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 ......
Research Letters |

Longitudinal Cortical Atrophy in Amyotrophic Lateral Sclerosis With Frontotemporal Dementia FREE

Brian Avants, PhD; Alea Khan; Leo McCluskey, MD, MBE; Lauren Elman, MD; Murray Grossman, MD, EdD
Arch Neurol. 2009;66(1):138-141. doi:10.1001/archneurol.2008.542.
Text Size: A A A
Published online

Frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) presents with impaired language or behavior and declining motor function. Frontotemporal lobar degeneration with ubiquinated transactivating responsive sequence DNA-binding protein (TDP-43) inclusions is found postmortem in the affected brain areas of patients with ALS, FTD/ALS, and many patients with FTD.1 Prior magnetic resonance imaging (MRI) observations revealed cross-sectional atrophy in the motor and/or premotor cortices of patients with FTD/ALS,2 while a longitudinal study using diffusion tensor imaging revealed corticospinal tract changes.3 We used high-resolution diffeomorphic image normalization4,5 and serial MRI to provide the first assessment of longitudinal cortical atrophy in patients with FTD/ALS relative to controls.

Subjects

We contrasted 4 elderly controls with 4 patients with FTD/ALS, performed by an experienced neurologist (M.G.) at the University of Pennsylvania Department of Neurology. Two trained reviewers (M.G. and L.M.) of a consensus committee confirmed the presence of specific diagnostic criteria based on an independent review of the semistructured history, detailed mental status examination, and complete neurological examination. These patients and their legal representatives participated in an informed consent procedure approved by the institutional review board at the University of Pennsylvania. The age-matched (P < .61) patients (mean [SD] age, 61.3 [6.1] years) were right-handed, high school-educated (mean [SD] education, 17.5 [1.9] years), native English speakers with a mean (SD) Mini-Mental State Examination score at the first examination of 27.0 (3.2). The second evaluation was conducted a mean (SD) of 5.3 (0.5) months after the first evaluation, and the mean (SD) score at the second evaluation was 21.3 (8.5).

Imaging

Baseline and follow-up image acquisitions (Trio 3.0T MRI scanner; Siemens, Munich, Germany) began with a sagittal T1-weighted localizer. A T1 structural axial image was acquired with a repetition time of 1620 milliseconds; TE echo time, 3 seconds; slice thickness, 1 mm; in-plane resolution, 0.9766 mm × 0.9766 mm; and field of view, 256 × 256 × 192 voxels.

Imaging Normalization and Longitudinal Atrophy Assessment

We use a longitudinal extension4 of large deformation tensor-based morphometry (LDTBM)5 in this study. This framework first generates an unbiased intrasubject measurement of atrophy from each subject's baseline and follow-up image.4 One high-resolution voxelwise map of annual atrophy for each individual is transferred to a local template space that allows statistical contrast of subject and control longitudinal change via the t test, computed within an explicit gray matter mask.

We rendered cortical regions with significant annual atrophy due to FTD/ALS on the local template in the Figure. Significant effects occur in the premotor cortex, primary motor cortex, and parietal lobe bilaterally in Brodmann areas (BA) 4, 6, and 7. The average annual cortical atrophy over significant voxels in FTD/ALS on the right and left is 8.5% and 7.6%, respectively, in BA4; 8.1% and 5.9% in BA6; and 3.6% and 2.2% in BA7. For all cortices in FTD/ALS, the atrophy rate was 1.0% per year; in elderly controls, 0.25% per year. The local atrophy rate did not correlate with global brain atrophy; the age and global brain atrophy rates did not correlate.

Place holder to copy figure label and caption
Figure.

The significant areas of annual atrophy in our amyotrophic lateral sclerosis (ALS) population are highlighted and color-coded by neuroanatomical area on the cortex of a population-specific template. Atrophy was measured by a fine-grained quantitative structural analysis based on diffeomorphic image normalization. Such methods quantify structure in the spirit of voxel-based morphometry, but with higher anatomic fidelity and sensitivity.4,5 Significance is defined as a voxelwise false discovery rate–corrected P value of .05 with contiguous gray matter voxel clusters larger than 500 voxels. These areas indicate regions of cortical gray matter undergoing annual atrophy that are consistently greater in ALS than in the age- and education-matched elderly control population. In contrast, a cross-sectional morphometric comparison of the elderly and motor neuron degeneration cortical volumes in this cohort produced no significant effects.

Graphic Jump Location

We found significant differences in longitudinal cortical atrophy in motor and premotor areas in patients with clinical features of both ALS and FTD. Amyotrophic lateral sclerosis cooccurs with FTD in 5% to 10% of cases. This is owing, in part, to the presence of ubiquitinated TDP-43 underlying both FTD and ALS.6 Presumably, regional motor and premotor cortical atrophy reflect the motor and cognitive changes, respectively, that are characteristic of this condition. Additional study is needed to establish whether there are clinically observable changes corresponding to these parietal changes.

