Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease

Lehmann, Manja; Ghosh, Partha Pratim; Madison, Cindee; Laforce, Robert; Corbetta-Rastelli, Chiara; Weiner, Michael W.; Greicius, Michael D.; Seeley, William W.; Gorno‐Tempini, Maria Luisa; Rosen, Howard J.; Miller, Bruce L.; Jagust, William J.; Rabinovici, Gil D.

doi:10.1093/brain/aws327

Cited by 286 publications

(275 citation statements)

References 94 publications

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“…Maps of cerebral metabolic rate for glucose (CMRgl) were obtained from FDG‐PET images preprocessed at the University of California – Berkeley, following a standardized procedure described previously 41. Briefly, FDG‐PET frames were summed and standard uptake volume ratios (SUVR) were calculated by normalizing the summed FDG image to mean activity in the pons for each subject 42…”

Section: Methodsmentioning

confidence: 99%

Diagnostic utility of ASL‐MRI and FDG‐PET in the behavioral variant of FTD and AD

Tosun

Schuff

Rabinovici

et al. 2016

Ann Clin Transl Neurol

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ObjectiveTo compare the values of arterial spin‐labeled (ASL) MRI and fluorodeoxyglucose (FDG) PET in the diagnosis of behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).MethodsPartial least squares logistic regression was used to identify voxels with diagnostic value in cerebral blood flow (CBF) and cerebral metabolic rate of glucose (CMRgl) maps from patients with bvFTD (n = 32) and AD (n = 28), who were compared with each other and with cognitively normal controls (CN, n = 15). Diagnostic values of these maps were compared with each other.ResultsRegions that differentiated each disorder from controls were similar for CBF and CMRgl. For differentiating AD from CN, the areas under the curve (AUC) for CBF (0.89) and CMRgl (0.91) were similar, with similar sensitivity (CBF: 86%, CMRgl: 78%) and specificity (CBF: 92%, CMRgl: 100%). Likewise, for differentiating bvFTD from CN performances of CBF (AUC = 0.83) and CMRgl (AUC = 0.85) were equivalent, with similar sensitivity (CBF: 78%, CMRgl: 79%) and specificity (CBF: 92%, CMRgl: 100%). In differentiating bvFTD from AD, classification was again similar for CBF (AUC = 0.87) and CMRgl (AUC = 0.79), as were sensitivity (CBF: 83%, CMRgl: 89%) and specificity (CBF: 93%, CMRgl: 78%). None of the differences in any performance measure were statistically significant.InterpretationASL‐MRI has similar diagnostic utility as FDG‐PET in the diagnosis of AD and bvFTD. Continued development of ASL‐MRI as a diagnostic tool for neurodegenerative dementias is warranted.

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Section: Methodsmentioning

confidence: 99%

Diagnostic utility of ASL‐MRI and FDG‐PET in the behavioral variant of FTD and AD

Tosun

Schuff

Rabinovici

et al. 2016

Ann Clin Transl Neurol

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“…Most importantly, FDG-PET is also highly useful in differentiating within amyloid-positive subtypes of disease which cannot be distinguished on the basis of their amyloid PET-scan. This includes Lewy-body dementia, posterior cortical atrophy, and the logopenic variant of progressive aphasia [255,261]. A tight correlation between the level of metabolic decline with the degree of cognitive impairment has been demonstrated consistently [262], which qualifies this method for follow-up and therapy control studies [263].…”

Section: Fluorodeoxyglucose-petmentioning

confidence: 95%

“…Thus, amyloid-imaging may not be able to differentiate between Lewy-body dementia and AD. Furthermore, amyloidimaging alone may not be helpful with regard to distinguishing between amyloid-positive subtypes of AD (typical AD, logopenic variant of progressive aphasia, and posterior cortical atrophy) [261]. With regard to early diagnosis, a number of studies demonstrated a high predictive value of a positive amyloid-scan in the stage of MCI with regard to conversion to AD [275,276].…”

