The adducin saga: Pleiotropic genomic targets for precision medicine in human hypertension; vascular, renal, and cognitive diseases

Hypertension is a leading risk factor for stroke, heart disease, chronic kidney disease, vascular cognitive impairment, and Alzheimer's disease. Previous genetic studies have nominated hundreds of genes linked to hypertension and renal and cognitive diseases. Some have been advanced as candidate genes by showing that they can alter blood pressure or renal and cerebral vascular function in knockout animals; however, final validation of the causal variants and underlying mechanisms have remained elusive. This review chronicles 40 years of work, from the initial identification of adducin (ADD) as an ACTIN-binding protein suggested to increase blood pressure in Milan hypertensive rats, to the discovery of a mutation in ADD1 as a candidate gene for hypertension in rats that were subsequently linked to hypertension in man. More recently, a recessive K572Q mutation in ADD3 was identified in Fawn-Hooded Hypertensive (FHH) and Milan Normotensive (MNS) rats that develop renal disease, which is absent in resistant strains. ADD3 dimerizes with ADD1 to form functional ADD protein. The mutation in ADD3 disrupts a critical ACTIN-binding site necessary for its interactions with actin and spectrin to regulate the cytoskeleton. Studies using Add3 knockout and transgenic strains, as well as a genetic complementation study in FHH and MNS rats, confirmed that the K572Q mutation in ADD3 plays a causal role in altering the myogenic response and autoregulation of renal and cerebral blood flow, resulting in increased susceptibility to hypertension-induced renal disease and cerebral vascular and cognitive dysfunction.

Cognitive Impairment and Dementia Data Modelling

Recently, a huge amount of data is available for clinical research on cognitive diseases. A lot of challenges arise when data from different repositories should be integrated. Since data entities are stored with different names at different levels of granularity, a common data model is needed, providing a unified description of different factors and indicators of cognitive diseases. This paper proposes a common hierarchical data model of patients with cognitive disorders, which keeps the semantics of the data in a human-readable format and accelerates interoperability of clinical datasets. It defines data entities, their attributes and relationships related to diagnosis and treatment. The data model covers four main aspects of the patient’s profile: (1) personal profile; (2) anamnestic profile, including social status, everyday habits, and head trauma history; (3) clinical profile, describing medical investigations and assessments, comorbidities and the most likely diagnose; and (4) treatment profile with prescribed medications. It provides a native vocabulary, improving data availability, saving efforts, accelerating clinical data interoperability and standardizing data to minimize risk of rework and misunderstandings. The data model enables the application of machine learning algorithms by helping scientists to understand the semantics of information through a holistic view of patient.

Creating Comfort in the Absence of Memory

<p><b>As New Zealand’s population ages, so does the risk of developing age-related cognitive diseases such as dementia. Whilst most associate dementia with memory loss alone, the progressive nature of the disease can affect and create problems with thinking and behaviour, as well as memory. To date, there is no known cure.</b></p> <p>Increasingly, rural areas such as Alexandra, located in the Central Otago region, find that aged-care services cannot meet the growing demand. This issue has had a negative impact on the local community, causing stress for individuals who must move far from their home - losing their sense of ‘place-identity’ and, therefore, ‘self’ in the process.</p> <p>Stemming from the notion of ‘difference’, people living with dementia are equally at risk of being stigmatised due to the misunderstanding of behaviours and historical representation of aged-care architecture, which cut off individuals from the wider society. As a result, the unfamiliar and often unhome-like quality of these environments, alongside the stigma associated with cognitive diseases, can lead to a faster deterioration of a person’s condition.</p> <p>Through a design-led research approach, this thesis explores the design of a ‘normative aged-care environment’ – one that can allow an individual to live well with dementia. An independent review of literature and a case study analysis established that integrating an intergenerational programme can promote a sense of community and remove the stigma of ‘difference’ through architectural intervention. By designing for community engagement, this thesis aims to suggest an architecture that can provide support and comfort to an individual in the absence of memory.</p>

Creating Comfort in the Absence of Memory

<p><b>As New Zealand’s population ages, so does the risk of developing age-related cognitive diseases such as dementia. Whilst most associate dementia with memory loss alone, the progressive nature of the disease can affect and create problems with thinking and behaviour, as well as memory. To date, there is no known cure.</b></p> <p>Increasingly, rural areas such as Alexandra, located in the Central Otago region, find that aged-care services cannot meet the growing demand. This issue has had a negative impact on the local community, causing stress for individuals who must move far from their home - losing their sense of ‘place-identity’ and, therefore, ‘self’ in the process.</p> <p>Stemming from the notion of ‘difference’, people living with dementia are equally at risk of being stigmatised due to the misunderstanding of behaviours and historical representation of aged-care architecture, which cut off individuals from the wider society. As a result, the unfamiliar and often unhome-like quality of these environments, alongside the stigma associated with cognitive diseases, can lead to a faster deterioration of a person’s condition.</p> <p>Through a design-led research approach, this thesis explores the design of a ‘normative aged-care environment’ – one that can allow an individual to live well with dementia. An independent review of literature and a case study analysis established that integrating an intergenerational programme can promote a sense of community and remove the stigma of ‘difference’ through architectural intervention. By designing for community engagement, this thesis aims to suggest an architecture that can provide support and comfort to an individual in the absence of memory.</p>

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad

Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic β-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.

