TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia

Rohrer, Jonathan D.; Geser, Felix; Zhou, Juan; Gennatas, Efstathios D.; Sidhu, M.; Trojanowski, John Q.; DeArmond, Stephen J.; Miller, Bruce L.; Seeley, William W.

doi:10.1212/wnl.0b013e318202038c

Cited by 169 publications

(144 citation statements)

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“…30 Consistent with our results, a recent study found mild to moderate p62 and TDP-43 staining in the thalamus of 4 C9ϩ carriers with MND. 31 Thalamic atrophy has been described in FTLD-TDP type A, 5,32 but not in type B, which is typically associated with FTD-MND. Although most FTD-MND cases show FTLD-TDP type B histology, an unexpected feature of C9ORF72 pathology is the frequency of FTLD-TDP type A.…”

Section: Demographicsmentioning

confidence: 99%

“…3,4 Many patients with FTD and ALS exhibit autosomal dominant family histories (FTD 10% 5 ; ALS 5%-10% 6 ; FTD-motor neuron disease [MND] 37% 7 ) and a number of large familial cohorts have been linked to a chromosome 9p region. [7][8][9][10][11][12] Recently, a noncoding expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) was identified as the cause of chromosome 9p-associated FTD and ALS.…”

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confidence: 99%

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Frontotemporal dementia due to C9ORF72 mutations

et al. 2012

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Objective: To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion. Methods:A total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9ϩ Results: All C9ϩ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9ϩ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9ϩFTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers. Conclusions: GLOSSARYAD ϭ Alzheimer disease; ALS ϭ amyotrophic lateral sclerosis; bvFTD ϭ behavioral variant frontotemporal dementia; CBS ϭ corticobasal syndrome; CDR-SB ϭ Clinical Dementia Rating Scale sum of boxes; FTD ϭ frontotemporal dementia; FWE ϭ familywise error; glm ϭ generalized linear model; lvPPA ϭ logopenic variant primary progressive aphasia; MND ϭ motor neuron disease; nfvPPA ϭ nonfluent variant primary progressive aphasia; NPI ϭ Neuropsychiatric Inventory; PSP ϭ progressive supranuclear palsy; svPPA ϭ semantic variant primary progressive aphasia; UCSF ϭ University of California, San Francisco; VBM ϭ voxel-based morphometry.Frontotemporal dementia (FTD) is a common dementia syndrome among patients presenting before 65 years of age with prevalence equal to Alzheimer disease (AD) dementia.1,2 FTD often overlaps with amyotrophic lateral sclerosis (ALS), with symptoms of FTD occurring in 15%-41% of patients with ALS and features of ALS occurring in 15% of FTD.3,4 Many patients with FTD and ALS exhibit autosomal dominant family histories (FTD 10% 5 ; ALS 5%-10% 6 ; FTD-motor neuron disease [MND] 37% 7 ) and a number of large familial cohorts have been linked to a chromosome 9p region. [7][8][9][10][11][12] Recently, a noncoding expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) was identified as the cause of chromosome 9p-associated FTD and ALS. 13,14 This mutation is the most common genetic cause of familial and sporadic behavioral variant FTD (bvFTD) and ALS.In one study, the C9ORF72 (C9FTD/ALS) expansion accounted for 11.7% of familial FTD, 22.5% of familial ALS, and 4% of sporadic ALS.13 Previous family studies of chromosome 9p-linked families 7,8,10 suggested that some features may distinguish this mutation from sporadic

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Section: Demographicsmentioning

confidence: 99%

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confidence: 99%

Frontotemporal dementia due to C9ORF72 mutations

et al. 2012

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“…Few studies, however, have investigated whether these morphological features characterize the spectrum of FTDs, and whether thalamic morphology could assist in delineating various subtypes of this entity. Rohrer et al (2010) investigated 18 FTD patients who had antemortem MRI and postmortem confirmation of the TDP-43 subtype of FTD (positive immunoreactive inclusions), and using voxel-based morphometry reported that thalamic atrophy was useful in distinguishing FTD TDP-43 type 3 relative to types 1 and 2. Sharon et al (2012) investigated patterns of brain atrophy in FTD patients who were carriers for chromosome open reading frame 72 (C9ORF72) expansions, and reported greater thalamic atrophy (left > right) in carriers vs non carriers of this expansion.…”

