Cognitive decline and reduced survival in<i>C9orf72</i>expansion frontotemporal degeneration and amyotrophic lateral sclerosis

Irwin, David J.; McMillan, Corey T.; Brettschneider, Johannes; Libon, David J.; Powers, John; Rascovsky, Katya; Toledo, Jon B.; Boller, Ashley; Bekisz, Jonathan M.; Chandrasekaran, Keerthi; Wood, Elisabeth McCarty; Shaw, Leslie M.; Woo, John; Cook, Philip A.; Wolk, David A.; Arnold, Steven E.; Deerlin, Vivianna M. Van; McCluskey, Leo; Elman, Lauren; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Grossman, Murray

doi:10.1136/jnnp-2012-303507

Cited by 141 publications

(150 citation statements)

References 43 publications

(28 reference statements)

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“…In our study, we confirmed that frontotemporal hypometabolism is associated with a worse individual prognosis, likely because of an underlying frontotemporal dementia or cognitive/behavioral dysfunction, a finding already reported in previous studies (19)(20)(21)(22)28). In this study, there is a significant difference in survival between patients with and without extensive frontotemporal hypometabolism on a visual basis but we were not able to find a significant linear correlation between the survival and the volumeweighted average of frontotemporal 18 F-FDG activity.…”

Section: Discussionsupporting

confidence: 76%

Prospective Validation of ¹⁸F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

et al. 2016

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An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. 18 F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-ofinterest (VOI) and voxel-based (using a support vector machine [SVM] approach) 18 F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a prioriderived classifiers. Furthermore, the prognostic value of 18 F-FDG PET was evaluated. Methods: A prospective cohort of patients with a suspected diagnosis of a motor neuron disorder (n 5 119; mean age ± SD, 61 ± 12 y; 81 men and 38 women) was recruited. One hundred five patients were diagnosed with ALS (mean age ± SD, 61.0 ± 12 y; 74 men and 31 women) (group 2), 10 patients with primary lateral sclerosis (mean age ± SD, 55.5 ± 12 y; 3 men and 7 women), and 4 patients with progressive muscular atrophy (mean age ± SD, 59.2 ± 5 y; 4 men). The mean disease duration of all patients was 15.0 ± 13.4 mo at diagnosis, with PET conducted 15.2 ± 13.3 mo after the first symptoms. Data were compared with a previously gathered dataset of 20 screened healthy subjects (mean age ± SD, 62.4 ± 6.4 y; 12 men and 8 women) and 70 ALS patients (mean age ± SD, 62.2 ± 12.5 y; 44 men and 26 women) (group 1). Data were spatially normalized and analyzed on a VOI basis (statistical software (using the Hammers atlas) and voxel basis using statistical parametric mapping. Discriminant analysis and SVM were used to classify new cases based on the classifiers derived from group 1. Results: Compared with controls, ALS patients showed a nearly identical pattern of hypo-and hypermetabolism in groups 1 and 2. VOI-based discriminant analysis resulted in an 88.8% accuracy in predicting the new ALS cases. For the SVM approach, this accuracy was 100%. Brain metabolism between ALS and primary lateral sclerosis patients was nearly identical and not separable on an individual basis. Extensive frontotemporal hypometabolism was predictive for a lower survival using a Kaplan-Meier survival analysis (P , 0.001). Conclusion: On the basis of a previously acquired training set, 18 F-FDG PET with advanced discriminant analysis methods is able to accurately distinguish ALS from controls and aids in assessing individual prognosis. Further validation on multicenter datasets and ALS-mimicking disorders is needed to fully assess the general applicability of this approach.

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Section: Discussionsupporting

confidence: 76%

Prospective Validation of ¹⁸F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

et al. 2016

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“…4,8,28,29 Earlier age at onset in C9Pos patients has been used as a rationale to describe C9orf72-related ALS as a more aggressive form of the disease. Our inability to confirm this finding might be explained by our study design, which compared the C9Pos group to a concurrent and unselected group of patients with ALS, rather than a designated comparison cohort.…”

Section: Demographic and Clinical Information Acquisitionmentioning

confidence: 99%

“…Our inability to confirm this finding might be explained by our study design, which compared the C9Pos group to a concurrent and unselected group of patients with ALS, rather than a designated comparison cohort. 8 Additionally, the published reports of increased prevalence of bulbar onset in C9Pos patients has been used to suggest a more severe disease since patients with bulbar disease are typically thought to carry a worse prognosis. 30,31 Bulbar onset was not overrepresented in our C9pos cohort, though we acknowledge that the numbers of C9Pos compared to C9Neg patients were relatively small.…”

Section: Demographic and Clinical Information Acquisitionmentioning

confidence: 99%

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Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Umoh

Fournier

et al. 2016

Neurology

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Objective: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.Methods: Between 2001 and, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.Results: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank x 2 [1] 5 45.323, p , 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD. Conclusions:Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

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“…These nuclei play a role in numerous behavioral functions including motivation and drive, memory, emotional experience and expression, executive functions and attention [34]. A gray matter atrophy of the medial thalamus has been previously detected in patients with the C9ORF72 expansion [35,36]. We used gray matter volumes as regressors to minimize the effects of atrophy on the functional connectivity analysis and hence the present finding of increased anti-correlation is not due to atrophy.…”

Section: Discussionmentioning

confidence: 99%

Functional MRI in Patients with the C9ORF72 Expansion associate Frontotemporal Dementia

Rytty¹,

Nikkinen²,

Noora³

et al. 2014

Mol Biol

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Functional MRI studies have revealed connectivity changes in several brain networks in patients with neurodegenerative diseases and imaging genomics is an emerging field to investigate the role of genetics in brain function. A hexanucleotide repeat expansion in open reading frame in chromosome 9 (C9ORF72) is a common cause of familial frontotemporal dementia. The aim of this study was to evaluate resting state networks in behavioral variant frontotemporal dementia (bvFTD) patients with the C9ORF72 expansion by using functional MRI. Seven patients and matched healthy controls were examined. The group specific resting state networks were identified by independent component analysis and the dual regression technique was used to detect between-group differences in the resting state networks with p<0.05 threshold corrected for multiple comparisons. Increased anti-correlation between bilateral thalamic parts of the salience network and anterior sub-network of the Default mode network (DMN) was found in patients with the C9ORF72 expansion. In addition, increased resting state connectivity was detected in the right-sided dorsal attention network. The changes in these cognitive networks may explain executive dysfunction as well as neuropsychiatric symptoms in patients with bvFTD.

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Cognitive decline and reduced survival inC9orf72expansion frontotemporal degeneration and amyotrophic lateral sclerosis

Cited by 141 publications

References 43 publications

Prospective Validation of ¹⁸F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

Prospective Validation of ¹⁸F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Functional MRI in Patients with the C9ORF72 Expansion associate Frontotemporal Dementia

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Cognitive decline and reduced survival inC9orf72expansion frontotemporal degeneration and amyotrophic lateral sclerosis

Cited by 141 publications

References 43 publications

Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Functional MRI in Patients with the C9ORF72 Expansion associate Frontotemporal Dementia

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Prospective Validation of ¹⁸F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

Prospective Validation of ¹⁸F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis