The heritability of cerebral amyloid in older people and its relationship to vascular risk factors, cerebral small vessel disease and cognition

Abnormal β-amyloid (Aβ) plaque accumulation, a hallmark pathological feature of Alzheimer’s disease (AD), commonly co-occurs with cerebral small vessel disease (SVD). However, the nature of the relationship between AD pathology and SVD remains controversial. This thesis aimed to (1) determine the relative genetic and environmental contributions to cerebral Aβ; (2) investigate the role of vascular risk factors and cerebral SVD in Aβ accumulation; and (3) disentangle the relative genetic and environmental relationships of these pathologies with each other and with cognition. Participants were drawn from two cohorts of older adults who had undergone amyloid positron emission tomography: the Older Australian Twins Study (OATS) (n=206) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n=216). Aβ was quantified using the standardised uptake value ratio. SVD was quantified on magnetic resonance imaging by total white matter hyperintensity volume using T2-weighted FLAIR imaging and peak width of skeletonized mean diffusivity using diffusion tensor imaging. Using the classical twin design in the OATS cohort, the first study found that the heritability of cortical Aβ was moderate, suggesting that Aβ was susceptible to significant environmental influence. Contrary to expectation, cerebral SVD and Aβ did not have a shared genetic basis, although the sample size was a limitation. Using structural equation modelling in the ADNI cohort, study two showed that cerebral SVD had no significant direct effect on Aβ load over time. Fasting blood glucose level was the only vascular risk factor which had a direct influence on Aβ accumulation at 24-months. The third study, using the OATS cohort, found that higher white matter hyperintensity volume had significant inverse genetic correlations with processing speed, pointing to their shared genetic basis. There were no significant phenotypic or genetic correlations between Aβ load and cognition. Taken together, this research has significant practical implications as it indicates that Aβ is under strong environmental influences and may be amenable to intervention. Furthermore, although Aβ and cerebral SVD commonly co-occur, their deleterious effects on cognition likely occur via independent pathways. This thesis highlights the role of environmental determinants of cerebral Aβ which warrant further exploration, but suggests that vascular risk factors only make a minor contribution. It demonstrates the power of the twin method in determining the independence of AD and SVD pathologies, both of which are important for cognition

Incidental findings on cerebral MRI in twins: the Older Australian Twins Study

Incidental findings on structural cerebral magnetic resonance imaging (MRI) are common in healthy subjects, and the prevalence increases with age. There is a paucity of data regarding incidental cerebral findings in twins. We examined brain MRI data acquired from community-dwelling older twins to determine the prevalence and concordance of incidental cerebral findings, as well as the associated clinical implications. Participants (n = 400) were drawn from the Older Australian Twins Study. T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) cerebral MRI scans were systematically reviewed by a trained, blinded clinician. Incidental findings were recorded according to pre-determined categories, and the diagnosis confirmed by an experienced neuroradiologist. Periventricular and deep white matter hyperintensities (WMH) were scored visually. WMH heritability was calculated for those with the twin pair included in the study (n = 320 individuals; monozygotic (MZ) = 92 twin pairs, dizygotic (DZ) = 68 twin pairs). Excluding infarcts and WMH, a total of 47 (11.75%) incidental abnormalities were detected. The most common findings were hyperostosis frontalis interna (8 participants; 2%), meningiomas, (6 participants; 1.5%), and intracranial lipomas (5 participants; 1.25%). Only 3% of participants were referred for follow-up. Four twin pairs, all monozygotic, had lesions concordant with their twin. Periventricular WMH was moderately heritable (0.61, CI 0.43–0.75, p = 7.21E-08) and deep WMH highly heritable (0.80, CI 0.66–0.88, p = 1.76E-13). As in the general population, incidental findings on cerebral MRI in older twins are common, although concordance rates are low. Such findings can alter the clinical outcome of participants, and should be anticipated by researchers when designing trials involving cerebral imaging

Mapping the interconnected neural systems underlying motivation and emotion: A key step toward understanding the human affectome

As a part of a larger Affectome Project (http://neuroqualia.org/background.php) with an overarching goal of mapping and redefining biological substrates of feelings and emotions, we explored the neural underpinnings for the functions of motivation and emotion. Historically emotion and motivation have been placed into distinct neural circuits and examined separately. We propose a novel view of significant neural convergence of emotion and motivation, in contrast to conventional neural-based frameworks emphasizing segregation. Evidence from diverse research areas in emotion and motivation was reviewed, pinpointing key neural regions of overlap. The findings support important neural sharing between emotion and motivation, suggesting that these two functions are tightly intertwined with one another in the brain. Neural overlap does not necessarily imply continuous functional overlap. Even if identical brain regions/systems are activated for motivation and emotion, this ac- tivation may involve distinct and unique patterns of connection and information flow as the network shifts functionality. This review highlights the crucial importance of further research to explicate the patterns and modes of responding of these overlapping systems

The Human Affectome

Over the last decades, the interdisciplinary field of the affective sciences has seen proliferation rather than integration of theoretical perspectives. This is due to differences in metaphysical and mechanistic assumptions about human affective phenomena (what they are and how they work) which, shaped by academic motivations and values, have determined the affective constructs and operationalizations. An assumption on the purpose of affective phenomena can be used as a teleological principle to guide the construction of a common set of metaphysical and mechanistic assumptions—a framework for human affective research. In this capstone paper for the special issue “Towards an Integrated Understanding of the Human Affectome”, we gather the tiered purpose of human affective phenomena to synthesize assumptions that account for human affective phenomena collectively. This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research

Multiple candidate effectors from the oomycete pathogen Hyaloperonospora arabidopsidis suppress host plant immunity

Oomycete pathogens cause diverse plant diseases. To successfully colonize their hosts, they deliver a suite of effector proteins that can attenuate plant defenses. In the oomycete downy mildews, effectors carry a signal peptide and an RxLR motif. Hyaloperonospora arabidopsidis (Hpa) causes downy mildew on the model plant Arabidopsis thaliana (Arabidopsis). We investigated if candidate effectors predicted in the genome sequence of Hpa isolate Emoy2 (HaRxLs) were able to manipulate host defenses in different Arabidopsis accessions. We developed a rapid and sensitive screening method to test HaRxLs by delivering them via the bacterial type-three secretion system (TTSS) of Pseudomonas syringae pv tomato DC3000-LUX (Pst-LUX) and assessing changes in Pst-LUX growth in planta on 12 Arabidopsis accessions. The majority (~70%) of the 64 candidates tested positively contributed to Pst-LUX growth on more than one accession indicating that Hpa virulence likely involves multiple effectors with weak accession-specific effects. Further screening with a Pst mutant (ΔCEL) showed that HaRxLs that allow enhanced Pst-LUX growth usually suppress callose deposition, a hallmark of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). We found that HaRxLs are rarely strong avirulence determinants. Although some decreased Pst-LUX growth in particular accessions, none activated macroscopic cell death. Fewer HaRxLs conferred enhanced Pst growth on turnip, a non-host for Hpa, while several reduced it, consistent with the idea that turnip's non-host resistance against Hpa could involve a combination of recognized HaRxLs and ineffective HaRxLs. We verified our results by constitutively expressing in Arabidopsis a sub-set of HaRxLs. Several transgenic lines showed increased susceptibility to Hpa and attenuation of Arabidopsis PTI responses, confirming the HaRxLs' role in Hpa virulence. This study shows TTSS screening system provides a useful tool to test whether candidate effectors from eukaryotic pathogens can suppress/trigger plant defense mechanisms and to rank their effectiveness prior to subsequent mechanistic investigation

The Human Affectome

Over the last decades, the interdisciplinary field of the affective sciences has seen proliferation rather than integration of theoretical perspectives. This is due to differences in metaphysical and mechanistic assumptions about human affective phenomena (what they are and how they work) which, shaped by academic motivations and values, have determined the affective constructs and operationalizations. An assumption on the purpose of affective phenomena can be used as a teleological principle to guide the construction of a common set of metaphysical and mechanistic assumptions-a framework for human affective research. In this capstone paper for the special issue "Towards an Integrated Understanding of the Human Affectome", we gather the tiered purpose of human affective phenomena to synthesize assumptions that account for human affective phenomena collectively. This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research