Hippocampal blood flow rapidly and preferentially increases after a bout of moderate-intensity exercise in older adults with poor cerebrovascular health.

Over the course of aging, there is an early degradation of cerebrovascular health, which may be attenuated with aerobic exercise training. Yet, the acute cerebrovascular response to a single bout of exercise remains elusive, particularly within key brain regions most affected by age-related disease processes. We investigated the acute global and region-specific cerebral blood flow (CBF) response to 15 minutes of moderate-intensity aerobic exercise in older adults (≥65 years; n = 60) using arterial spin labeling magnetic resonance imaging. Within 0-6 min post-exercise, CBF decreased across all regions, an effect that was attenuated in the hippocampus. The exercise-induced CBF drop was followed by a rebound effect over the 24-minute postexercise assessment period, an effect that was most robust in the hippocampus. Individuals with low baseline perfusion demonstrated the greatest hippocampal-specific CBF effect post-exercise, showing no immediate drop and a rapid increase in CBF that exceeded baseline levels within 6-12 minutes postexercise. Gains in domain-specific cognitive performance postexercise were not associated with changes in regional CBF, suggesting dissociable effects of exercise on acute neural and vascular plasticity. Together, the present findings support a precision-medicine framework for the use of exercise to target brain health that carefully considers age-related changes in the cerebrovascular system.

When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective.

This paper focuses on the question of, "When is the best time to identify an individual at risk for a treatable genetic condition?" In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a "Genomics Passbook" is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a "living document" that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.

Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.

Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery and gene editing systems. Early successes are encouraging, however, given the substantial number of distinct rare diseases, the ability to scale these successes will be unsustainable without new development efficiencies. Herein, we discuss the need for genomic newborn screening to match pace with the growing development of targeted therapeutics and ability to rapidly develop individualized therapies for rare variants. We offer approaches to move beyond conventional "one disease at a time" preclinical and clinical drug development and discuss planned regulatory innovations that are necessary to speed therapy delivery to individuals in need. These proposals leverage the shared properties of platform classes of therapeutics and innovative trial designs including master and platform protocols to better serve patients and accelerate drug development. Ultimately, there are risks to these novel approaches; however, we believe that close partnership and transparency between health authorities, patients, researchers, and drug developers present the path forward to overcome these challenges and deliver on the promise of gene-targeted therapies for rare diseases.

Are we prepared to deliver gene-targeted therapies for rare diseases?

The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach… or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.

Next-generation strategies for gene-targeted therapies of central nervous system disorders: A workshop summary.

The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop titled "Next generation strategies for gene-targeted therapies of central nervous system (CNS) disorders" in September 2019 in Bethesda, MD, USA. The meeting brought together a multi-disciplinary group of experts in the field of CNS-directed gene-targeted therapy delivery from academia, industry, advocacy, and the government. The group was charged with identifying the key challenges and gaps in this evolving field, as well as suggesting potential solutions. The workshop was divided into four sessions: (1) control of level and location, (2) improving delivery and distribution, (3) enhancing models and manufacturing, and (4) impacting patients. Prior to the workshop, NINDS established working groups of key opinion leaders (KOLs) for each session. In pre-meeting teleconferences, KOLs were tasked with identifying the research gaps and key obstacles that delay and/or prevent gene-targeted therapies to move into the clinic. This approach allowed for the workshop to begin with problem-solving discussions and strategy development, as the key issues had been established. The overall purpose of the workshop was to consider knowledge gaps and potential strategies to inform the community around CNS gene-targeted therapies, including but not limited to researchers and funders.

Exploring nutrition education for migrants to Canada in Alberta's health and community sectors: Promising practices and gaps as informed by community workers and healthcare providers.

This qualitative study explored how migrant-serving agencies and healthcare providers in Alberta can support migrants to maintain healthy eating patterns. Through semi-structured interviews, respondents provided insight on their experiences working with migrant populations in the community. Observations about dietary acculturation (including food access, unfamiliar food environments, and perceptions of common foods in Canada) point to nutrition information that may be relevant for migrants. Respondents provided recommendations, noting the importance of culturally appropriate services, visual education materials, and collaboration between healthcare providers and community workers. The collective knowledge presented here could be applied by those developing programming supports for migrant communities.

Apolipoprotein E4 Moderates the Association Between Vascular Risk Factors and Brain Pathology.

