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      Regional structural hypo- and hyperconnectivity of frontal-striatal and frontal-thalamic pathways in behavioral variant frontotemporal dementia

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          Abstract

          Behavioral variant frontotemporal dementia (bvFTD) has been predominantly considered as a frontotemporal cortical disease, with limited direct investigation of frontal–subcortical connections. We aim to characterize the grey and white matter components of frontal–thalamic and frontal–striatal circuits in bvFTD. Twenty‐four patients with bvFTD and 24 healthy controls underwent morphological and diffusion imaging. Subcortical structures were manually segmented according to published protocols. Probabilistic pathways were reconstructed separately from the dorsolateral, orbitofrontal and medial prefrontal cortex to the striatum and thalamus. Patients with bvFTD had smaller cortical and subcortical volumes, lower fractional anisotropy, and higher mean diffusivity metrics, which is consistent with disruptions in frontal–striatal–thalamic pathways. Unexpectedly, regional volumes of the striatum and thalamus connected to the medial prefrontal cortex were significantly larger in bvFTD (by 135% in the striatum, p  = .032, and 217% in the thalamus, p  = .004), despite smaller dorsolateral prefrontal cortex connected regional volumes (by 67% in the striatum, p  = .002, and 65% in the thalamus, p  = .020), and inconsistent changes in orbitofrontal cortex connected regions. These unanticipated findings may represent compensatory or maladaptive remodeling in bvFTD networks. Comparisons are made to other neuropsychiatric disorders suggesting a common mechanism of changes in frontal–subcortical networks; however, longitudinal studies are necessary to test this hypothesis.

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          Most cited references 26

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          Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review.

          Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
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            Striatal volume on magnetic resonance imaging and repetitive behaviors in autism.

            The repetitive behaviors seen in autism phenotypically resemble those seen in obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), disorders in which structural and functional abnormalities of the basal ganglia (BG) are present and correspond to the severity of repetitive behaviors. Seventeen subjects with autism by DSM-IV and Autism Diagnostic Interview (ADI) and 17 matched controls completed a 1.5 T magnetic resonance image (MRI) of the brain. Two blinded researchers, with good inter-rater reliability, outlined the right and left caudate and putamen. Autistic and control BG volumes covaried for total brain volume were compared using analysis of covariance. BG volumes within the autistic group were correlated with the ADI Repetitive Behavior scores (ADI-C domain). Right caudate volume controlled for total brain volume was significantly larger in autistic subjects than in controls. In addition, right caudate and total putamen volumes correlated positively with repetitive behavior scores on the ADI-C domain, particularly the higher order OCD-like repetitive behaviors. Increased right caudate volume in autism is of interest, since this has also been observed in OCD patients. Increased volume of the right caudate and total putamen positively correlated with greater repetitive behaviors, supporting the hypothesis of BG dysfunction associated with repetitive behaviors in autistic adults.
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              Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies.

              Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new FTD-causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of FTD to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, TDP-43 or FET protein accumulation. This review will describe our current understanding of the molecular basis of FTD, focusing on insights gained from the study of human postmortem tissue, as well as some of the current controversies. Most cases of FTD can be subclassified into one of three broad molecular subgroups based on the predominant protein that accumulates as pathological cellular inclusions. Understanding the associated pathogenic mechanisms and recognizing these FTD molecular subtypes in vivo will likely be crucial for the development and use of targeted therapies. This article is part of the Frontotemporal Dementia special issue.
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                Author and article information

                Journal
                Human Brain Mapping
                Hum. Brain Mapp.
                Wiley
                10659471
                October 2018
                October 2018
                June 20 2018
                : 39
                : 10
                : 4083-4093
                Affiliations
                [1 ]Graduate School of Medicine; University of Wollongong; Wollongong Australia
                [2 ]School of Medicine, The University of Notre Dame Australia, Fremantle, Australia; Clinical Research Centre; North Metropolitan Health Service - Mental Health; Perth Australia
                [3 ]Illawarra Shoalhaven Local Health District; Wollongong Australia
                [4 ]Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, Department of Psychiatry; Melbourne Medical School, University of Melbourne; Melbourne Australia
                [5 ]Centre for Medical Imaging and Physiology; Skåne University Hospital; Lund Sweden
                [6 ]Department of Radiology, Department of Clinical Sciences Lund; Lund University; Lund Sweden
                [7 ]Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine; Australian National University Medical School, Canberra Hospital; Canberra Australia
                [8 ]Clinical Memory Research Unit, Department of Clinical Sciences; Lund University; Lund Sweden
                Article
                10.1002/hbm.24233
                6866429
                29923666
                © 2018

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