Section: Amyloid-pet Imagingmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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“…With noninvasive PET biomarkers, such as Pittsburgh compound B ( 11 C-PiB) and 18 F-FDG, AD-related pathologies, namely fibrillary amyloid burden and hypometabolism, as well as their longitudinal alterations and associations can be investigated in vivo. Compared with healthy subjects, AD patients show specific patterns of reduced 18 F-FDG metabolism, as a measure for neuronal dysfunction (4), and increased amyloid deposition (5-7), which are highly overlapping especially in the posterior cingulate cortex (PCC) and parietal and temporal cortical areas (8).…”

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confidence: 99%

Prefrontal Hypometabolism in Alzheimer Disease Is Related to Longitudinal Amyloid Accumulation in Remote Brain Regions

et al. 2015

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In PET studies of patients with Alzheimer disease (AD), prominent hypometabolism can occur in brain regions without major amyloid load. These hypometabolism-only (HO) areas may not be explained easily as a consequence of local amyloid toxicity. The aim of this longitudinal multimodal imaging study was the investigation of locoregional and remote relationships between metabolism in HO areas and longitudinal amyloid increase in functionally connected brain areas, with a particular focus on intrinsic functional connectivity as a relevant linking mechanism between pathology and dysfunction. Methods: Fifteen AD patients underwent longitudinal examinations with 11 C-Pittsburgh compound B ( 11 C-PiB) and 18 F-FDG PET (mean follow-up period, 2 y). The peak HO region was identified by the subtraction of equally thresholded statistical T maps (hypometabolism minus amyloid burden), resulting from voxel-based statistical parametric mapping group comparisons between the AD patients and 15 healthy controls. Then functionally connected and nonconnected brain networks were identified by means of seedbased intrinsic functional connectivity analysis of the resting-state functional MRI data of healthy controls. Finally, network-based, regionof-interest-based, and voxel-based correlations were calculated between longitudinal changes of normalized 11 C-PiB binding and 18 F-FDG metabolism. Results: Positive voxel-based and region-ofinterest-based correlations were demonstrated between longitudinal 11 C-PiB increases in the HO-connected network, encompassing bilateral temporoparietal and frontal brain regions, and metabolic changes in the peak HO region as well as locoregionally within several AD-typical brain regions. Conclusion: Our results indicate that in AD amyloid accumulation in remote but functionally connected brain regions may significantly contribute to longitudinally evolving hypometabolism in brain regions not strongly affected by local amyloid pathology, supporting the amyloid-and networkdegeneration hypothesis. Al zheimer disease (AD) is a progressive neurodegenerative disorder (1). Current hypotheses about the pathogenesis assume that the aggregation of b-amyloid peptides plays an important role and represents an early event of this disease by leading to synaptic dysfunction and synaptic loss, finally causing neuronal cell death and cognitive decline (2,3). The understanding of causal relations and chronologic sequences of amyloid deposition and neuronal dysfunction in the development of AD is important for the classification of disease severity and for the evaluation of new treatment approaches. The current study aims at such sequences of patterns of both amyloid plaque deposition and neural dysfunction, with particular focus on intrinsic functional connectivity as a relevant linking mechanism between pathology and dysfunction.With noninvasive PET biomarkers, such as Pittsburgh compound B ( 11 C-PiB) and 18 F-FDG, AD-related pathologies, namely fibrillary amyloid burden and hypometabolism, as well as their longitudina...

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Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease

Cited by 286 publications

References 94 publications

Diagnostic utility of ASL‐MRI and FDG‐PET in the behavioral variant of FTD and AD

Diagnostic utility of ASL‐MRI and FDG‐PET in the behavioral variant of FTD and AD

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Prefrontal Hypometabolism in Alzheimer Disease Is Related to Longitudinal Amyloid Accumulation in Remote Brain Regions

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