Mapping behavioural, cognitive and affective transdiagnostic dimensions in frontotemporal dementia

Two common clinical variants of frontotemporal dementia (FTD) are the behavioural variant (bvFTD) presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia (SD) displaying early semantic dysfunction primarily due to anterior temporal degeneration. Despite representing independent diagnostic entities, mounting evidence indicates overlapping cognitive-behavioural profiles in these syndromes, particularly with disease progression. Why such overlap occurs remains unclear. Understanding the nature of this overlap, however, is essential to improve early diagnosis, characterisation, and management of those affected. Here, we explored common cognitive-behavioural and neural mechanisms contributing to heterogeneous FTD presentations, irrespective of clinical diagnosis. This transdiagnostic approach allowed us to ascertain whether symptoms not currently considered core to these two syndromes are present in a significant proportion of cases and explore the neural basis of clinical heterogeneity. Sixty-two FTD patients (31 bvFTD, 31 SD) underwent comprehensive neuropsychological, behavioural, and structural neuroimaging assessments. Orthogonally-rotated principal component analysis of neuropsychological and behavioural data uncovered eight statistically independent factors explaining the majority of cognitive-behavioural performance variation in bvFTD and SD. These factors included Behavioural changes, Semantic dysfunction, General Cognition, Executive function, Initiation, Disinhibition, Visuospatial function, and Affective changes. Marked individual-level overlap between bvFTD and SD was evident on the Behavioural changes, General Cognition, Initiation, Disinhibition, and Affective changes factors. Compared to bvFTD, SD patients displayed disproportionate impairment on the Semantic dysfunction factor, whereas greater impairment on Executive and Visuospatial function factors was noted in bvFTD. Both patient groups showed comparable magnitude of atrophy to frontal regions, whereas severe temporal lobe atrophy was characteristic of SD. Whole-brain voxel-based morphometry correlations with emergent factors revealed associations between fronto-insular and striatal grey matter changes with Behavioural, Executive, and Initiation factor performance, bilateral temporal atrophy with Semantic dysfunction factor scores, parietal-subcortical regions with General Cognitive performance, and ventral temporal atrophy associated with Visuospatial factor scores. Together, these findings indicate that cognitive-behavioural overlap (i) occurs systematically in FTD, (ii) varies in a graded manner between individuals, and (iii) is associated with degeneration of different neural systems. Our findings suggest that phenotypic heterogeneity in FTD syndromes can be captured along continuous, multidimensional spectra of cognitive-behavioural changes. This has implications for the diagnosis of both syndromes amidst overlapping features as well as the design of symptomatic treatments applicable to multiple syndromes.

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Establishing two principal dimensions of cognitive variation in logopenic progressive aphasia

Brain Communications ◽

10.1093/braincomms/fcaa125 ◽

2020 ◽

Cited By ~ 1

Author(s):

Siddharth Ramanan ◽

Daniel Roquet ◽

Zoë-lee Goldberg ◽

John R Hodges ◽

Olivier Piguet ◽

...

Keyword(s):

Principal Component Analysis ◽

Speech Production ◽

Cognitive Performance ◽

Cognitive Deficits ◽

Verbal Memory ◽

Principal Component ◽

Cognitive Profiles ◽

Factor Scores ◽

Level Variation ◽

Individual Level

Abstract Logopenic progressive aphasia (LPA) is a neurodegenerative syndrome characterised by sentence repetition and naming difficulties arising from left-lateralised temporoparietal atrophy. Clinical descriptions of LPA largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits even on tasks with minimal language demands. Although non-linguistic cognitive deficits in LPA are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose individual-level variation in cognitive performance in 43 well-characterised LPA patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify LPA. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralised temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, LPA patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralised temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in LPA, suggesting the presence of a genuine co-occurring cognitive impairment that is statistically independent of language function and disease severity.

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Establishing two principal dimensions of cognitive variation in Logopenic Progressive Aphasia

10.1101/767269 ◽

2019 ◽

Cited By ~ 1

Author(s):

Siddharth Ramanan ◽

Daniel Roquet ◽

Zoë-lee Goldberg ◽

John. R. Hodges ◽

Olivier Piguet ◽

...

