Pittsburgh Compound B Uptake Research Articles

Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden

Patients with early age-of-onset Alzheimer's disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer's disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer's disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimer's disease. Our data are consistent with a model in which both early amyloid-beta accumulation and increased vulnerability to amyloid-beta pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

Posterior cortical atrophy with [11C] Pittsburgh compound B accumulation in the primary visual cortex

Sirs, Posterior cortical atrophy (PCA) is a presenile dementia that presents primarily with signs and symptoms of cortical visual dysfunction [1]. The most common associated pathologic findings of PCA are amyloid plaques and neurofibrillary tangles predominantly affecting the visual association areas [8]. Although [C] Pittsburgh compound B (PIB) PET studies of amnestic Alzheimer’s disease (AD) have been conducted [2, 3, 5], the link between amyloid-b (Ab) and regional brain dysfunction remains controversial. However, two PIB studies of PCA supported the possible link between Ab deposition and clinical features [7, 10]. Here, we describe a patient with PCA who showed left homonymous hemianopsia and uncoupling between PIB uptake and glucose metabolism in the right occipital lobe. A 63-year-old woman consulted our hospital with a 5-year history of poor vision. She first noticed that characters on posters appeared to be shaking. One year later, she found difficulty in reading subtitles in movies and then she became unable to read books. On neurological examination, she showed left homonymous hemianopsia. A Goldmann dynamic visual field examination demonstrated macular-sparing left homonymous hemianopsia. Visual acuity was normal and bilateral light reflexes were prompt. Other neurological examinations were normal. On neuropsychological evaluations, she showed visuospatial dysfunction and dyscalculia. MMSE score was 26 of 30. Memory function was preserved. She demonstrated disturbed recognition of superimposed figures. Face and color recognition were normal. Cerebrospinal fluid (CSF) Ab42 was decreased (297 pg/ ml) and in normal controls, the levels are 874 ± 293 pg/ml (mean ± SD, INNOTEST b-AMYLOID(1-42), Innogenetics, Ghent, Belgium). CSF tau protein phosphorylated at serine 199 was increased (1.36 pM). In normal controls, these levels are 0.6 ± 0.4 pM [4]. [F] fluorodeoxyglucose (FDG) PET image was acquired for 6 min starting 45 min after the injection of 150 MBq of tracer. The accumulation of [C] PIB was evaluated by a standardized uptake value ratio (SUVR) on a summing image obtained 40–60 min after injection of 500 MBq of tracer taking the cerebellar cortex as a reference region. [F] FDG PET showed hypometabolism in the temporo-parieto-occipital lobe predominantly on the right (Fig. 1d–f). [C] PIB PET demonstrated increased uptake in the bilateral frontal lobes and parietal and occipital cortices with more intense uptake on the right (Fig. 1g–i). In the right occipital lobe, FDG uptake showed lower metabolism in the lateral occipital cortex (Fig. 1d, e, arrow) than in the calcarine cortex (Fig. 1d, e, arrowhead). In contrast, amyloid imaging demonstrated high PIB uptake in the right calcarine cortex (Fig. 1g, h, arrowhhead) while the adjacent lateral occipital cortex showed normal PIB uptake (Fig. 1g, h, arrow). It was shown that macular sparing occurred when the posterior part of the calcarine cortex was spared in patients with striate cortical disease such as infarction, neoplasm and cerebromalacia, while macular splitting occurred when the occipital pole and operculum were involved [6]. Neuroimaging studies of our patient demonstrated that in the occipital lobe, there were two regions showing different T. Kambe Y. Motoi (&) N. Hattori Department of Neurology, Juntendo University School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo 113-8421, Japan e-mail: motoi@juntendo.ac.jp

HAI Seattle: Does Brain Amyloid Correlate With Sagging Metabolism?

