Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-ß (Aß)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer's Disease Mice.

BACKGROUND: Prior research supports a strong link between Alzheimer's disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-ß (Aß) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis. OBJECTIVE: We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. METHODS: We conducted an early intervention study in male and female transgenic (AßPP/PS1) and knock-in (APPNL - F/NL - F) AD mice to assess the on- and off-treatment effects of prodromal glutamatergic modulation (2-6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment. RESULTS: Results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment. CONCLUSION: These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance.

Health disparities in aging: Improving dementia care for Black women.

In the United States, 80% of surveyed Black patients report experiencing barriers to healthcare for Alzheimer's disease and related dementias (ADRD), delaying the time-sensitive treatment of a progressive neurodegenerative disease. According to the National Institute on Aging, Black study participants are 35% less likely to be given a diagnosis of ADRD than white participants, despite being twice as likely to suffer from ADRD than their white counterparts. Prior analysis of prevalence for sex, race, and ethnicity by the Centers for Disease Control indicated the highest incidence of ADRD in Black women. Older (≥65 years) Black women are at a disproportionately high risk for ADRD and yet these patients experience distinct inequities in obtaining clinical diagnosis and treatment for their condition. To that end, this perspective article will review a current understanding of biological and epidemiological factors that underlie the increased risk for ADRD in Black women. We will discuss the specific barriers Black women face in obtaining access to ADRD care, including healthcare prejudice, socioeconomic status, and other societal factors. This perspective also aims to evaluate the performance of intervention programs targeted toward this patient population and offer possible solutions to promote health equity.

Chronic, Mild Hypothermic Environmental Temperature Does Not Ameliorate Cognitive Deficits in an Alzheimer's Disease Mouse.

Metabolic dysfunction increases with age and is a contributing factor to Alzheimer's disease (AD) development. We have previously observed impaired insulin sensitivity and glucose homeostasis in the APP/PS1 model of AD. To improve these parameters, we chronically exposed male and female mice to mild hypothermic environmental temperature (eT), which positively modulates metabolism. Although a hypothermic eT normalized insulin sensitivity, glucose tolerance was still impaired in both sexes of AD mice. We observed increased plasma glucagon and B-cell activating factor in both sexes, but additional sexually dimorphic mechanisms may explain the impaired glucose homeostasis in AD mice. Hepatic Glut2 was decreased in females while visceral adipose tissue TNFα was increased in male APP/PS1 mice. A mild hypothermic eT did not improve spatial learning and memory in either sex and increased amyloid plaque burden in male APP/PS1 mice. Overall, plasma markers of glucose homeostasis and AD pathology were worse in females compared to male APP/PS1 mice suggesting a faster disease progression. This could affect the therapeutic outcomes if interventional strategies are administered at the same chronological age to male and female APP/PS1 mice. Furthermore, this data suggests a dichotomy exists between mechanisms to improve metabolic function and cognitive health that may be further impaired in AD.

Friend or Foe? Defining the Role of Glutamate in Aging and Alzheimer's Disease.

Aging is a naturally occurring decline of physiological processes and biological pathways that affects both the structural and functional integrity of the body and brain. These physiological changes reduce motor skills, executive function, memory recall, and processing speeds. Aging is also a major risk factor for multiple neurodegenerative disorders including Alzheimer's disease (AD). Identifying a biomarker, or biomarkers, that signals the transition from physiological to pathological aging would aid in earlier therapeutic options or interventional strategies. Considering the importance of glutamate signaling in synaptic plasticity, motor movement, and cognition, this neurotransmitter serves as a juncture between cognitive health and disease. This article discusses glutamatergic signaling during physiological aging and the pathological changes observed in AD patients. Findings from studies in mouse models of successful aging and AD are reviewed and provide a biological context for this transition. Finally, current techniques to monitor brain glutamate are highlighted. These techniques may aid in elucidating time-point specific therapeutic windows to modify disease outcome.

The progression of diversity: Black women in neurosurgery.

While diversity in organized medicine has undoubtedly improved, a disparity remains in the racial and gender makeup of its constituents. This disparity is not distributed equally among all specialties of practice. The surgical subspecialties exemplify this phenomenon by having large gaps between the number of women and racial/ethnic minorities compared to their majority counterparts. Pertaining to neurosurgery in the US, this gap is substantial, with women reaching minority status only within the last 2 years. Among international women in neurosurgery, Black women are even further underrepresented despite efforts in recent years to close the gender gap. The reason for this disparity is likely multifactorial, as Black women demonstrate a unique intersectionality as a minority in regard to both race and gender. In this study, the authors provide historical context for the current state of diversity in neurosurgery and the global strides made by Black women within the field. The authors report recurrent themes in the experiences of Black female neurosurgery attendings and residents as revealed through personal interviews. Furthermore, they examine factors that contribute to the disproportionate representation of Black women in neurosurgery.