High Striatal Amyloid β-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types

Villemagne, Victor L.; Ataka, Suzuka; Mizuno, Toshiki; Brooks, William S.; Wada, Yasuhiro; Kondo, Masaki; Jones, Gareth; Watanabe, Yasuyoshi; Mulligan, Rachel; Nakagawa, Masanori; Miki, Takami; Shimada, Hiroyuki; O’Keefe, Graeme; Masters, Colin L.; Mori, Hiroshi; Rowe, Christopher C.

doi:10.1001/archneurol.2009.285

Cited by 165 publications

(148 citation statements)

References 53 publications

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“…The rates of PiB-negative AD (11%) and PiBpositive FTLD (16%) in our study are similar to rates of clinically misclassified patients in autopsy series, 9,10,32 suggesting that PiB may have outperformed the clinical diagnostic standard in some cases. Additional causes of false-negative PiB scans are likely to include low A␤ burden, 33 high amyloid load in the cerebellar reference region, 34 and failure of PiB to bind amyloid. 35 False-positive PiB scans are likely to represent comorbid A␤ plaques in patients with FTLD or another primary pathology.…”

Section: Pet Results In Patients With Known Histopathologymentioning

confidence: 99%

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

Rabinovici¹,

Rosen²,

Alkalay³

et al. 2011

Neurology

292

221

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Objective:To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods:Patients meeting clinical criteria for AD (n ϭ 62) and FTLD (n ϭ 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n ϭ 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.Results: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB ( ϭ 0.96) than FDG ( ϭ 0.72), as was agreement between visual and quantitative classification (PiB ϭ 0.88-0.92; FDG ϭ 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n ϭ 12 patients) and 87% for FDG (n ϭ 10). Conclusions:PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology. Neurology Differentiating Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) has implications for prognosis and symptomatic treatment, 1,2 and is critical for the efforts to develop disease-specific therapies. Making an accurate diagnosis during life can be challenging given overlapping clinical features.3,4 MRI or fluorodeoxyglucose PET (FDG-PET) can improve diagnostic accuracy by demonstrating distinct topographic patterns of atrophy or hypometabolism (temporoparietal predominant in AD; frontal and anterior temporal involvement in FTLD), 5,6 but anatomic overlap between the diseases is increasingly apparent. 5,7 Consequently, many patients with pathologically confirmed FTLD are diagnosed with AD during

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Section: Pet Results In Patients With Known Histopathologymentioning

confidence: 99%

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

Rabinovici¹,

Rosen²,

Alkalay³

et al. 2011

Neurology

292

221

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“…However, the neuroimaging literature suggests that otherwise ADAD and LOAD are substantially similar. ADAD and sAD are both associated with elevated cortical PiB uptake, especially in the in the precuneus/posterior cingulate and prefrontal cortex (54)(55)(56). Reductions in glucose metabolism in the temporal and parietal lobes have also been observed in both diseases (57)(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

Benzinger¹,

Blazey²,

Jack

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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333

341

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, and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, wholebrain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.neuroimaging | aging | dementia | neurodegeneration | DIAN T he pathological mechanisms underlying nondominantly inherited late onset Alzheimer's disease (LOAD) remain an active area of investigation (1). According to the amyloid cascade hypothesis, the precipitating event in LOAD is an alteration of the balance between production and clearance of the metabolites of amyloid precursor protein (APP) (2). Abnormalities in APP metabolism then lead to β-amyloid (Aβ) deposition in the cerebral cortex, the formation of neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein, neuronal dysfunction, cell loss, and, ultimately, dementia. In vivo biomarkers of LOAD include cerebrospinal fluid (CSF) Aβ 42 , CSF tau, amyloid deposition imaged with Pittsburgh compound B PET (PiB PET) and other amyloid tracers, altered glucose metabolism imaged with fluro-deoxyglucose PET (FDG PET), and structural atrophy assessed by volumetric MRI. A theoretical model of biomarker changes has been proposed by Jack et al. (3) that links these Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer's disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer's disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [18 F] fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism follo...

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“…In contrast to the retention pattern observed in sporadic AD, individuals with mutations within the amyloid precursor protein or presenilin 1 genes associated with familial AD present with high 11 CPiB retention in the striatum preceding the accumulation of amyloid plaques and 11 C-PiB binding in the cortical areas affected in typical sporadic AD (68)(69)(70).…”

Section: C-pib In Other Conditionsmentioning

confidence: 93%

Brain Amyloid Imaging

2011

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Imaging of brain b-amyloid plaques with 18 F-labeled tracers for PET will likely be available in clinical practice to assist the diagnosis of Alzheimer disease (AD). With the rapidly growing prevalence of AD as the population ages, and the increasing emphasis on early diagnosis and treatment, brain amyloid imaging is set to become a widely performed investigation. All physicians reading PET scans will need to know the complex relationship between amyloid and cognitive decline, how to best acquire and display images for detection of amyloid, and how to recognize the patterns of tracer binding in AD and other causes of dementia. This article will provide nuclear medicine physicians with the background knowledge required for understanding this emerging investigation, including its appropriate use, and prepare them for practical training in scan interpretation.

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High Striatal Amyloid β-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types

Cited by 165 publications

References 53 publications

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

Brain Amyloid Imaging

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