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

Gil D. Rabinovici, Ansgar J. Furst, Adi Alkalay, Caroline A. Racine, James P. O'Neil, Mustafa Janabi, Suzanne L. Baker, Neha Agarwal, Stephen J. Bonasera, Elizabeth C. Mormino, Michael W. Weiner, Maria L. Gorno-Tempini, Howard J. Rosen, Bruce L. Miller, William J. Jagust

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

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-β. 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-β-ligand [11C]-labelled Pittsburgh compound-B and the glucose analogue [18F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 ± 6.4) was studied for comparison. [11C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [ 18F]-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 [11C]-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 [11C]-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 [11C]-labelled Pittsburgh compound-B and [18F]-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 [ 11C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-β 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-β accumulation and increased vulnerability to amyloid-β pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

Original languageEnglish (US)
Pages (from-to)512-528
Number of pages17
JournalBrain
Volume133
Issue number2
DOIs
StatePublished - Feb 1 2010

Fingerprint

Amyloid
Alzheimer Disease
Age of Onset
Parietal Lobe
Fluorodeoxyglucose F18
Atrophy
Glucose
Positron-Emission Tomography
National Institute of Neurological Disorders and Stroke
Communication Disorders
Occipital Lobe
Pons
Gyrus Cinguli
Temporal Lobe
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Research Design
Pathology
Ligands
Education
Brain

Keywords

  • Age of onset
  • Alzheimer's disease
  • Amyloid-β
  • [C]-labelled Pittsburgh compound-B
  • [F]-labelled fluorodeoxyglucose

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Rabinovici, G. D., Furst, A. J., Alkalay, A., Racine, C. A., O'Neil, J. P., Janabi, M., ... Jagust, W. J. (2010). Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. Brain, 133(2), 512-528. https://doi.org/10.1093/brain/awp326

Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. / Rabinovici, Gil D.; Furst, Ansgar J.; Alkalay, Adi; Racine, Caroline A.; O'Neil, James P.; Janabi, Mustafa; Baker, Suzanne L.; Agarwal, Neha; Bonasera, Stephen J.; Mormino, Elizabeth C.; Weiner, Michael W.; Gorno-Tempini, Maria L.; Rosen, Howard J.; Miller, Bruce L.; Jagust, William J.

In: Brain, Vol. 133, No. 2, 01.02.2010, p. 512-528.

Research output: Contribution to journalArticle

Rabinovici, GD, Furst, AJ, Alkalay, A, Racine, CA, O'Neil, JP, Janabi, M, Baker, SL, Agarwal, N, Bonasera, SJ, Mormino, EC, Weiner, MW, Gorno-Tempini, ML, Rosen, HJ, Miller, BL & Jagust, WJ 2010, 'Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden', Brain, vol. 133, no. 2, pp. 512-528. https://doi.org/10.1093/brain/awp326
Rabinovici GD, Furst AJ, Alkalay A, Racine CA, O'Neil JP, Janabi M et al. Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. Brain. 2010 Feb 1;133(2):512-528. https://doi.org/10.1093/brain/awp326
Rabinovici, Gil D. ; Furst, Ansgar J. ; Alkalay, Adi ; Racine, Caroline A. ; O'Neil, James P. ; Janabi, Mustafa ; Baker, Suzanne L. ; Agarwal, Neha ; Bonasera, Stephen J. ; Mormino, Elizabeth C. ; Weiner, Michael W. ; Gorno-Tempini, Maria L. ; Rosen, Howard J. ; Miller, Bruce L. ; Jagust, William J. / Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. In: Brain. 2010 ; Vol. 133, No. 2. pp. 512-528.
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AU - Rabinovici, Gil D.

AU - Furst, Ansgar J.

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AU - Racine, Caroline A.

AU - O'Neil, James P.

AU - Janabi, Mustafa

AU - Baker, Suzanne L.

AU - Agarwal, Neha

AU - Bonasera, Stephen J.

AU - Mormino, Elizabeth C.

AU - Weiner, Michael W.

AU - Gorno-Tempini, Maria L.

AU - Rosen, Howard J.

AU - Miller, Bruce L.

AU - Jagust, William J.

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N2 - 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-β. 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-β-ligand [11C]-labelled Pittsburgh compound-B and the glucose analogue [18F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 ± 6.4) was studied for comparison. [11C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [ 18F]-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 [11C]-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 [11C]-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 [11C]-labelled Pittsburgh compound-B and [18F]-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 [ 11C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-β 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-β accumulation and increased vulnerability to amyloid-β pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

AB - 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-β. 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-β-ligand [11C]-labelled Pittsburgh compound-B and the glucose analogue [18F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 ± 6.4) was studied for comparison. [11C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [ 18F]-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 [11C]-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 [11C]-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 [11C]-labelled Pittsburgh compound-B and [18F]-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 [ 11C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-β 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-β accumulation and increased vulnerability to amyloid-β pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

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