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      Anatomical evidence of an indirect pathway for word repetition

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          Abstract

          Objective

          To combine MRI-based cortical morphometry and diffusion white matter tractography to describe the anatomical correlates of repetition deficits in patients with primary progressive aphasia (PPA).

          Methods

          The traditional anatomical model of language identifies a network for word repetition that includes Wernicke and Broca regions directly connected via the arcuate fasciculus. Recent tractography findings of an indirect pathway between Wernicke and Broca regions suggest a critical role of the inferior parietal lobe for repetition. To test whether repetition deficits are associated with damage to the direct or indirect pathway between both regions, tractography analysis was performed in 30 patients with PPA (64.27 ± 8.51 years) and 22 healthy controls. Cortical volume measurements were also extracted from 8 perisylvian language areas connected by the direct and indirect pathways.

          Results

          Compared to healthy controls, patients with PPA presented with reduced performance in repetition tasks and increased damage to most of the perisylvian cortical regions and their connections through the indirect pathway. Repetition deficits were prominent in patients with cortical atrophy of the temporo-parietal region with volumetric reductions of the indirect pathway.

          Conclusions

          The results suggest that in PPA, deficits in repetition are due to damage to the temporo-parietal cortex and its connections to Wernicke and Broca regions. We therefore propose a revised language model that also includes an indirect pathway for repetition, which has important clinical implications for the functional mapping and treatment of neurologic patients.

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          Most cited references38

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          Perisylvian language networks of the human brain.

          Early anatomically based models of language consisted of an arcuate tract connecting Broca's speech and Wernicke's comprehension centers; a lesion of the tract resulted in conduction aphasia. However, the heterogeneous clinical presentations of conduction aphasia suggest a greater complexity of perisylvian anatomical connections than allowed for in the classical anatomical model. This article re-explores perisylvian language connectivity using in vivo diffusion tensor magnetic resonance imaging tractography. Diffusion tensor magnetic resonance imaging data from 11 right-handed healthy male subjects were averaged, and the arcuate fasciculus of the left hemisphere reconstructed from this data using an interactive dissection technique. Beyond the classical arcuate pathway connecting Broca's and Wernicke's areas directly, we show a previously undescribed, indirect pathway passing through inferior parietal cortex. The indirect pathway runs parallel and lateral to the classical arcuate fasciculus and is composed of an anterior segment connecting Broca's territory with the inferior parietal lobe and a posterior segment connecting the inferior parietal lobe to Wernicke's territory. This model of two parallel pathways helps explain the diverse clinical presentations of conduction aphasia. The anatomical findings are also relevant to the evolution of language, provide a framework for Lichtheim's symptom-based neurological model of aphasia, and constrain, anatomically, contemporary connectionist accounts of language.
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            A novel frontal pathway underlies verbal fluency in primary progressive aphasia.

            The frontal aslant tract is a direct pathway connecting Broca's region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.
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              Primary progressive aphasia and the evolving neurology of the language network.

              Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.
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                Author and article information

                Journal
                Neurology
                Neurology
                neurology
                neur
                neurology
                NEUROLOGY
                Neurology
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0028-3878
                1526-632X
                11 February 2020
                11 February 2020
                : 94
                : 6
                : e594-e606
                Affiliations
                From the Departments of Neuroimaging and Forensic and Neurodevelopmental Sciences (S.J.F., N.D.S., L.D., P.L.L., F.D., M.C.), Natbrainlab, Sackler Institute of Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Mesulam Center for Cognitive Neurology and Alzheimer's Disease (E.R., J.S., S.W., M.-M.M.), Department of Psychiatry and Behavioral Sciences (E.R.), and Department of Neurology (M.M.M.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Neuroscience and Experimental Psychology, School of Biological Sciences (N.D.S., S.W.), University of Manchester, UK; and Neurobiology of Language Recovery, Aphasia and Neurolinguistics Research Laboratory, Communication Sciences and Disorders, and Neurology (C.T.), Northwestern University, Chicago, IL.
                Author notes
                Correspondence Dr. Catani m.catani@ 123456iop.kcl.ac.uk

                Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

                The Article Processing Charge was funded by the Wellcome Trust.

                Author information
                http://orcid.org/0000-0003-0493-0283
                http://orcid.org/0000-0002-6472-1363
                https://orcid.org/0000-0002-9191-7409
                http://orcid.org/0000-0001-5313-5476
                http://orcid.org/0000-0003-2605-5205
                http://orcid.org/0000-0003-3718-7545
                http://orcid.org/0000-0001-5731-851X
                http://orcid.org/0000-0002-5488-6463
                Article
                NEUROLOGY2018956391 00008
                10.1212/WNL.0000000000008746
                7136066
                31996450
                de50cb77-2953-4d8d-a137-c1111b0d4ed5
                Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

                This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 November 2018
                : 11 August 2019
                Funding
                Funded by: Wellcome Trust
                Award ID: 103759/Z/14/Z
                Funded by: National Institute on Deafness and Other Communication Disorders
                Award ID: DC008552
                Funded by: National Institute on Aging
                Award ID: AG13854
                Funded by: Alzheimer Disease Core Center
                Award ID: AG056258
                Funded by: National Institute of Neurologic Disorders and Stroke
                Award ID: NS075075
                Categories
                2
                14
                25
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                Custom metadata
                TRUE
                ONLINE-ONLY

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