Section: Thalamic Morphology In Other Neurodegenerative Disordersmentioning

confidence: 99%

The thalamus as a putative biomarker in neurodegenerative disorders

Power

Looi

2015

Aust N Z J Psychiatry

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Objective: This review provides a brief account of the clinically relevant functional neuroanatomy of the thalamus, before considering the utility of various modalities utilized to image the thalamus and technical challenges therein, and going on to provide an overview of studies utilizing structural imaging techniques to map thalamic morphology in the spectrum of neurodegenerative disorders. Methods:A systematic search was conducted for peer-reviewed studies involving structural neuroimaging modalities investigating the morphology (shape and/or size) of the thalamus in the spectrum of neurodegenerative disorders.Results: While the precise role of the thalamus in the healthy brain remains unclear, there is a large body of knowledge accumulating which defines more precisely its functional connectivity within the connectome, and a burgeoning literature implicating its involvement in neurodegenerative disorders. It is proposed that correlation of clinical features with thalamic morphology (as a component of a quantifiable subcortical connectome) will provide a better understanding of neuropsychiatric dysfunction in various neurodegenerative disorders, potentially yielding clinically useful endophenotypes and disease biomarkers. Conclusion:Thalamic biomarkers in the neurodegenerative disorders have great potential to provide clinically meaningful knowledge regarding not only disease onset and progression but may yield targets of and perhaps a way of gauging response to future disease-modifying modalities.

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“…35,36 Temporoparietal atrophy with sparing of midbrain can also be seen with Alzheimer disease. However, Alzheimer disease is unlikely in agPPA because no subject showed positive PiB-PET.…”

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Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA

et al. 2013

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Objective: We assessed whether clinical and imaging features of subjects with apraxia of speech (AOS) more severe than aphasia (dominant AOS) are more similar to agrammatic primary progressive aphasia (agPPA) or to primary progressive AOS (PPAOS).Methods: Sixty-seven subjects (PPAOS 5 18, dominant AOS 5 10, agPPA 5 9, age-matched controls 5 30) who all had volumetric MRI, diffusion tensor imaging, F18-fluorodeoxyglucose and C11-labeled Pittsburgh compound B (PiB)-PET scanning, as well as neurologic and speech and language assessments, were included in this case-control study. AOS was classified as either type 1, predominated by sound distortions and distorted sound substitutions, or type 2, predominated by syllabically segmented prosodic speech patterns. Results:The dominant AOS subjects most often had AOS type 2, similar to PPAOS. In contrast, agPPA subjects most often had type 1 (p 5 0.01). Both dominant AOS and PPAOS showed focal imaging abnormalities in premotor cortex, whereas agPPA showed widespread involvement affecting premotor, prefrontal, temporal and parietal lobes, caudate, and insula. Only the dominant AOS and PPAOS groups showed midbrain atrophy compared with controls. No differences were observed in PiB binding across all 3 groups, with the majority being PiB negative. Conclusion:These results suggest that dominant AOS is more similar to PPAOS than agPPA, with dominant AOS and PPAOS exhibiting a clinically distinguishable subtype of progressive AOS compared with agPPA. Neurology â 2013;81:337-345 GLOSSARY agPPA 5 agrammatic primary progressive aphasia; AOS 5 apraxia of speech; ASRS 5 Apraxia of Speech Rating Scale; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; FDG 5 F18-fluorodeoxyglucose; MD 5 mean diffusivity; NOS 5 not otherwise specified; PiB 5 Pittsburgh compound B; PPA 5 primary progressive aphasia; PPAOS 5 primary progressive apraxia of speech; PSPS 5 progressive supranuclear palsy syndrome; TDP-43 5 TAR DNA binding protein of 43 kDa; WAB 5 Western Aphasia Battery.The term apraxia of speech (AOS) is used to denote a motor speech disorder in which abnormalities reflect deficits in the programming of movements for speech production.1,2 Although usually caused by left hemisphere stroke, AOS can also be associated with neurodegenerative disease, and when it is the only sign or symptom, it is labeled primary progressive AOS (PPAOS).3,4 Unlike PPAOS, the term primary progressive aphasia (PPA) is reserved for a neurodegenerative disorder in which the most salient feature is language dysfunction. 5-7 Agrammatic PPA (agPPA) is one subtype of PPA, characterized by specific abnormalities that affect grammar and syntax in verbal or written expression. 8,9 Although it is recognized that many subjects with agPPA may have AOS, the most salient feature of agPPA is aphasia. In fact, to be diagnosed with any variant of PPA, 8 language difficulty must be the most prominent clinical feature at symptom onset and for the initial phases of the disease; deficits cannot be due to "disruption o...

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TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia

Abstract: FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation.

Cited by 169 publications

References 30 publications

Frontotemporal dementia due to C9ORF72 mutations

Frontotemporal dementia due to C9ORF72 mutations

The thalamus as a putative biomarker in neurodegenerative disorders

Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA

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