A whole-brain functional connectivity model of Alzheimer's disease pathology.

Introduction: Alzheimer's disease (AD) is characterized by the presence of two proteinopathies, amyloid and tau, which have a cascading effect on the functional and structural organization of the brain.

Methods: In this study, we used a supervised machine learning technique to build a model of functional connections that predicts cerebrospinal fluid (CSF) p-tau/Aβ (the PATH-fc model). Resting-state functional magnetic resonance imaging (fMRI) data from 289 older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were utilized for this model.

Examining resilience to Alzheimer's disease through the lens of monoaminergic neuromodulator systems.

The monoaminergic nuclei are thought to be some of the earliest sites of Alzheimer's disease (AD) pathology in the brain, with tau-containing pretangles appearing in these nuclei decades before the onset of clinical impairments. It has increasingly been recognized that monoamine systems represent a critical target of investigation towards understanding the progression of AD and designing early detection and treatment approaches. This review synthesizes evidence across animal studies, human neuropathology, and state-of-the-art neuroimaging and daily life assessment methods in humans, which demonstrate robust relationships between monoamine systems and AD pathophysiology and behavior.

Avidity sequencing of whole genomes from retinal degeneration pedigrees identifies causal variants.

Whole genome sequencing has been an effective tool in the discovery of variants that cause rare diseases. In this study, we determined the suitability of a novel avidity sequencing approach for rare disease applications. We built a sample to results workflow, combining this sequencing technology with standard library preparation kits, analysis workflows, and interpretation tools.

A dopaminergic basis of behavioral control.

Both goal-directed and automatic processes shape human behavior, but these processes often conflict. is the decision about which process guides behavior. Despite the importance of behavioral control for adaptive decision-making, its neural mechanisms remain unclear.

Pathological and neurochemical correlates of locus coeruleus functional network activity.

The locus coeruleus (LC) produces the neuromodulators norepinephrine and dopamine, and projects widely to subcortical and cortical brain regions. The LC has been a focus of neuroimaging biomarker development for the early detection of Alzheimer's disease (AD) since it was identified as one of the earliest brain regions to develop tau pathology. Our recent research established the use of positron emission tomography (PET) to measure LC catecholamine synthesis capacity in cognitively unimpaired older adults.

Association of Psychiatric Emergency Visits and Warm Ambient Temperature during Pregnancy: A Time-Stratified Case-Crossover Study.

Background: Acute exposure to high ambient temperature and heat waves during the warm season has been linked with psychiatric disorders. Emerging research has shown that pregnant people, due to physiological and psychological changes, may be more sensitive to extreme heat, and acute exposure has been linked to increased risk of pregnancy complications; however, few studies have examined psychiatric complications.

Objective: Our objective was to examine the association between acute exposure to warm ambient temperatures and emergency department (ED) visits for mental disorders during pregnancy.

DAT1 and BDNF polymorphisms interact to predict Aβ and tau pathology.

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal β-amyloid (Aβ) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

Background: The locus coeruleus (LC) produces catecholamines (norepinephrine and dopamine) and is implicated in a broad range of cognitive functions including attention and executive function. Recent advancements in magnetic resonance imaging (MRI) approaches allow for the visualization and quantification of LC structure. Human research focused on the LC has since exploded given the LC's role in cognition and relevance to current models of psychopathology and neurodegenerative disease.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [F]Fluoro-m-tyrosine ([F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young.

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride.

Screening for Latent Tuberculosis Infection in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality.

Objective: To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF).

Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023.

New perspectives on the basal forebrain cholinergic system in Alzheimer's disease.

The basal forebrain cholinergic system (BFCS) has long been implicated in age-related cognitive changes and the pathophysiology of Alzheimer's disease (AD). Limitations of cholinergic interventions helped to inspire a shift away from BFCS in AD research. A resurgence in interest in the BFCS following methodological and analytical advances has resulted in a call for the BFCS to be examined in novel frameworks.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [F]Fluoro-m-tyrosine PET, and tau burden measured with [F]Flortaucipir PET in cognitively normal older adults (n = 47).

A Mouse Model with Ablated Asparaginase and Isoaspartyl Peptidase 1 () Develops Early Onset Retinal Degeneration (RD) Recapitulating the Human Phenotype.