Keyword(s):

Principal Component Analysis ◽

Speech Production ◽

Cognitive Performance ◽

Cognitive Deficits ◽

Verbal Memory ◽

Principal Component ◽

Cognitive Profiles ◽

Factor Scores ◽

Level Variation ◽

Individual Level

ABSTRACTLogopenic Progressive Aphasia (LPA) is a neurodegenerative syndrome characterised by sentence repetition and naming difficulties arising from left-lateralised temporoparietal atrophy. Clinical descriptions of LPA largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits, even on tasks with minimal language demands. Although non-linguistic cognitive deficits in LPA are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose individual-level variation in cognitive performance in 43 well-characterised LPA patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify LPA. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralised temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, LPA patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralised temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in LPA, suggesting the presence of a genuine co-occurring cognitive impairment that is independent of language function and disease severity.

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COVID-19 Pandemic and Adaptive Shopping Patterns: An Insight from Indonesian Consumers

Global Business Review ◽

10.1177/09721509211013512 ◽

2021 ◽

pp. 097215092110135

Author(s):

Arif Hartono ◽

Asma'i Ishak ◽

Agus Abdurrahman ◽

Budi Astuti ◽

Endy Gunanto Marsasi ◽

...

Keyword(s):

Principal Component Analysis ◽

Cluster Analysis ◽

Principal Component ◽

Demographic Characteristics ◽

Depth Information ◽

Factor Scores ◽

Consumer Spending ◽

Consumer Responses ◽

Buying Behaviour ◽

Manova Analysis

Although existing studies on consumers typology are extensively conducted, insights on consumers typology in adapting their shopping attitude and behaviour during the COVID-19 pandemic remain unexplored. Current studies on consumer responses to the COVID-19 pandemic tend to focus on the following themes: panic buying behaviour, consumer spending and consumer consumption. This study explores a typology of adaptive shopping patterns in response to the COVID-19 pandemic. The study involved a survey of 465 Indonesian consumers. Principal component analysis is used to identify the variables related to adaptive shopping patterns. Cluster analysis of the factor scores obtained on the adaptive shopping attitude and behaviour revealed the typology of Indonesian shoppers’ adaptive patterns. Multivariate Analysis of Variance (MANOVA) analysis is used to profile the identified clusters based on attitude, behaviour and demographic characteristics. Results revealed five adaptive shopping patterns with substantial differences among them. This study provides in-depth information about the profile of Indonesian shoppers’ adaptive patterns that would help retailers in understanding consumers and choosing their target group. The major contribution of this study is providing segmentation on shopping adaptive patterns in the context of the COVID-19 pandemic which presents interesting differences compared with previous studies. This study reveals new insights on shoppers’ adaptive attitude and behaviour as consumers coped with the pandemic.

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C-factor: a summary measure for systemic arterial calcifications

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02126-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lieke M. Kuiper ◽

M. Kamran Ikram ◽

Maryam Kavousi ◽

Meike W. Vernooij ◽

M. Arfan Ikram ◽

...

Keyword(s):

Cox Regression ◽

Intraclass Correlation ◽

Principal Component ◽

Arterial Calcification ◽

Standard Deviation Increase ◽

Single Measure ◽

Individual Level ◽

Enhanced Ct ◽

Study Participants ◽

Overall Mortality

Abstract Background Arterial calcification, the hallmark of arteriosclerosis, has a widespread distribution in the human body with only moderate correlation among sites. Hitherto, a single measure capturing the systemic burden of arterial calcification was lacking. In this paper, we propose the C-factor as an overall measure of calcification burden. Methods To quantify calcification in the coronary arteries, aortic arch, extra- and intracranial carotid arteries, and vertebrobasilar arteries, 2384 Rotterdam Study participants underwent cardiac and extra-cardiac non-enhanced CT. We performed principal component analyses on the calcification volumes of all twenty-six possible combinations of these vessel beds. Each analysis’ first principal component represents the C-factor. Subsequently, we determined the correlation between the C-factor derived from all vessel beds and the other C-factors with intraclass correlation coefficient (ICC) analyses. Finally, we examined the association of the C-factor and calcification in the separate vessel beds with cardiovascular, non-cardiovascular, and overall mortality using Cox–regression analyses. Results The ICCs ranged from 0.80 to 0.99. Larger calcification volumes and a higher C-factor were all individually associated with higher risk of cardiovascular, non-cardiovascular, and overall mortality. When included simultaneously in a model, the C-factor was still associated with all three mortality types (adjusted hazard ratio per standard deviation increase (HR) > 1.52), whereas associations of the separate vessel beds with mortality attenuated substantially (HR < 1.26). Conclusions The C-factor summarizes the systemic component of arterial calcification on an individual level and appears robust among different combinations of vessel beds. Importantly, when mutually adjusted, the C-factor retains its strength of association with mortality while the site-specific associations attenuate.