BACKGROUND: The strongest genetic risk factor for late-onset Alzheimer disease (AD), Apolipoprotein E4 (APOE4), increases cardiovascular disease risk and may also act synergistically with vascular risk factors to contribute to AD pathogenesis. Here, we assess the interaction between APOE4 and vascular risk on cerebrovascular dysfunction and brain pathology. METHODS: This is an observational study of cognitively normal older adults, which included positron emission tomography imaging and vascular risk factors. We measured beat-to-beat blood pressure and middle cerebral artery velocity at rest and during moderate-intensity exercise. Cerebrovascular measures included cerebrovascular conductance index and the cerebrovascular response to exercise. RESULTS: There was a significant interaction between resting cerebrovascular conductance index and APOE4 carrier status on ß-amyloid deposition (P=0.026), with poor conductance in the cerebrovasculature associated with elevated ß-amyloid for the APOE4 carriers only. There was a significant interaction between non-high-density lipoprotein cholesterol and APOE4 carrier status (P=0.014), with elevated non-high-density lipoprotein cholesterol predicting a blunted cerebrovascular response to exercise in APOE4 carriers and the opposite relationship in noncarriers. CONCLUSIONS: Both cerebral and peripheral vascular risk factors are preferentially associated with brain pathology in APOE4 carriers. These findings provide insight into pathogenic vascular risk mechanisms and target strategies to potentially delay AD onset.

Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts.

INTRODUCTION: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. METHODS: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. RESULTS: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P = .007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P = .063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P = .20), and haplogroup K frequencies were 4.9% versus 8.7% (P = .11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P = .006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P = .010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. CONCLUSION: This exploratory analysis suggests inherited mtDNA variants influence AD risk.

The serum metabolomics signature of type 2 diabetes is obscured in Alzheimer's disease.

There is evidence for systemic metabolic impairment in Alzheimer's disease (AD), and type 2 diabetes (T2D) increases AD risk. Although studies analyzing blood metabolomics signatures have shown differences between cognitively healthy (CH) and AD subjects, these signatures have not been compared with individuals with T2D. We utilized untargeted analysis platforms (primary metabolism and complex lipids) to characterize the serum metabolome of 126 overnight-fasted elderly subjects classified into four groups based upon AD status (CH or AD) and T2D status [nondiabetic (ND) or T2D]. Cognitive diagnosis groups were a priori weighted equally with T2D subjects. We hypothesized that AD subjects would display a metabolic profile similar to cognitively normal elderly individuals with T2D. However, partial least squares-discriminant analysis (PLS-DA) modeling resulted in poor classification across the four groups (<50% classification accuracy of test subjects). Binary classification of AD vs. CH was poor, but binary classification of T2D vs. ND was good, providing >79.5% and >76.9% classification accuracy for held-out samples using primary metabolism and complex lipids, respectively. When modeling was limited to CH subjects, T2D discrimination improved for the primary metabolism platform (>89.5%) and remained accurate for complex lipids (>73% accuracy). Greater abundances of glucose, fatty acids (C20:2), and phosphatidylcholines and lower abundances of glycine, maleimide, octanol, and tryptophan, cholesterol esters, phosphatidylcholines, and sphingomyelins were identified in CH subjects with T2D relative to those without T2D. In contrast, T2D was not accurately discriminated within AD subjects. Results herein suggest that AD may obscure the typical metabolic phenotype of T2D.

Bovine tuberculosis in working foxhounds: lessons learned from a complex public health investigation.

In 2017, Public Health England South East Health Protection Team (HPT) were involved in the management of an outbreak of Mycobacterium bovis (the causative agent of bovine tuberculosis) in a pack of working foxhounds. This paper summarises the actions taken by the team in managing the public health aspects of the outbreak, and lessons learned to improve the management of future potential outbreaks. A literature search was conducted to identify relevant publications on M. bovis. Clinical notes from the Public Health England (PHE) health protection database were reviewed and key points extracted. Animal and public health stakeholders involved in the management of the situation provided further evidence through unstructured interviews and personal communications. The PHE South East team initially provided 'inform and advise' letters to human contacts whilst awaiting laboratory confirmation to identify the infectious agent. Once M. bovis had been confirmed in the hounds, an in-depth risk assessment was conducted, and contacts were stratified in to risk pools. Eleven out of 20 exposed persons with the greatest risk of exposure were recommended to attend TB screening and one tested positive, but had no evidence of active TB infection. The number of human contacts working with foxhound packs can be large and varied. HPTs should undertake a comprehensive risk assessment of all potential routes of exposure, involve all other relevant stakeholders from an early stage and undertake regular risk assessments. Current guidance should be revised to account for the unique risks to human health posed by exposure to infected working dogs.

Metabolic Derangements Contribute to Reduced sRAGE Isoforms in Subjects with Alzheimer's Disease.