Cortical atrophy is thought to be difficult to detect in ALS because the relatively rapid rate of clinical progression minimizes the opportunity for noticeable cortical atrophy to emerge and motor disease limits the practical limitation of follow-up assessments. This may be the first demonstration of longitudinal cortical atrophy in FTD/ALS because normalization with LDTBM reduces residual intersubject variance in neuroanatomy while retaining sensitivity to intrasubject effects, augmenting detection power in neuromorphometry.

ARTICLE INFORMATION

Correspondence: Dr Avants, 3600 Market St, Ste 360, Philadelphia, PA 19104 (avants@grasp.cis.upenn.edu).

Author Contributions: Dr Grossman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Avants and Grossman. Acquisition of data: Khan, McCluskey, and Elman. Analysis and interpretation of data: Avants, Khan, and Grossman. Drafting of the manuscript: Avants, Khan, and Grossman. Critical revision of the manuscript for important intellectual content: Avants, McCluskey, Elman, and Grossman. Statistical analysis: Avants. Obtained funding: Avants. Administrative, technical, and material support: Khan. Study supervision: Grossman.

Financial Disclosures: None reported.

Funding/Support: This study was supported in part by grants AG17586, AG15116, NS44266, and NS53488 from the National Institutes of Health.

Forman  MSFarmer  JJohnson  JK  et al.  Frontotemporal dementia: clinicopathological correlations. Ann Neurol 2006;59 (6) 952- 962
PubMed Link to Article
Chang  JLLomen-Hoerth  CMurphy  J  et al.  A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD. Neurology 2005;65 (1) 75- 80
PubMed Link to Article
Blain  CWilliams  VJohnston  CStanton  BRGanesalingam  JJarosz  JMJones  DKBarke  GJWilliams  SCLeigh  NPSimmons  A A longitudinal study of diffusion tensor MRI in ALS. Amyotroph Lateral Scler 2007 Dec;8 (6) 348- 55Epub 2007 Oct 8
PubMed Link to Article
Avants  BAnderson  CGrossman  MGee  JC Spatiotemporal normalization for longitudinal analysis of gray matter atrophy in frontotemporal dementia. Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv 2007;10 (pt 2) 303- 310
PubMed
Kim  JAvants  BPatel  S  et al.  Structural consequences of diffuse traumatic brain injury: a large deformation tensor-based morphometry study. Neuroimage 2008;39 (3) 1014- 1026
PubMed Link to Article
Neumann  MSampathu  DMKwong  LK  et al.  Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314 (5796) 130- 133
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

The significant areas of annual atrophy in our amyotrophic lateral sclerosis (ALS) population are highlighted and color-coded by neuroanatomical area on the cortex of a population-specific template. Atrophy was measured by a fine-grained quantitative structural analysis based on diffeomorphic image normalization. Such methods quantify structure in the spirit of voxel-based morphometry, but with higher anatomic fidelity and sensitivity.4,5 Significance is defined as a voxelwise false discovery rate–corrected P value of .05 with contiguous gray matter voxel clusters larger than 500 voxels. These areas indicate regions of cortical gray matter undergoing annual atrophy that are consistently greater in ALS than in the age- and education-matched elderly control population. In contrast, a cross-sectional morphometric comparison of the elderly and motor neuron degeneration cortical volumes in this cohort produced no significant effects.

Graphic Jump Location

Tables

References

Forman  MSFarmer  JJohnson  JK  et al.  Frontotemporal dementia: clinicopathological correlations. Ann Neurol 2006;59 (6) 952- 962
PubMed Link to Article
Chang  JLLomen-Hoerth  CMurphy  J  et al.  A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD. Neurology 2005;65 (1) 75- 80
PubMed Link to Article
Blain  CWilliams  VJohnston  CStanton  BRGanesalingam  JJarosz  JMJones  DKBarke  GJWilliams  SCLeigh  NPSimmons  A A longitudinal study of diffusion tensor MRI in ALS. Amyotroph Lateral Scler 2007 Dec;8 (6) 348- 55Epub 2007 Oct 8
PubMed Link to Article
Avants  BAnderson  CGrossman  MGee  JC Spatiotemporal normalization for longitudinal analysis of gray matter atrophy in frontotemporal dementia. Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv 2007;10 (pt 2) 303- 310
PubMed
Kim  JAvants  BPatel  S  et al.  Structural consequences of diffuse traumatic brain injury: a large deformation tensor-based morphometry study. Neuroimage 2008;39 (3) 1014- 1026
PubMed Link to Article
Neumann  MSampathu  DMKwong  LK  et al.  Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314 (5796) 130- 133
PubMed Link to Article

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.

Multimedia

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

785 Views
8 Citations
×

Related Content

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

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com