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Nutritional psychiatry: the present state of the evidence

Proceedings of The Nutrition Society ◽

10.1017/s0029665117002026 ◽

2017 ◽

Vol 76 (4) ◽

pp. 427-436 ◽

Cited By ~ 59

Author(s):

Wolfgang Marx ◽

Genevieve Moseley ◽

Michael Berk ◽

Felice Jacka

Keyword(s):

Mental Illness ◽

Mental Disorders ◽

Diet Quality ◽

Age Groups ◽

Significant Proportion ◽

Behavioural Therapy ◽

Future Research ◽

Reverse Causality ◽

Dietary Interventions ◽

Cognitive Behavioural

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

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Geographical trajectories of refugees in Sweden: Uncovering patterns and drivers of inter-regional (im)mobility

Journal of Refugee Studies ◽

10.1093/jrs/feaa074 ◽

2020 ◽

Author(s):

Louisa Vogiazides ◽

Hernan Mondani

Keyword(s):

Event History Analysis ◽

Population Decline ◽

Regional Distribution ◽

Significant Proportion ◽

Large City ◽

Rural Regions ◽

Individual Level ◽

Settlement Policies ◽

Multinomial Logit Regression ◽

History Analysis

Abstract Many countries actively seek to disperse refugees to counteract residential segregation or/and take measures to attract and retain international migrants in smaller communities to mitigate or reverse population decline. This study explores the regional distribution and inter-regional mobility among refugees in Sweden. It uses individual-level register data to follow two cohorts for 8 years after their arrival in Sweden, distinguishing between refugees subject to a placement policy in the 1990s and recent cohorts that either had arranged their own housing or had been assigned housing. It uses sequence analysis and multinomial logit regression to analyse regional trajectories, and event history analysis to examine mobility determinants. The results indicate that most refugees remained in the same type of region throughout the period. A significant proportion of refugees with assigned housing in large city or small city/rural regions stayed there over a long period, suggesting that refugee settlement policies have long-lasting consequences.

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Association between area-level education and the co-occurrence of behavior-related risk factors: a multilevel analysis

Revista Brasileira de Epidemiologia ◽

10.1590/1980-549720190052 ◽

2019 ◽

Vol 22 ◽

Author(s):

Antonio Fernando Boing ◽

SV Subramanian ◽

Alexandra Crispim Boing

Keyword(s):

Risk Factors ◽

Chronic Diseases ◽

Educational Level ◽

Physical Inactivity ◽

Eating Habits ◽

Significant Proportion ◽

Simultaneous Occurrence ◽

Cross Sectional ◽

Individual Level ◽

Unhealthy Eating

ABSTRACT: Introduction: This study aimed to investigate the association of four different risk factors for chronic diseases and accumulation of these health behaviors with area-level education, regardless of individual-level characteristics in Brazil. Methods: A population-based cross-sectional study was carried out in Southern Brazil including 1,720 adults in 2009/2010. The simultaneous occurrence of tobacco smoking, abusive drinking, unhealthy eating habits, and physical inactivity was investigated. Using multilevel models, we tested whether area-level education was associated with each risk factor and with the co-occurrence of them after controlling sociodemographic individual-level variables. Results: We observed a between-group variance of 7.79, 7.11, 6.84 and 1.08% for physical inactivity, problematic use of alcohol, unhealthy eating habits, and smoking, respectively. The between-group variance for the combination of four behaviors was 14.2%. Area-level education explained a significant proportion of the variance observed in physical inactivity and unhealthy eating habits. Residents of low educational level neighborhoods showed a 2.40 (95%CI 1.58 - 3.66) times higher chance of unhealthy eating and 1.78 (95%CI 1.19 - 2.67) times higher chance of physical inactivity. The likelihood of individuals with two or three/four risk factors was simultaneously higher among residents of low educational level neighborhoods. Conclusion: Public policies should consider the area-level characteristics, including education to control risk factors for chronic diseases.