We previously identified a homozygous G178R mutation in human () through whole-exome analysis responsible for early onset retinal degeneration (RD) in patients with cone-rod dystrophy. The mutant G178R ASRGL1 expressed in Cos-7 cells showed altered localization, while the mutant ASRGL1 in lacked the autocatalytic activity needed to generate the active protein. To evaluate the effect of impaired ASRGL1 function on the retina in vivo, we generated a mouse model with c.

An integrative effort: Bridging motivational intensity theory and recent neurocomputational and neuronal models of effort and control allocation.

An increasing number of cognitive, neurobiological, and computational models have been proposed in the last decade, seeking to explain how humans allocate physical or cognitive effort. Most models share conceptual similarities with motivational intensity theory (MIT), an influential classic psychological theory of motivation. Yet, little effort has been made to integrate such models, which remain confined within the explanatory level for which they were developed, that is, psychological, computational, neurobiological, and neuronal.

Associations among locus coeruleus catecholamines, tau pathology, and memory in aging.

The locus coeruleus (LC) is the brain's major source of the neuromodulator norepinephrine, and is also profoundly vulnerable to the development of Alzheimer's disease (AD)-related tau pathology. Norepinephrine plays a role in neuroprotective functions that may reduce AD progression, and also underlies optimal memory performance. Successful maintenance of LC neurochemical function represents a candidate mechanism of protection against the propagation of AD-related pathology and may facilitate the preservation of memory performance despite pathology.

Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging.

Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system's cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age.

Making the jump: Expert guidance on transitioning to academic independence.

Obtaining a position as an independent investigator is a daunting prospect, and often requires skill sets that are not emphasized during graduate or postdoctoral training. Here, we present insight from a seminar series designed to guide young researchers looking to "make the jump", covering the fundamental steps of the job search (preparation of an application package, Skype/remote interview, campus visit, and negotiations). We summarize the many useful insights distilled throughout these roundtable sessions with the goal of providing information and guidance to a broader community of researchers on the best way to prepare for and tackle the faculty job market.

Poor Sleep Quality and Compromised Visual Working Memory Capacity.

Objectives: Reduction in the amount of information (storage capacity) retained in working memory (WM) has been associated with sleep loss. The present study examined whether reduced WM capacity is also related to poor everyday sleep quality and, more importantly, whether the effects of sleep quality could be dissociated from the effects of depressed mood and age on WM.

Methods: In two studies, WM was assessed using a short-term recall task, producing behavioral measures for both the amount of retained WM information (capacity) and how precise the retained WM representations were (precision).

Dopaminergic Mechanisms Underlying Normal Variation in Trait Anxiety.

Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans.

Age-related variability in decision-making: Insights from neurochemistry.

Despite dopamine's significant role in models of value-based decision-making and findings demonstrating loss of dopamine function in aging, evidence of systematic changes in decision-making over the life span remains elusive. Previous studies attempting to resolve the neural basis of age-related alteration in decision-making have typically focused on physical age, which can be a poor proxy for age-related effects on neural systems. There is growing appreciation that aging has heterogeneous effects on distinct components of the dopamine system within subject in addition to substantial variability between subjects.

The Influence of Dopamine on Cognitive Flexibility Is Mediated by Functional Connectivity in Young but Not Older Adults.

Dopaminergic signaling in striatum is strongly implicated in executive functions including cognitive flexibility. However, there is a paucity of multimodal research in humans defining the nature of relationships between endogenous dopamine, striatal network activity, and cognition. Here, we measured dopamine synthesis capacity in young and older adults using the PET tracer 6-[F]fluoro-l- m-tyrosine and examined its relationship with cognitive performance and functional connectivity during an fMRI study of task switching.

Spontaneous eye blink rate and dopamine synthesis capacity: preliminary evidence for an absence of positive correlation.

Dopamine is central to a number of cognitive functions and brain disorders. Given the cost of neurochemical imaging in humans, behavioural proxy measures of dopamine have gained in popularity in the past decade, such as spontaneous eye blink rate (sEBR). Increased sEBR is commonly associated with increased dopamine function based on pharmacological evidence and patient studies.

Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release.

Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (K) using 6-[F]fluoro-l-m-tyrosine ([F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [C]raclopride paired with oral methylphenidate administration.