Using neuro-cognitive modelling to link attention deficits to structural and functional brain changes

‘Visual attention’ is an emerging property of interconnected neural networks, in which the interconnections are biased to promote targets over distracting stimuli. It has been shown that efficiency of the attention system is lost after many kinds of brain damage, with each presumably effecting different aspects of basic visual attention functions. Yet, our understanding of these processes is limited by the methodological shortcomings of classical neuropsychological assessment. The overarching goal of the current thesis was to overcome these constrains and thereby extend the link between attention deficits and underlying brain changes. The here used approach incorporates parametric measurement of visual attention derived from the computational Theory of Visual Attention (TVA, Bundesen, 1990) and modern magnetic resonance imaging techniques. Project 1 of the current thesis applied a combined TVA–neuroimaging analysis in a neurodevelopmental model (preterm birth) to relate attention deficits with changes in functional connectivity networks. We found that pre- versus full-term born adults show a selective reduction of visual short-term memory capacity. The remarkable changes we observed in attention-related large-scale brain networks of the occipital and posterior parietal cortices were most pronounced in those preterm born individuals with the most preserved attention functions. This finding was interpreted as evidence for a compensatory reorganization of functional connectivity in order to ameliorate the advert consequences of preterm birth on visual short-term memory. Project 2 of this thesis applied a combined TVA-neuroimaging analysis in a neurodegenerative model (posterior cortical atrophy) to relate attention deficits with structural changes in grey and white matter morphometry. Compared to healthy control participants, patients with posterior cortical atrophy suffered from a selective disturbance of visual processing speed. The individual rate of processing speed slowing was a valid predictor for the severity of simultanagnosia, the core symptom in this clinical condition. We further found wide-spread atrophy in occipital as well as parietal and to a smaller degree in temporal brain areas. White matter degeneration in the superior parietal lobe, rather than atrophy of any grey matter cluster, was significantly associated with patients’ impaired processing speed. Based on these results we propose that disruption of white matter pathways especially within the superior parietal lobe leads to reduced processing speed which then results in the overt clinical symptoms of simultanagnosia. Altogether, projects of the current thesis expanded the link between specific attention deficits and underlying brain damage by using neuro-cognitive modelling. We demonstrated that parametric measurements of attention facilitate, in the role of intermediate cognitive constructs, the mapping between etiological factors and behavioral outcomes. Identifying predictable behavior-brain relationships in attention disorders may offer new perspectives for diagnosis and treatment. The clinical application of an integrated TVA-neuroimaging analysis could additionally compliment insights from healthy participants toward understanding the principles of normal visual attention as well as identifying their neuronal basis

Using neuro-cognitive modelling to link attention deficits to structural and functional brain changes

‘Visual attention’ is an emerging property of interconnected neural networks, in which the interconnections are biased to promote targets over distracting stimuli. It has been shown that efficiency of the attention system is lost after many kinds of brain damage, with each presumably effecting different aspects of basic visual attention functions. Yet, our understanding of these processes is limited by the methodological shortcomings of classical neuropsychological assessment. The overarching goal of the current thesis was to overcome these constrains and thereby extend the link between attention deficits and underlying brain changes. The here used approach incorporates parametric measurement of visual attention derived from the computational Theory of Visual Attention (TVA, Bundesen, 1990) and modern magnetic resonance imaging techniques. Project 1 of the current thesis applied a combined TVA–neuroimaging analysis in a neurodevelopmental model (preterm birth) to relate attention deficits with changes in functional connectivity networks. We found that pre- versus full-term born adults show a selective reduction of visual short-term memory capacity. The remarkable changes we observed in attention-related large-scale brain networks of the occipital and posterior parietal cortices were most pronounced in those preterm born individuals with the most preserved attention functions. This finding was interpreted as evidence for a compensatory reorganization of functional connectivity in order to ameliorate the advert consequences of preterm birth on visual short-term memory. Project 2 of this thesis applied a combined TVA-neuroimaging analysis in a neurodegenerative model (posterior cortical atrophy) to relate attention deficits with structural changes in grey and white matter morphometry. Compared to healthy control participants, patients with posterior cortical atrophy suffered from a selective disturbance of visual processing speed. The individual rate of processing speed slowing was a valid predictor for the severity of simultanagnosia, the core symptom in this clinical condition. We further found wide-spread atrophy in occipital as well as parietal and to a smaller degree in temporal brain areas. White matter degeneration in the superior parietal lobe, rather than atrophy of any grey matter cluster, was significantly associated with patients’ impaired processing speed. Based on these results we propose that disruption of white matter pathways especially within the superior parietal lobe leads to reduced processing speed which then results in the overt clinical symptoms of simultanagnosia. Altogether, projects of the current thesis expanded the link between specific attention deficits and underlying brain damage by using neuro-cognitive modelling. We demonstrated that parametric measurements of attention facilitate, in the role of intermediate cognitive constructs, the mapping between etiological factors and behavioral outcomes. Identifying predictable behavior-brain relationships in attention disorders may offer new perspectives for diagnosis and treatment. The clinical application of an integrated TVA-neuroimaging analysis could additionally compliment insights from healthy participants toward understanding the principles of normal visual attention as well as identifying their neuronal basis