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Activation of GCN2 by the ribosomal P-stalk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1813352116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 4946-4954 ◽

Cited By ~ 43

Author(s):

Alison J. Inglis ◽

Glenn R. Masson ◽

Sichen Shao ◽

Olga Perisic ◽

Stephen H. McLaughlin ◽

...

Keyword(s):

Conformational Changes ◽

Principal Component ◽

Protein Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Exchange Mass Spectrometry ◽

Hydrogen Deuterium ◽

Hdx Ms ◽

Ribosomal P

Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates translation initiation factor eIF2α, initiating the integrated stress response (ISR). To examine the mechanism of GCN2 activation, we have reconstituted this process in vitro, using purified components. We find that recombinant human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by tRNA. Hydrogen/deuterium exchange–mass spectrometry (HDX-MS) mapped GCN2–ribosome interactions to domain II of the uL10 subunit of the ribosomal P-stalk. Using recombinant, purified P-stalk, we showed that this domain of uL10 is the principal component of binding to GCN2; however, the conserved 14-residue C-terminal tails (CTTs) in the P1 and P2 P-stalk proteins are also essential for GCN2 activation. The HisRS-like and kinase domains of GCN2 show conformational changes upon binding recombinant P-stalk complex. Given that the ribosomal P-stalk stimulates the GTPase activity of elongation factors during translation, we propose that the P-stalk could link GCN2 activation to translational stress, leading to initiation of ISR.

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Education modulates brain maintenance in presymptomatic frontotemporal dementia

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320439 ◽

2019 ◽

Vol 90 (10) ◽

pp. 1124-1130 ◽

Cited By ~ 7

Author(s):

Stefano Gazzina ◽

Mario Grassi ◽

Enrico Premi ◽

Maura Cosseddu ◽

Antonella Alberici ◽

...

Keyword(s):

At Risk ◽

Frontotemporal Dementia ◽

Grey Matter ◽

Principal Component ◽

Grey Matter Volume ◽

Brain Reserve ◽

Matter Volume ◽

Brain Maintenance ◽

Over Time

ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

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Summarizing Patient Preferences for the Competitive Landscape of Multiple Sclerosis Treatment Options

Medical Decision Making ◽

10.1177/0272989x19897944 ◽

2020 ◽

Vol 40 (2) ◽

pp. 198-211 ◽

Cited By ~ 1

Author(s):

Marcel F. Jonker ◽

Bas Donkers ◽

Lucas M.A. Goossens ◽

Renske J. Hoefman ◽

Lea J. Jabbarian ◽

...

Keyword(s):

Multiple Sclerosis ◽

United Kingdom ◽

Patient Preferences ◽

Treatment Options ◽

Mixed Logit ◽

Principal Component ◽

Choice Data ◽

Individual Level ◽

The United Kingdom ◽

The Impact

Objective. Quantitatively summarize patient preferences for European licensed relapsing-remitting multiple sclerosis (RRMS) disease-modifying treatment (DMT) options. Methods. To identify and summarize the most important RRMS DMT characteristics, a literature review, exploratory physician interviews, patient focus groups, and confirmatory physician interviews were conducted in Germany, the United Kingdom, and the Netherlands. A discrete choice experiment (DCE) was developed and executed to measure patient preferences for the most important DMT characteristics. The resulting DCE data ( n=799 and n=363 respondents in the United Kingdom and Germany, respectively) were analyzed using Bayesian mixed logit models. The estimated individual-level patient preferences were subsequently summarized using 3 additional analyses: the quality of the choice data was assessed using individual-level R2 estimates, individual-level preferences for the available DMTs were aggregated into DMT-specific preference shares, and a principal component analysis was performed to explain the patients’ choice process. Results. DMT usage differed between RRMS patients in Germany and the United Kingdom but aggregate patient preferences were similar. Across countries, 42% of all patients preferred oral medications, 38% infusions, 16% injections, and 4% no DMT. The most often preferred DMT was natalizumab (26%) and oral DMT cladribine tablets (22%). The least often preferred were mitoxantrone and the beta-interferon injections (1%–3%). Patient preferences were strongly correlated with patients’ MS disease duration and DMT experience, and differences in patient preferences could be summarized using 8 principle components that together explain 99% of the variation in patients’ DMT preferences. Conclusion. This study summarizes patient preferences for the included DMTs, facilitates shared decision making along the dimensions that are relevant to RRMS patients, and introduces methods in the medical DCE literature that are ideally suited to summarize the impact of DMT introductions in preexisting treatment landscapes.

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