Brain Imaging in Alzheimer Disease

Departments of Radiology and Neurology, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Cold Spring Harbor Perspectives in Medicine (Impact Factor: 9.47). 04/2012; 2(4):a006213. DOI: 10.1101/cshperspect.a006213
Source: PubMed

ABSTRACT Imaging has played a variety of roles in the study of Alzheimer disease (AD) over the past four decades. Initially, computed tomography (CT) and then magnetic resonance imaging (MRI) were used diagnostically to rule out other causes of dementia. More recently, a variety of imaging modalities including structural and functional MRI and positron emission tomography (PET) studies of cerebral metabolism with fluoro-deoxy-d-glucose (FDG) and amyloid tracers such as Pittsburgh Compound-B (PiB) have shown characteristic changes in the brains of patients with AD, and in prodromal and even presymptomatic states that can help rule-in the AD pathophysiological process. No one imaging modality can serve all purposes as each have unique strengths and weaknesses. These modalities and their particular utilities are discussed in this article. The challenge for the future will be to combine imaging biomarkers to most efficiently facilitate diagnosis, disease staging, and, most importantly, development of effective disease-modifying therapies.

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    • "In terms of pathological relevance , amyloid-β deposition is thought to be an initiating event of AD that then drives further pathological changes eventually resulting in neuronal dysfunction [10]. The above PET tracers adhere to this time course with amyloid PET representing an early disease biomarker that outperforms [ 18 F]-FDG in identifying prodromal AD subtypes [3] [11] [12] [13]. "
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    ABSTRACT: Positron emission tomography studies of cerebral glucose utilization and amyloid-β deposition with fluoro-deoxy-D-glucose ([18F]-FDG) and amyloid tracers have shown characteristic pathological changes in Alzheimer's Disease that can be used for disease diagnosis and monitoring. Application of this technology to preclinical research with transgenic animal models would greatly facilitate drug discovery and further understanding of disease processes. The results from preclinical studies with these imaging biomarkers have however been highly inconsistent, causing doubts over whether animal models can truly replicate an AD-like phenotype. In this study we performed in vivo imaging with [18F]-FDG and [18F]-AV45 in double transgenic TASTPM mice, a transgenic model that been previously demonstrated high levels of fibrillar amyloid-β and decreases in cerebral glucose utilization with ex vivo techniques. Our results show widespread and significant retention of [18F]-AV45 (p < 0.0001) in aged TASTPM mice in addition to significantregional decreases in [18F]-FDG uptake (p < 0.05). In vivo quantification of amyloid-β showed a strong (Pearson's r = 0.7078), but not significant (p = 0.1156), positive correlation with ex vivo measures suggesting some limitations on tracer sensitivity. In the case of [18F]-FDG, voxelwise analysis greatly enhanced detection of hypometabolic regions. We further evidenced modest neuronal loss (thalamus p = 0.0318) that could underlie the observed hypometabolism. This research was performed in conjunction with the European Community's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under the PharmaCog Grant Agreement n°115009.
    Current Alzheimer research 07/2015; 12(7). DOI:10.2174/1567205012666150710104713 · 3.89 Impact Factor
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    • "This pattern of atrophy then extends to the temporal neocortex, followed by all neocortical association areas, usually in a rather symmetrical manner. This sequence of progression of atrophy on magnetic resonance imaging (MRI) most closely fits histopathological studies that have derived stages for the spread of neurofibrillary tangles (Johnson et al., 2012). Cerebrospinal fluid (CSF) concentrations of Ab42 as well as total and phosphorylated tau (p-tau181p) have been shown to serve as in vivo proxy measures of the central neuropathological hallmarks of AD (Braak et al., 2013). "
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    ABSTRACT: The progression of Alzheimer's disease (AD) is characterized by complex trajectories of cerebral atrophy that are affected by interactions with age and apolipoprotein E allele ε4 (APOE4) status. In this article, we report the nonlinear volumetric changes in gray matter across the full biological spectrum of the disease, represented by the AD-cerebrospinal fluid (CSF) index. This index reflects the subject's level of pathology and position along the AD continuum. We also evaluated the associated impact of the APOE4 genotype. The atrophy pattern associated with the AD-CSF index was highly symmetrical and corresponded with the typical AD signature. Medial temporal structures showed different atrophy dynamics along the progression of the disease. The bilateral parahippocampal cortices and a parietotemporal region extending from the middle temporal to the supramarginal gyrus presented an initial increase in volume which later reverted. Similarly, a portion of the precuneus presented a rather linear inverse association with the AD-CSF index whereas some other clusters did not show significant atrophy until index values corresponded to positive CSF tau values. APOE4 carriers showed steeper hippocampal volume reductions with AD progression. Overall, the reported atrophy patterns are in close agreement with those mentioned in previous findings. However, the detected nonlinearities suggest that there may be different pathological processes taking place at specific moments during AD progression and reveal the impact of the APOE4 allele. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 07/2015; 36(10). DOI:10.1016/j.neurobiolaging.2015.06.027 · 5.01 Impact Factor
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    • "Like MRI, FDG PET has demonstrated sensitivity for AD identification at the MCI [22] and even the normal stages of cognition [7] [23], but these modalities are not pathologically specific. Amyloid PET has demonstrated some specificity for AD lesions [24], but the sensitivity of this modality continues to be investigated. Although protein content is lower in cerebrospinal fluid (CSF) than in serum, CSF is an ideal source for developing viable biomarkers in AD as it directly interacts with the extracellular space in the brain, thus potentially reflecting the associated biochemical/pathologic changes [25]. "
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    ABSTRACT: Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 05/2014; 11(1). DOI:10.1016/j.jalz.2014.02.004 · 12.41 Impact Factor
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