The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology

FORMAÇÃO DOCENTE FRENTE AOS IMPERATIVOS DE FORMAÇÃO POR COMPETÊNCIAS DA BNCC

O presente artigo deriva do trabalho de investigação de mestrado, sendo uma revisão bibliográfica e documental em perspectiva hermenêutica e analítica, com o objetivo de discutir e refletir sobre o conceito de competência presente na Base Nacional Curricular Comum (BNCC). A investigação dialoga com um conjunto de documentos e referências, com ênfase nos escritos de Philippe Perrenoud. Resgata a trajetória de construção e aprovação da BNCC, documento que norteia e orienta o currículo escolar da educação básica brasileira e reconstrói alguns elementos políticos dos bastidores da construção da política. Estes acabaram inclinando a BNCC para uma perspectiva neoliberal e mercadológica, enfatizando a formação técnica e, consequentemente, enfraquecendo o lugar da docência. Assim, estabelece algumas reflexões a respeito das implicações do termo “competência”, “pedagogia das competências” para a escola e a formação de professores.  O caráter técnico-profissional da BNCC, de certo modo enfraquece a formação crítica e humana. Consequentemente descontrói o papel social e formativo da escola, que passa a ocupar o lugar de subordinação às exigências do mercado, sendo o professor um mero executor de tarefas

Perspectives on How Human simultaneous Multi-Modal imaging Adds Directionality to spread Models of Alzheimer's Disease

Previous animal research suggests that the spread of pathological agents in Alzheimer's disease (AD) follows the direction of signaling pathways. Specifically, tau pathology has been suggested to propagate in an infection-like mode along axons, from transentorhinal cortices to medial temporal lobe cortices and consequently to other cortical regions, while amyloid-beta (A beta) pathology seems to spread in an activity-dependent manner among and from isocortical regions into limbic and then subcortical regions. These directed connectivity-based spread models, however, have not been tested directly in AD patients due to the lack of an in vivo method to identify directed connectivity in humans. Recently, a new method-metabolic connectivity mapping (MCM)-has been developed and validated in healthy participants that uses simultaneous FDG-PET and resting-state fMRI data acquisition to identify directed intrinsic effective connectivity (EC). To this end, postsynaptic energy consumption (FDG-PET) is used to identify regions with afferent input from other functionally connected brain regions (resting-state fMRI). Here, we discuss how this multi-modal imaging approach allows quantitative, whole-brain mapping of signaling direction in AD patients, thereby pointing out some of the advantages it offers compared to other EC methods (i.e., Granger causality, dynamic causal modeling, Bayesian networks). Most importantly, MCM provides the basis on which models of pathology spread, derived from animal studies, can be tested in AD patients. In particular, future work should investigate whether tau and A beta in humans propagate along the trajectories of directed connectivity in order to advance our understanding of the neuropathological mechanisms causing disease progression

The bidirectional relationship between brain structure and physical activity:A longitudinal analysis in the UK Biobank

Physical activity is a protective factor against brain atrophy, while loss of brain volume could also be a determinant of physical activity. Therefore, we aimed to explore the bidirectional association of physical activity with brain structures in middle-aged and older adults from the UK Biobank. Overall, 3027 participants (62.45 ± 7.27 years old, 51.3% females) had data at two time points. Hippocampal volume was associated with total (β=0.048, pFDR=0.016) and household (β=0.075, pFDR&lt;0.001) physical activity. Global fractional anisotropy (β=0.042, pFDR=0.028) was also associated with household physical activity. In the opposite direction, walking was negatively associated with white matter volume (β=-0.026, pFDR=0.008). All these associations were confirmed by the linear mixed models. Interestingly, sports at baseline were linked to hippocampal and frontal cortex volumes at follow-up but these associations disappeared after adjusting for multiple comparisons (pall&gt;0.104). In conclusion, we found more consistent evidence that a healthier brain structure predicted higher physical activity levels than for the inverse, more established relationship.</p

