White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration
Laura DowneyColin MahoneyAisling BuckleyHannah L. GoldenSusie M.D. HenleyNicole SchmitzJonathan M. SchottIvor SimpsonSébastien OurselinNick C. FoxSebastian J. CrutchJason D. Warren
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Abstract:
Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration.However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined.Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification.Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry.The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere.The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification).DTI associations of impaired social cognition were more consistent than corresponding grey matter associations.These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes.The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.Keywords:
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Frontotemporal lobar degenerations are clinically, genetically, and molecularly heterogeneous diseases characterized by mainly frontal and temporal atrophy and affecting behavioral, language, cognitive, and motor functions. The term frontotemporal dementia incorporates 3 distinct clinical syndromes seen in frontotemporal degenerations: behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease syndrome are also associated with frontotemporal lobar degenerations. The neuropathologic hallmark of frontotemporal lobar degenerations is accumulation of abnormal proteins in the cytoplasm and nuclei of neurons and glial cells. Proteins involved in pathologic processes that represent the basis for frontotemporal lobar degeneration classification are tau protein, transactive response DNA-binding protein of 43 kDa, and "fused in sarcoma" protein. The aim of this review is to provide a summary of practical approaches for neuropathologic diagnostics of the rapidly evolving classifications of frontotemporal lobar degenerations.
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Frontotemporal dementia (FTD) is an uncommon but important form of degenerative disease characterized by clinical syndromes that result from degeneration of the frontal and temporal lobes. FTD is divided based on clinical presentation into behavioral variant FTD (bvFTD), semantic dementia, and progressive nonfluent/agrammatic aphasia. Several recent studies have advanced our knowledge of the genetics of FTD, with the three most common FTD genes being microtubule-associated protein tau (MAPT) and progranulin (GRN), and a noncoding repeat expansion in C9ORF72. Tau and TDP-43 are the most common pathologies associated with FTD. No pharmacological therapies are currently approved for use in FTD.
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Frontotemporal lobar degeneration
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Research into the non-Alzheimer dementias has exploded over the last 2 decades, and frontotemporal lobar degeneration has emerged as the most common cause of dementia in patients below the age of 65. In 1998, an international consortium of investigators focusing on this disease entity met and agreed upon the classification of 3 subtypes of frontotemporal lobar degeneration, using regional atrophy to distinguish them. These are: a frontally predominant form called frontotemporal dementia, a temporally predominant form called semantic dementia, and a left-frontally predominant syndrome, called progressive nonfluent aphasia. With the rise of genetic and neuropathologic findings, however, the usefulness of this subtype classification has been called into question. This paper discusses the major pertinent findings, and the implications of classifying the disease on the basis of atrophy versus genetic or molecular mechanisms.
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Frontotemporal dementia is the second most common early onset dementia after Alzheimer disease. Frontotemporal dementias are a complex group of dementias. The clinical diagnosis can be perplexing because of concurring psychiatric and neurologic syndromes. Frontotemporal lobar degeneration, the underlying pathology, represents an emerging group of proteinopathies. Genetic factors play an important part in the etiologies of dementias. This article overviews current defining characteristics of frontotemporal dementias known also as frontotemporal lobar degenerations.
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