0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

The Role of Clusterin in Amyloid-β–Associated Neurodegeneration

Rahul S. Desikan, MD, PhD1; Wesley K. Thompson, PhD2; Dominic Holland, PhD3; Christopher P. Hess, MD, PhD4; James B. Brewer, MD, PhD1,3; Henrik Zetterberg, MD, PhD5,6; Kaj Blennow, MD, PhD5; Ole A. Andreassen, MD, PhD2,7; Linda K. McEvoy, PhD1; Bradley T. Hyman, MD, PhD8; Anders M. Dale, PhD1,2; for the Alzheimer’s Disease Neuroimaging Initiative Group
[+] Author Affiliations
1Department of Radiology, University of California, San Diego, La Jolla
2Department of Psychiatry, University of California, San Diego, La Jolla
3Department of Neurosciences, University of California, San Diego, La Jolla
4Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco
5Clinical Neurochemistry Laboratory, The Sahlgrenska Academy at Göteburg University, Mölndal, Gotheburg, Sweden
6University College London Institute of Neurology, Queen Square, London, England
7Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
8Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
JAMA Neurol. 2014;71(2):180-187. doi:10.1001/jamaneurol.2013.4560.
Text Size: A A A
Published online

Importance  Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.

Objective  To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.

Design, Setting, and Participants  This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).

Main Outcomes and Measures  Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.

Results  Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42–positive individuals but not among CSF Aβ1-42–negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.

Conclusions and Relevance  In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.

Figures in this Article

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

First Page Preview

View Large
First page PDF preview

Figures

Place holder to copy figure label and caption
Figure 1.
T1-Weighted Magnetic Resonance Images

Images in the coronal dimension and a medial semi-inflated gray matter cortical surface depicting the hippocampus (A) and entorhinal cortex (B) and 1-year volume change fields (C and D) for a participant with mild cognitive impairment at the median for hippocampus and entorhinal cortex volume loss (annualized percentage change) who was amyloid-β positive, phosphorylated tau positive, and demonstrated elevated clusterin levels. A, Automated segmentation of the baseline, structural magnetic resonance image with subcortical structures (including the hippocampus) depicted in various colors. B, The red overlay shows the gray matter/cerebrospinal fluid boundary, the white overlay depicts the gray/white matter boundary, and the distance between these surfaces represents the cortical thickness. Here, we were primarily interested in evaluating longitudinal thinning of the entorhinal cortex. C, Heat map representation of the voxelwise estimates of volumetric change at 1 year. Note that volumetric change is most pronounced in the medial temporal lobe. D, Semi-inflated gray matter cortical surface (medial hemisphere) with a heat map representation of cortical volumetric change at 1 year. Note that volumetric change is most pronounced in the medial temporal and temporopolar cortices. A indicates amygdala; EC, entorhinal cortex; GP, globus pallidus; H, hippocampus; P, putamen; RS, rhinal sulcus; TH, temporal horn lateral ventricles.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Diagram of the Primary Hypotheses Evaluated in the Current Study Where the Primary Outcome Was Longitudinal Medial Temporal Lobe Atrophy

The diagram shows the main effect of clusterin (β1), the main effect of amyloid-β 1-42 (Aβ1-42)(β2), the main effect of phosphorylated tau (p-tau) (β3), an interactive effect between clusterin and Aβ1-42 4 and circle with dot in the center), and an interactive effect between clusterin and p-tau (β5 and circle with dot in the center). CSF indicates cerebrospinal fluid. The circle with the dot in the center illustrates an interactive effect.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Spaghetti Plots of Participants With and Without Amyloid-β 1-42 (Aβ1-42)

Spaghetti plots illustrating atrophy of the entorhinal cortex among all nondemented older participants classified as Aβ1-42 positive and high clusterin (based on median value of clusterin) (A), Aβ1-42 positive and low clusterin (B), Aβ1-42 negative and high clusterin (C), and Aβ1-42 negative and low clusterin (D). The red line indicates the mean atrophy rate for the 4 respective groups (ie, Aβ1-42 positive and high clusterin, Aβ1-42 positive and low clusterin, Aβ1-42 negative and high clusterin, and Aβ1-42 negative and low clusterin). As illustrated in parts A and B, the slopes of the red lines between the Aβ1-42–positive and high-clusterin and Aβ1-42–positive and low-clusterin individuals are significantly different, corresponding to the significant interaction between cerebrospinal fluid Aβ1-42, cerebrospinal fluid clusterin, and time (see text for further details).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Spaghetti Plots of Participants With and Without Phosphorylated Tau (P-tau)

Spaghetti plots illustrating atrophy of the entorhinal cortex among all nondemented older participants classified as p-tau positive and high clusterin (based on median value of cerebrospinal fluid clusterin) (A), p-tau positive and low clusterin (B), p-tau negative and high clusterin (C), and p-tau negative and low clusterin (D). The red line indicates the mean atrophy rate for the 4 respective groups (ie, p-tau positive and high clusterin, p-tau positive and low clusterin, p-tau negative and high clusterin, and p-tau negative and low clusterin). As illustrated in parts A and B, the slopes of the red lines between the p-tau–positive and high-clusterin and p-tau–positive and low-clusterin individuals are not significantly different, corresponding to the nonsignificant interaction between cerebrospinal fluid p-tau, cerebrospinal fluid clusterin, and time (see text for further details).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.
Results From Linear Mixed-Effects Model

Diagram demonstrates the independent effects of clusterin and phosphorylated tau (p-tau) on Amyloid-β (Aβ)–associated volume loss in nondemented older individuals (see text for details). The circle with the dot in the center illustrates an interactive effect and the arrow demonstrates a main effect of Aβ. AD indicates Alzheimer disease.

Graphic Jump Location

Tables

References

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 2

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
Jobs
brightcove.createExperiences();