression. Several spectral markers of resting state EEG rhythms that might reflect neurodegenerative processes in the prodromal stage of AD (EEG power density, functional coupling, spectral coherence, and synchronization) suffer from lack of appropriately designed studies. Although serial studies on late event-related potentials (ERPs) in healthy elders or MCI patients are inconclusive, others tracking disease progression and effects of cholinesterase inhibiting drugs in AD, and cross-sectional including MCI or predicting development of AD offer preliminary evidence of validity as a marker of disease progression from the MCI stage. CSF Markers, such as Aβ 1-42, t-tau and p-tau are valuable markers which support the clinical diagnosis of Alzheimer's disease. However, these markers are not sensitive to disease progression and cannot be used to monitor the severity of Alzheimer's disease. For Isoprostane F2 some evidence exists that its increase correlates with the progression and the severity of AD.
    Full-text · Article · Jan 2011 · Journal of Alzheimer's disease: JAD
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