Although there is evidence for metabolic dysfunction and chronic inflammation in Alzheimer's disease (AD), circulating levels of soluble receptor for advanced glycation end products (sRAGE) and the receptor for advanced glycation end products (RAGE) ligand S100B have not been characterized. sRAGE is an important mediator in disease as it can act as a ligand decoy for RAGE and attenuate downstream inflammatory signaling. Cognitively healthy elderly and AD participants with and without type 2 diabetes (n = 135) were stratified according to the clinical dementia rating (CDR; 0 = normal cognition (NC); ≥0.5 = AD). Total serum sRAGE, endogenous secretory RAGE (esRAGE), and S100B were assayed via ELISAs, and cleaved RAGE (cRAGE) and the cRAGE : esRAGE ratio were calculated. cRAGE : esRAGE was lower in AD compared to NC (p < 0.05). Metabolic substratifications were used to investigate the factors that influence sRAGE pathology in AD. Stratification by BMI classification, median fat mass, median HOMA-IR, median insulin, and median amylin were all metabolic or anthropometric factors which significantly interacted with sRAGE profiles within AD subjects. There were no significant differences in serum S100B between groups. These characterizations of sRAGE contribute evidence to the link between impaired metabolism and cognitive decline due to AD.

Are pertussis cases reported too late for public health interventions? Retrospective analysis of cases in London and South East England, 2010 to 2015.

In the United Kingdom, pertussis guidance recommends prophylaxis for household contacts within 21 days of case symptom onset if the household includes a vulnerable contact. The aim of our study was to identify characteristics associated with cases reported late for public health action. We reviewed the epidemiology of cases reported in London and South East England for the period 2010 to 2015. We characterised risk factors associated with late reporting of cases and described public health actions taken on timely reported cases. From 2010 to 2015, 9,163 cases of pertussis were reported to health protection teams. Only 11% of cases were reported within 21 days of onset, limiting opportunities for secondary prevention. Timely reporting was associated with younger age groups, pregnancy, being a healthcare worker and being reported by schools or hospital clinicians. Late reporting was associated with older age groups and general practitioner or laboratory reporting. Delays, such as those due to insidious onset and late presentation to healthcare, may be unavoidable; however, delay in reporting once a patient presents can be reduced since cases can be reported before laboratory confirmation. Thus we recommend working with clinicians and laboratories to determine causes and improve early reporting to public health.

Safety of disclosing amyloid status in cognitively normal older adults.

INTRODUCTION: Disclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the test's clinical significance and unknown psychological risk. METHODS: We assessed the effect of amyloid status disclosure on anxiety and depression before disclosure, at disclosure, and 6 weeks and 6 months postdisclosure and test-related distress after disclosure. RESULTS: Clinicians disclosed amyloid status to 97 cognitively normal older adults (27 had elevated cerebral amyloid). There was no difference in depressive symptoms across groups over time. There was a significant group by time interaction in anxiety, although post hoc analyses revealed no group differences at any time point, suggesting a minimal nonsustained increase in anxiety symptoms immediately postdisclosure in the elevated group. Slight but measureable increases in test-related distress were present after disclosure and were related to greater baseline levels of anxiety and depression. DISCUSSION: Disclosing amyloid imaging results to cognitively normal adults in the clinical research setting with pre- and postdisclosure counseling has a low risk of psychological harm.

Exercise Test Performance Reveals Evidence of the Cardiorespiratory Fitness Hypothesis.

Positive physiologic and cognitive responses to aerobic exercise have resulted in a proposed cardiorespiratory (CR) fitness hypothesis in which fitness gains drive changes leading to cognitive benefit. The purpose of this study was to directly assess the CR fitness hypothesis. Using data from an aerobic exercise trial, we examined individuals who completed cardiopulmonary and cognitive testing at baseline and 26 weeks. Change in cognitive test performance was not related to CR fitness change (r2 = .06, p = .06). However, in the subset of individuals who gave excellent effort during exercise testing, change in cognitive test performance was related to CR fitness change (r2 = .33, p < .01). This was largely due to change in the cognitive domain of attention (r2 = .36, p < .01). The magnitude of change was not explained by duration of exercise. Our findings support further investigation of the CR fitness hypothesis and mechanisms by which physiologic adaptation may drive cognitive change.

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.

Cerebral ß-Amyloid Angiopathy Is Associated with Earlier Dementia Onset in Alzheimer's Disease.

BACKGROUND: Cerebral ß-amyloid angiopathy (CAA) occurs when ß-amyloid (Aß) is deposited in the vascular media and adventitia. It is a common pathology in the brains of older individuals and has been linked to cognitive decline, but relatively little is known about the influence that CAA has on the clinical manifestation of Alzheimer's disease (AD). The aim of this retrospective analysis was to quantify the effect that CAA had on the manifestation of initial AD-related cognitive change and subsequent progression of dementia. METHODS: We analyzed neuropathological data from the National Alzheimer's Coordinating Center's data set, performing parametric analyses to assess differences in age of progression to moderate-stage dementia. RESULTS: We found that individuals with both CAA burden and Aß neuritic plaque burden at death had the greatest risk of earlier conversion to very mild and moderate-stage dementia, but not necessarily faster progression. CONCLUSIONS: Our results suggest that CAA contributes to changes in early AD pathogenesis. This supports the idea that vascular change and neuritic plaque deposition are not just parallel processes but reflect additive pathological cascades that influence the course of clinical AD manifestation. Further inquiry into the role of CAA and its contribution to early cognitive change in AD is suggested.