Intracranial arteriosclerosis is not associated with cerebral amyloid deposition

BACKGROUND: Intracranial arteriosclerosis and cerebral amyloid beta (Aβ) are both involved in the etiology of Alzheimer's disease (AD) dementia, but the direct link between these two pathologies remains elusive.METHODS: In 633 participants (mean age 69 years, 51% women) from the population-based Rotterdam Study, we quantified cerebral Aβ accumulation on amyloid positron emission tomography (PET). We assessed calcification of the intracranial internal carotid (ICAC) and vertebrobasilar arteries (VBAC) as proxies of arteriosclerosis on non-enhanced computed tomography (CT). Using logistic and linear regression, we studied the relationship of presence, burden, and type of calcification with the presence and burden of Aβ. RESULTS: We found no associations of ICAC [odds ratio (OR): 0.85, 95% confidence interval (CI): 0.43, 1.72] or VBAC [OR: 0.59, CI: 0.26, 1.24] with cerebral Aβ. The results did not vary across ICAC subtypes.DISCUSSION: Intracranial arteriosclerosis was not associated with cerebral Aβ, underscoring their independence in the etiology of AD dementia. Highlights: Comprehensive assessment of intracranial arteriosclerosis (e.g., including subtypes). Intracranial arteriosclerosis in different arteries and cerebral Aβ are not related. Arteriosclerosis and Aβ likely influence Alzheimer's disease dementia independently.</p

Diabetes and hypertension are related to amyloid-beta burden in the population-based Rotterdam Study

Higher vascular disease burden increases the likelihood of developing dementia, including Alzheimer’s disease. Better understanding the association between vascular risk factors and Alzheimer’s disease pathology at the predementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of six vascular risk factors on the presence and severity of in vivo measured brain amyloid-beta (Aβ) plaques in participants from the population-based Rotterdam Study. Vascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, physical inactivity and smoking) were assessed 13 (2004–2008) and 7 years (2009–2014) prior to 18F-florbetaben PET (2018–2021) in 635 dementia-free participants. Vascular risk factors were associated with binary amyloid PET status or continuous PET readouts (standard uptake value ratios, SUVrs) using logistic and linear regression models, respectively, adjusted for age, sex, education, APOE4 risk allele count and time between vascular risk and PET assessment. Participants’ mean age at time of amyloid PET was 69 years (range: 60–90), 325 (51.2%) were women and 190 (29.9%) carried at least one APOE4 risk allele. The adjusted prevalence estimates of an amyloid-positive PET status markedly increased with age [12.8% (95% CI 11.6; 14) in 60–69 years versus 35% (36; 40.8) in 80–89 years age groups] and APOE4 allele count [9.7% (8.8; 10.6) in non-carriers versus 38.4% (36; 40.8) to 60.4% (54; 66.8) in carriers of one or two risk allele(s)]. Diabetes 7 years prior to PET assessment was associated with a higher risk of a positive amyloid status [odds ratio (95% CI) = 3.68 (1.76; 7.61), P &lt; 0.001] and higher standard uptake value ratios, indicating more severe Aβ pathology [standardized beta = 0.40 (0.17; 0.64), P = 0.001]. Hypertension was associated with higher SUVr values in APOE4 carriers (mean SUVr difference of 0.09), but not in non-carriers (mean SUVr difference 0.02; P = 0.005). In contrast, hypercholesterolaemia was related to lower SUVr values in APOE4 carriers (mean SUVr difference −0.06), but not in non-carriers (mean SUVr difference 0.02). Obesity, physical inactivity and smoking were not related to amyloid PET measures. The current findings suggest a contribution of diabetes, hypertension and hypercholesterolaemia to the pathophysiology of Alzheimer’s disease in a general population of older non-demented adults. As these conditions respond well to lifestyle modification and drug treatment, further research should focus on the preventative effect of early risk management on the development of Alzheimer’s disease neuropathology

Midlife vascular risk factors and risk of incident dementia:Longitudinal cohort and Mendelian randomization analyses in the UK Biobank

Introduction Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. Methods Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. Results Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI;0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). Discussion These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk