Functional Connectivity Changes in Behavioral, Semantic, and Nonfluent Variants of Frontotemporal Dementia.
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ABSTRACT:
SUBMITTER: Reyes P
PROVIDER: S-EPMC5902123 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Functional Connectivity Changes in Behavioral, Semantic, and Nonfluent Variants of Frontotemporal Dementia.
Reyes P P Ortega-Merchan M P MP Rueda A A Uriza F F Santamaria-García Hernando H Rojas-Serrano N N Rodriguez-Santos J J Velasco-Leon M C MC Rodriguez-Parra J D JD Mora-Diaz D E DE Matallana D D
Behavioural neurology 20180401
Frontotemporal dementia (FTD) affects behavior, language, and personality. This study aims to explore functional connectivity changes in three FTD variants: behavioral (bvFTD), semantic (svPPA), and nonfluent variant (nfvPPA). Seventy-six patients diagnosed with FTD by international criteria and thirty-two controls were investigated. Functional connectivity from resting functional magnetic resonance imaging (fMRI) was estimated for the whole brain. Two types of analysis were done: network basic ...[more]
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Project description:ObjectivesPhenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD.MethodsSeven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups.ResultsPhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes.ConclusionsOur findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD.Key points• PhFTD shows brain abnormalities that are similar to bvFTD. • PhFTD shows increased functional connectivity in the parietal default mode network. • PhFTD shows microstructural white matter abnormalities in the frontal lobe. • We hypothesise phFTD and bvFTD may belong to the same disease spectrum.
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Project description:ObjectiveBehavioral-variant frontotemporal dementia (bvFTD) is a progressive neurodegenerative brain disorder, clinically characterized by changes in cognition, personality, and behavior. Marked disturbances in eating behavior, such as overeating and preference for sweet foods, are also commonly reported. The hypothalamus plays a critical role in feeding regulation, yet the relation between pathology in this region and eating behavior in FTD is unknown. This study aimed to address this issue using 2 complementary approaches.MethodsFirst, 18 early stage bvFTD patients and 16 healthy controls underwent high-resolution structural magnetic resonance imaging and assessment of eating behavior. Hypothalamic volumes were traced manually on coronal images. Second, postmortem analyses of 12 bvFTD cases and 6 matched controls were performed. Fixed hypothalamic tissue sections were stained for a cell marker and for peptides regulating feeding behaviors using immunohistochemistry. Stereological estimates of the hypothalamic volume and the number of neurons and glia were performed.ResultsSignificant atrophy of the hypothalamus in bvFTD was present in both analyses. Patients with high feeding disturbance exhibited significant atrophy of the posterior hypothalamus. Neuronal loss, which was observed only in bvFTD cases with Tar DNA protein-43 deposition, was also predominant posteriorly. In contrast, orexin (hypocretin), neuropeptide Y, cocaine- and amphetamine-regulating transcript, and vasopressin-containing neurons that regulate appetite were spared in posterior nuclei known to participate in feeding regulation.InterpretationDegeneration and consequent dysregulation within the hypothalamus relates to significant feeding disturbance in bvFTD. These findings provide a basis for the development of therapeutic models.
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Project description:IntroductionTBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far.MethodsWe describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes.ResultsTwo carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS.DiscussionThis study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.
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Project description:IntroductionTrials to test disease-modifying treatments for frontotemporal dementia are eagerly awaited and sensitive instruments to assess potential treatment effects are increasingly urgent, yet lacking thus far. We aimed to identify gene-specific instruments assessing clinical onset and disease progression by comparing cognitive functioning between bvFTD patients across genetic mutations.MethodsWe examined differences in 7 cognitive domains between bvFTD patients with GRN (n = 20), MAPT (n = 29) or C9orf72 (n = 31) mutations, and non-carriers (n = 24), and described longitudinal (M = 22.6 months, SD = 16.6) data in a subsample (n = 27).ResultsPatients showed overall cognitive impairment, except memory recall, working memory and visuoconstruction. GRN patients performed lower on executive function (mean difference - 2.1; 95%CI - 4.1 to - 0.5) compared to MAPT and lower on attention compared to MAPT (mean difference - 2.5; 95%CI - 4.7 to - 0.3) and C9orf72 (mean difference - 2.4; 95%CI - 4.5 to - 0.3). Only MAPT patients were impaired on delayed recall (mean difference - 1.4; 95%CI - 2.1 to - 0.7). GRN patients declined rapidly on attention and memory, MAPT declined in confrontation naming, whereas C9orf72 patients were globally impaired but remained relatively stable over time on all cognitive domains.DiscussionThis study shows gene-specific cognitive profiles in bvFTD, which underlines the value of neuropsychological tests as outcome measures in upcoming trials for genetic bvFTD.
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Project description:ObjectiveWe aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations.MethodsIn this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex.ResultsAlthough carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found.ConclusionsThis study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.
| S-EPMC3598452 | biostudies-literature
Project description:ObjectiveTo identify distinct behavioral phenotypes of behavioral-variant frontotemporal dementia (bvFTD) and to elucidate differences in functional, neuroimaging, and progression to residential care placement.MethodsEighty-eight patients with bvFTD were included in a cluster analysis applying levels of disinhibition and apathy (Cambridge Behavioural Inventory-Revised) to identify phenotypic subgroups. Between-group (Kruskal-Wallis, Mann-Whitney U) functional differences (Disability Assessment for Dementia) and time to residential care placement (survival analyses) were examined. Cortical thickness differences (whole-brain MRI) were analyzed in patients with bvFTD vs healthy controls (n = 30) and between phenotypic subgroups.ResultsFour phenotypic subgroups were identified: primary severe apathy (n = 26), severe apathy and disinhibition (n = 26), mild apathy and disinhibition (n = 27), and primary severe disinhibition (n = 9). Patients with severely apathetic phenotypes were more functionally impaired and had more extensive brain atrophy than those with mild apathy or severe disinhibition alone. Further imaging analyses indicated that the right middle temporal region is critical for the development of disinhibition, an association that remains with disease progression and in the context of severe apathy. Finally, no difference in time to residential care admission was found between phenotypes.ConclusionsThis study reveals that different clinical behavioral phenotypes of bvFTD have differing profiles of functional decline and distinct patterns of associated cortical changes. These findings emphasize the importance of apathy in functional impairment, highlight the role of the right temporal region in disinhibition, and suggest that disability may be a sensitive outcome measure for treatments targeting reduction of apathy. These phenotypes could also support understanding of prognosis and clinical management.
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Project description:Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders.
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Project description:"Reserve" refers to the individual clinical differences in response to a neuropathological burden. We explored the behavioral reserve (BR) and associated neural substrates in 40 participants with behavioral variant frontotemporal dementia (bvFTD) who were assessed with the frontal behavioral inventory (FBI) and magnetic resonance imaging. Because neuroimaging abnormality showed a high negative correlation with the FBI negative (but not positive) symptom scores, we developed a linear model only to calculate the nBR (BR for negative symptoms) marker using neuroimaging abnormalities and the FBI score. Participants were divided into high nBR and low nBR groups based on the nBR marker. The FBI negative symptom score was lower in the high nBR group than in the low nBR group having the same neuroimaging abnormalities. However, the high nBR group noted a steeper decline in cortical atrophy and showed less atrophy in the left frontotemporal cortices than the low nBR group. In addition, the fractional anisotropy (FA) values were greater in the high nBR than in the low nBR group, except in the sensory-motor and occipital areas. We identified an nBR-related functional network composed of bilateral frontotemporal areas and the left occipital pole. We propose the concept of BR in bvFTD, and these findings can help predict the disease progression.
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Project description:Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer's disease cause atrophy within two major networks, an anterior 'Salience Network' (atrophied in behavioural variant frontotemporal dementia) and a posterior 'Default Mode Network' (atrophied in Alzheimer's disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer's disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer's disease) and the Default Mode Network (disrupted in Alzheimer's disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer's disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer's disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer's disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal 'test' patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer's disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.
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Project description:ObjectiveTo objectively quantify how cerebral volume loss could assist with clinical diagnosis and clinical trial design in the behavioural variant of frontotemporal dementia (bvFTD).MethodsWe applied deformation-based morphometric analyses with robust registration to precisely quantify the magnitude and pattern of atrophy in patients with bvFTD as compared to cognitively normal controls (CNCs), to assess the progression of atrophy over one year follow up and to generate clinical trial sample size estimates to detect differences for the structures most sensitive to change. This study included 203 subjects - 70 bvFTD and 133 CNCs - with a total of 482 timepoints from the Frontotemporal Lobar Degeneration Neuroimaging Initiative.ResultsDeformation based morphometry (DBM) revealed significant atrophy in the frontal lobes, insula, medial and anterior temporal regions bilaterally in bvFTD subjects compared to controls with outstanding subcortical involvement. We provide detailed information on regional changes per year. In both cross-sectional analysis and over a one-year follow-up period, ventricle expansion was the most prominent differentiator of bvFTD from controls and a sensitive marker of disease progression.ConclusionsAutomated measurement of ventricular expansion is a sensitive and reliable marker of disease progression in bvFTD to be used in clinical trials for potential disease modifying drugs, as well as possibly to implement in clinical practice. Ventricular expansion measured with DBM provides the lowest published estimated sample size for clinical trial design to detect significant differences over one and two years.
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