Is Alzheimer's disease a systemic disease?

Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.

Management of a Trichophyton tonsurans outbreak in a day-care center.

Trichophyton tonsurans is the leading cause of tinea capitis in the United Kingdom (UK) as well as causing tinea corporis. This organism has been linked to several outbreaks in the UK and abroad, and such outbreaks may be prolonged since T. tonsurans can be difficult to control. There remains an incomplete consensus in the literature on the optimal management of such outbreaks of this infection. Following notification that a child with T. tonsurans was identified at a day-care center in the UK, initial investigations identified nine cases of fungal infection involving children and staff over the previous 7 months. We report on the management of an outbreak of T. tonsurans tinea capitis and tinea corporis among children and staff in a day-care center. An outbreak control team with representatives from dermatology, microbiology, day-care center management, and the Health Protection Agency initiated case ascertainment by scalp inspection and brushing of all children and staff at the nursery. Two complete rounds of screening were required before the outbreak was declared over. Infection control measures included antifungal shampoo use, exclusion of identified cases for a short period, removal of shared items from the center, and enhanced decontamination of fomites. The outbreak, which lasted longer than 12 months, involved 12 children and 7 staff members. Of these, 12 cases were confirmed by positive fungal culture. T. tonsurans is difficult to manage, especially in childcare settings, but case ascertainment, appropriate treatment with oral agents, and sustained infection control measures can be effective in controlling such outbreaks.

SOD1-G93A mice exhibit muscle-fiber-type-specific decreases in glucose uptake in the absence of whole-body changes in metabolism.

BACKGROUND: Skeletal muscles play an important role in systemic glucose homeostasis and are purported to be the origin of the altered metabolic state observed in amyotrophic lateral sclerosis (ALS). OBJECTIVE: The purpose of this study was to evaluate whole-body and muscle-specific glucose metabolism in the SOD1-G93A mouse model of ALS. METHODS: We assessed glucose tolerance in early-, middle-, and late-stage SOD1-G93A and control mice using an intraperitoneal glucose tolerance test. We then measured the respiratory exchange ratio (CO2 production/O2 consumption) as a function of fasting and feeding using indirect calorimetry in a subset of male mice at these time points. Finally, muscles from all mice were harvested to evaluate basal and insulin-stimulated glucose transport in fast- and slow-twitch muscles. RESULTS: No changes in systemic glucose clearance were observed in SOD1-G93A mice at any stage, nor were there changes in fasting insulin levels. Indirect calorimetry revealed an increase in the respiratory exchange ratio during the fed state at middle, but not at early or late stages of disease. Middle-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in fast-twitch, but not slow-twitch, skeletal muscle. Late-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in both fast- and slow-twitch muscle, as well as increased basal (non-insulin-stimulated) glucose uptake. CONCLUSIONS: These results suggest that alterations in muscle metabolism occur in a fiber-type-specific manner in ALS, but do not necessarily lead to whole-body metabolic changes in SOD1-G93A mice.

Universal screening in kindergarten: Validity and classification accuracy of Istation's Indicators of Progress-Early Reading.

Universal screening in reading is a common, and often required, practice in early elementary school. Computer-adaptive screening tools, such as Istation's Indicators of Progress-Early Reading (ISIP-ER), are often chosen for this purpose in schools. In our present study, we examine the validity evidence between the ISIP-ER in kindergarten and third grade State of Texas Assessments of Academic Readiness (STAAR) reading scores, the classification accuracy of ISIP-ER to predict which students will meet STAAR reading expectations, and a cut score to maximize classification accuracy for the local context. The sample included 962 students (Mage = 6.19 years; SDage = 0.37) from 15 elementary schools in one suburban school district in Texas. As for validity, the correlation between ISIP-ER in kindergarten and the third grade STAAR was moderate (r = 0.48). Classification accuracy analyses using the vendor-recommended cut score found sensitivity (0.63) and specificity (0.70) were all below recommended levels. Using a locally determined cut score, sensitivity (0.92) was improved, but specificity (0.33) was substantially decreased. The findings suggest ISIP-ER has some limitations in the accurate identification of students at risk for poor outcomes on a state-mandated reading test and will likely need to be combined with other assessments or progress monitoring data. (PsycInfo Database Record (c) 2024 APA, all rights reserved).