Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration?

Whitwell, Jennifer L.; Jack, Clifford R.; Parisi, Joseph E.; Senjem, Matthew L.; Knopman, David S.; Boeve, Bradley F.; Rademakers, Rosa; Baker, Matthew; Petersen, Ronald C.; Dickson, Dennis W.; Josephs, Keith A.

doi:10.1212/wnl.0b013e31820203c2

Cited by 71 publications

(72 citation statements)

References 35 publications

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“…Subjects with bvFTD have heterogeneous pathologic and genetic etiologies, 2 which are typically associated with differing patterns of atrophy. 10,35 Patterns of functional change in bvFTD may also differ according to pathology or genetics, although without pathologic confirmation we cannot draw firm conclusions concerning any such relationships. The 4 subjects with bvFTD with mutations in MAPT did however show very similar patterns of functional change to the rest of the bvFTD cohort.…”

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Altered functional connectivity in asymptomatic MAPT subjects

Josephs²,

et al. 2011

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Objective: To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). Methods:In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. Results:The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. Conclusions:Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease. Neurology ® 2011;77:866-874 GLOSSARY AD ϭ Alzheimer disease; BOLD ϭ blood oxygenation level-dependent; bvFTD ϭ behavioral variant frontotemporal dementia; DMN ϭ default mode network; FOV ϭ field of view; FTD ϭ frontotemporal dementia; FWE ϭ familywise error; ICA ϭ independent component analysis; MPRAGE ϭ magnetization-prepared rapid acquisition gradient echo; PPND ϭ pallido-ponto-nigral degeneration; ROI ϭ region of interest; TE ϭ echo time; TIV ϭ total intracranial volume; TR ϭ repetition time.Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder characterized by behavioral and language deficits.1,2 A large proportion of subjects with FTD have an autosomal dominant pattern of inheritance, 3,4 with many showing mutations in the microtubule associated protein tau (MAPT) gene.5 Subjects with mutations in MAPT typically present with behavioral variant FTD (bvFTD), with poor semantic abilities, 6 -8 and show predominant temporal atrophy, with less severe involvement of frontal and parietal lobes.9,10 Families characterized by the presence of mutations in MAPT provide the ideal construct to identify preclinical disease changes. Case studies assessing imaging in asymptomatic MAPT carriers show

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confidence: 90%

Altered functional connectivity in asymptomatic MAPT subjects

Josephs²,

et al. 2011

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“…22,24,25 bvFTD patients are associated with TDP type A and B, with type A involving the frontal, temporal and parietal lobes and type B, the hippocampus. 20,21,26 However, it is still not possible to clinically distinguish between types A and B. 27 In a recent study on bvFTD with TDP-43 pathology, 100% of the cases investigated showed TDP-43 in the amygdala and the majority had the pathology in the medial temporal lobe (MTL; dentate gyrus and entorhinal cortex).…”

Section: Tdp-43 Pathology In the Als-ftd Continuummentioning

confidence: 99%

“…TDP pathology is particularly reported in SD, with TDP-43 type C associated to anterior temporal lobe (ATL) atrophy and with type A and, more important, type B in ALS-FTD. 16,20,21,28 In addition, it is suggested that the C9orf72 gene mutation is the most frequent cause of familial ALS and FTD and accounts for up to 10% of sporadic ALS cases. 29,30 The temporal lobes are shown to be critically affected in C9orf72 patients 31 linked to TDP-43 pathology types A and B.…”

Section: Tdp-43 Pathology In the Als-ftd Continuummentioning

confidence: 99%

“…10,18,19 Despite this shared overlap of frontal changes, these do not seem predictive of underlying pathology in FTD. 20 However, less emphasis has been given to the temporal lobe changes and how they might relate to TDP-43 proteinopathy. Since it is currently not possible to clinically distinguish the underlying pathology in FTD, as cases are an admixture of tau and TDP-43, being able to identify the pathology would have major implications for future disease intervention therapies targeting specific proteins.…”

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confidence: 99%

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How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

Bueno

Bertoux

Souza

et al. 2017

Ann Clin Neurophysiol

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Detection of underling proteinopathies is becoming increasingly important across neurodegenerative conditions due to upcoming disease intervention trials. In this review, we explored how temporal lobe changes in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) can potentially predict underlying TDP-43 pathology subtypes in FTD. To date, emphasis has been given to frontal lobe changes in the study of the cognitive and behavioural impairments in both syndromes but an increasing number of pathological, imaging and neuropsychological studies suggest how temporal lobe changes could critically affect the cognition and behaviour of these conditions. In this current article, we reviewed pathological, imaging as well as clinical/neuropsychological findings of temporal involvement in the ALS-FTD continuum, how they relate to temporal lobe changes and the underlying TDP-43 pathology in FTD. Findings across studies show that TDP-43 pathology occurs and coincides in many structures in ALS and FTD, but especially in the temporal lobes. In particular, anterior and medial temporal lobes atrophy is consistently found in ALS and FTD. In addition, memory and language impairment as well as emotional and Theory of Mind processing deficits that are characteristics of the two diseases are highly correlated to temporal lobe dysfunction. We conclude by showing that temporal lobe changes due to TDP-43 type B might be particular predictive of TDP-43 type B pathology in behavioural variant FTD, which clearly needs to be investigated further in the future.

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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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Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration?

Cited by 71 publications

References 35 publications

Altered functional connectivity in asymptomatic MAPT subjects

Altered functional connectivity in asymptomatic MAPT subjects

How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

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

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