Insulin Action in the Brain regulates both Central and Peripheral Functions

The brain has traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin sensitive tissues such as muscle, liver and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression and cognitive behavior. Additionally, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.

The capacity to designate a surrogate is distinct from decisional capacity: normative and empirical considerations

The capacity to designate a surrogate (CDS) is not simply another kind of medical decision-making capacity (DMC). A patient with DMC can express a preference, understand information relevant to that choice, appreciate the significance of that information for their clinical condition, and reason about their choice in light of their goals and values. In contrast, a patient can possess the CDS even if they cannot appreciate their condition or reason about the relative risks and benefits of their options. Patients who lack DMC for many or most kinds of medical choices may nonetheless possess the CDS, particularly since the complex means-ends reasoning required by DMC is one of the first capacities to be lost in progressive cognitive diseases (eg, Alzheimer’s disease). That is, patients with significant cognitive decline or mental illness may still understand what a surrogate does, express a preference about a potential surrogate, and be able to provide some kind of justification for that selection. Moreover, there are many legitimate and relevant rationales for surrogate selection that are inconsistent with the reasoning criterion of DMC. Unfortunately, many patients are prevented from designating a surrogate if they are judged to lack DMC. When such patients possess the CDS, this practice is ethically wrong, legally dubious and imposes avoidable burdens on healthcare institutions.

BLE-GSpeed: A New BLE-Based Dataset to Estimate User Gait Speed

To estimate the user gait speed can be crucial in many topics, such as health care systems, since the presence of difficulties in walking is a core indicator of health and function in aging and disease. Methods for non-invasive and continuous assessment of the gait speed may be key to enable early detection of cognitive diseases such as dementia or Alzheimer’s disease. Wearable technologies can provide innovative solutions for healthcare problems. Bluetooth Low Energy (BLE) technology is excellent for wearables because it is very energy efficient, secure, and inexpensive. In this paper, the BLE-GSpeed database is presented. The dataset is composed of several BLE RSSI measurements obtained while users were walking at a constant speed along a corridor. Moreover, a set of experiments using a baseline algorithm to estimate the gait speed are also presented to provide baseline results to the research community.

A new gaming platform to improve cognitive performance and promote healthy behavior: a pilot study

Background Brain training games can sharpen the mind and potentially prevent cognitive diseases, that are particularly relevant to the population ageing. The EU funded project ACDC, Adult Cognitive Decline Conscientiousness, developed an online training tool to train cognitive functions and promote healthy behaviors in the adult population. Methods An online platform, consisting of 16 games with different levels, was built. Three main brain domains were targeted: memory, visuospatial and verbal skill. After the completion of each game level, healthy lifestyle tips were presented to the users. Participants were actively recruited from the project partners; inclusion criteria were adult age (40-70 years) without cognitive diseases. An adapted version of the Montreal Cognitive Assessment was used to assess cognitive performance at the start and after two hours of active gaming. The paired t-test was used to compare the scores before and after the training. A satisfaction questionnaire was administered at the end of the training session. Results Fifty-six participants from three European countries (Austria, Spain and Italy) took part in the pilot phase (median age: 57, IQR: 47-66). Most of them were university graduates (38%) or had a high school diploma (41%), employed full-time (46%) and females (82%). Significant improvements were registered in the verbal domain, where the mean score increased from 4.18 to 4.83 (p = 0.047), and in the memory area, where the mean score grew from 4.80 to 6.60 (p &lt; 0.001). The visuospatial mean score improved from 4.55 to 5.16 (p = 0.0518). Most users (84%) were greatly satisfied with the platform and reported a high level of appreciation for the interactive gaming approach. Conclusions Despite the small sample size, the pilot phase detected some improvements in cognitive performance and a good appreciation of the training tool. Given these encouraging findings, the study will now be extended to more participants. Key messages The newly developed platform represented a promising tool to train cognitive functions. The proposed interactive gaming approach was greatly appreciated by the users.

ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

Despite that the human autosomal recessive disease ataxia telangiectasia (A-T) is a rare pathology, interest in the function of ataxia-telangiectasia mutated protein (ATM) is extensive. From a clinical point of view, the role of ATM in the central nervous system (CNS) is the most impacting, as motor disability is the predominant symptom affecting A-T patients. Coherently, spino-cerebellar neurodegeneration is the principal hallmark of A-T and other CNS regions such as dentate and olivary nuclei and brain stem are implicated in A-T pathophysiology. Recently, several preclinical studies also highlighted the involvement of ATM in the cerebral cortex and hippocampus, thus extending A-T symptomatology to new brain areas and pathways. Here, we review old and recent evidence that largely demonstrates not only the historical ATM account in DNA damage response and cell cycle regulation, but the multiple pathways through which ATM controls oxidative stress homeostasis, insulin signalling pathways, epigenetic regulation, synaptic transmission, and excitatory–inhibitory balance. We also summarise recent evidence on ATM implication in neurological and cognitive diseases beyond A-T, bringing out ATM as new pathological substrate and potential therapeutic target.