7 May 2009. Slowly but surely, Alzheimer’s disease (AD) researchers are coming to grips with the possibility that some experimental therapies could be failing because they have been tested in people whose disease is too advanced. The field’s focus is therefore shifting toward earlier diagnosis, even prevention. Reflecting the new emphasis, this year’s Human Amyloid Imaging (HAI) meeting drew some 150 researchers to Seattle on 24 April to share and discuss the latest in brain imaging, which will be crucial for identifying at-risk individuals and helping them resist impending AD. A growing literature documents elevated brain amyloid in a substantial proportion of seniors who appear cognitively normal. This finding has stirred up new questions – not the least of which is whether this amyloid foretells future AD. That issue remains to be clearly resolved. However, ask any number of researchers at the HAI meeting, and chances are they’ll reckon that having a head full of amyloid is worrisome. “There was consensus that among normal people, amyloid is associated with changes in the brain,” said Reisa Sperling of Brigham and Women’s Hospital in Boston, Massachusetts, in a conversation with this reporter during the poster session. “That might be very valuable in identifying individuals who will get preventive treatment. If we can identify people who are going to get AD a decade later, we have a window to treat people before they get symptoms,” Sperling noted. To address that “if,” HAI’s opening session explored the relationship between amyloid deposition and functional changes in the brain. Each can be measured by positron emission tomography (PET) – the former with radiolabeled amyloid tracers, the latter using fluorodeoxyglucose (FDG) metabolism. Previous live brain imaging with the PET tracer Pittsburgh Compound-B (PIB) has revealed elevated Aβ in 10 to 30 percent of cognitively normal elderly, and has shown that amyloid load tracks longitudinally with whole brain atrophy. Elizabeth Mormino, a Ph.D. student in Bill Jagust’s lab at the University of California, Berkeley, addressed whether high amyloid deposition also coincides with reduced glucose metabolism, i.e., portends a loss of brain function. In her study, normal seniors and AD patients received magnetic resonance imaging (MRI) to track brain atrophy, FDG-PET to measure glucose metabolism, and PIB-PET to detect amyloid load. Based on a published method for defining cut-offs, all AD patients in Mormino’s group were classified as “high PIB,” as were 11 of 40 normal participants. Among the remaining healthy seniors, 21 came up as having “low PIB,” and the rest fell into an intermediate zone. The subjects were also grouped according to FDG metabolism. Within the cognitively normal group, high PIB was associated with reduced glucose metabolism, albeit with FDG-PET patterns less pronounced than in demented populations. Among those with high PIB, lower glucose metabolism also correlated with worse episodic memory. This trend did not hold for the people with low PIB. All told, the data suggest that elevated PIB uptake in normal seniors may suggest preclinical AD, Mormino said. Ann Cohen, a postdoctoral fellow in Bill Klunk’s group at the University of Pittsburgh, Pennsylvania, also reported a link between amyloid load (PIB-PET) and cerebral metabolism (FDG-PET). In her study of 51 healthy seniors, 38 had high PIB uptake and 13 fell into the low-PIB group. Cohen used software

PET Amyloid Ligand [11C]PIB Uptake and Cerebrospinal Fluid β-Amyloid in Mild Cognitive Impairment

Background: In mild cognitive impairment (MCI), Alzheimer’s disease (AD)-type cerebrospinal fluid (CSF) biomarker profiles predict rapid progression and conversion to AD. An increased brain amyloid burden in AD and MCI has been demonstrated with PET using [¹¹C]PIB (Pittsburgh compound B). Little is known about the relationship between these biomarkers in MCI. Methods: We studied 15 patients with amnestic MCI and 22 controls with PET using [¹¹C]PIB. In MCI patients, CSF levels of Aβ42, pTAU, totalTAU and the Aβ42/pTAU ratio were measured. Results: In MCI patients, CSF Aβ42 was abnormal in 53% of patients, totalTAU in 67%, pTAU in 64% and the Aβ42/pTAU ratio in 64%. A composite neocortical [¹¹C]PIB uptake score was increased in 87% of the MCI patients. Only 54% of [¹¹C]PIB-positive subjects showed AD-type Aβ42 values. During a 2-year follow-up, 6 MCI patients converted to AD, all of them had increased neocortical PIB scores at the MCI stage. Abnormal CSF Aβ42 was found in 3 patients, pTAU in 3 patients and Aβ42/pTAU ratio in 4 patients. Conclusion: Follow-up studies are needed to confirm whether [¹¹C]PIB uptake might be more sensitive than CSF Aβ42 concentration in detecting increased amyloid burden in MCI, as suggested by the results of this study.

Molecular Imaging With Pittsburgh Compound B Confirmed at Autopsy

To determine the correspondence between uptake of Pittsburgh Compound B (PiB) in life and measures of beta-amyloid (Abeta) in postmortem tissue analysis. Patient A 76-year-old man with a clinical diagnosis of dementia with Lewy bodies underwent fluorodeoxyglucose (18)F and PiB positron emission tomographic brain scans. Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. Intervention Autopsy was performed 3 months after the PiB scan. Autopsy confirmed the clinical diagnosis; in addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal Abeta plaques. Biochemical measures revealed a positive correlation between Abeta levels and regional PiB binding. This report confirms that PiB detects Abeta in the living patient and demonstrates that amyloid deposited as cerebral amyloid angiopathy can be the dominant source of signal.