Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M
            <i>MAPT</i>
            mutations

Whitwell, Jennifer L.; Jack, Clifford R.; Boeve, Bradley F.; Senjem, Matthew L.; Baker, Matt; Ivnik, Robert J.; Knopman, David S.; Wszołek, Zbigniew K.; Petersen, Ron; Rademakers, Rosa; Josephs, Keith A.

doi:10.1212/wnl.0b013e3181b9c8b9

Cited by 70 publications

(73 citation statements)

References 30 publications

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“…Among the previous literature on VMB MRI analysis in other FTLD mutated genes [28,29], Rohrer et al [29] performed a VMB MRI analysis of MAPT and GRN mutations in FTLD carriers compared with healthy controls and found among GRN mutation carriers a brain atrophy pattern with areas in common with that which we identified in our study, which included the orbitofrontal cortex and ventral insula, with marked extra atrophy of the anterior and medial temporal lobes and cingular cortex with a strong asymmetric pattern. However, we have to consider that they used a different methodology that enhances the GM loss.…”

Section: Discussionsupporting

confidence: 72%

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations

Luis

Ortiz

Eudave

et al. 2016

JAD

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Abstract.Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineating a specific gene-linked atrophy pattern.

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Section: Discussionsupporting

confidence: 72%

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations

Luis

Ortiz

Eudave

et al. 2016

JAD

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“…Gray matter loss has been observed in these regions in symptomatic MAPT subjects, with particularly severe involvement of the temporal lobes. 9,10 However, no gray matter loss was observed in these regions in the asymptomatic subjects, suggesting, importantly, that changes in functional connectivity precede the occurrence of atrophy in these regions. Very similar patterns of reduced DMN functional connectivity were observed in bvFTD, involving both lateral temporal lobes and medial prefrontal cortex, again suggesting that these patterns are disease-related.…”

Section: Default Mode Network (Precuneus Seed)mentioning

confidence: 90%

“…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 mixed results, with atrophy and hypometabolism observed in some asymptomatic subjects, but not others.…”

mentioning

confidence: 99%

“…The less striking findings in this group concur with the finding that MAPT mutations are associated with predominant temporal lobe involvement, with less involvement of frontal regions that are considered part of the salience network. 9,10 Behavioral deficits that occur in symptomatic MAPT subjects could be due to deficits in the right temporal lobe. 33 Increased functional connectivity was also observed in medial parietal regions of the DMN in both the asymptomatic MAPT subjects and subjects with bvFTD.…”

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confidence: 99%

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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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“…Clinically, neuroimaging studies demonstrated a difference between the patients with mutations that increase the splicing of exon 10 and those without these mutations. IVS 10q16, 10q3, N279K, and S305N mutations (which influence the alternative splicing) were associated with gray matter loss mainly in the medial temporal lobe, whereas atrophy of patients with P301L or V337M (mutations that affect the structures of tau protein) was found in the lateral temporal lobe (7).…”

Section: Exon 10 Splicingmentioning

confidence: 99%

Tau and neurodegenerative disorders

Motoi

Sahara

Kambe

2010

BioMolecular Concepts

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The mechanisms that render tau a toxic agent are still unclear, although increasing evidence supports the assertion that alterations of tau can directly cause neuronal degeneration. In addition, it is unclear whether neurodegeneration in various tauopathies occurs via a common mechanism or that specific differences exist. The aim of this review is to provide an overview of tauopathies from bench to bedside. The review begins with clinicopathological findings of familial and sporadic tauopathies. It includes a discussion of the similarities and differences between these two conditions. The second part concentrates on biochemical alterations of tau such as phosphorylation, truncation and acetylation. Although pathological phosphorylation of tau has been studied for many years, recently researchers have focused on the physiological role of tau during development. Finally, the review contains a summary of the significance of tauopathy model mice for research on neurofibrillary tangles, axonopathies, and synaptic alteration.

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Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations

Cited by 70 publications

References 30 publications

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations

Altered functional connectivity in asymptomatic MAPT subjects

Tau and neurodegenerative disorders

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