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Retinal vessel calibers share anatomic and physiologic characteristics with the cerebral vasculature and can be visualized noninvasively. In light of the known microvascular contributions to brain health and cognitive function, we aimed to determine if, in a community based-study, retinal vessel calibers and change in caliber over 8 years are associated with cognitive function or trajectory. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who completed cognitive testing at Exam 5 (2010–2012) and had retinal vascular caliber measurements (Central Retinal Artery and Vein Equivalents; CRAE and CRVE) at Exam 2 (2002–2004) and Exam 5 were included. Using multivariable linear regression, we evaluated the association of CRAE and CRVE from Exam 2 and Exam 5 and their change between the two exams with scores on tests of global cognitive function (Cognitive Abilities Screening Instrument; CASI), processing speed (Digit Symbol Coding; DSC) and working memory (Digit Span; DS) at Exam 5 and with subsequent change in cognitive scores between Exam 5 and Exam 6 (2016–2018).The main effects are reported as the difference in cognitive test score per SD increment in retinal vascular caliber with 95% confidence intervals (CI). A total of 4334 participants (aged 61.6 ± 9.2 years; 53% female; 41% White) completed cognitive testing and at least one retinal assessment. On multivariable analysis, a 1 SD larger CRAE at exam 5 was associated with a lower concomitant CASI score (− 0.24, 95% CI − 0.46, − 0.02). A 1 SD larger CRVE at exam 2 was associated with a lower subsequent CASI score (− 0.23, 95%CI − 0.45, − 0.01). A 1 SD larger CRVE at exam 2 or 5 was associated with a lower DSC score [(− 0.56, 95% CI − 1.02, − 0.09) and − 0.55 (95% CI − 1.03, − 0.07) respectively]. The magnitude of the associations was relatively small (2.8–3.1% of SD). No significant associations were found between retinal vessel calibers at Exam 2 and 5 with the subsequent score trajectory of cognitive tests performance over an average of 6 years. Wider retinal venular caliber was associated with concomitant and future measures of slower processing speed but not with later cognitive trajectory. Future studies should evaluate the utility of these measures in risk stratification models from a clinical perspective as well as for screening on a population level. [ABSTRACT FROM AUTHOR]

In humans, social participation and integration wane with advanced age, a pattern hypothesized to stem from cognitive or physical decrements. Similar age-related decreases in social participation have been observed in several nonhuman primate species. Here, we investigated cross-sectional age-related associations between social interactions, activity patterns, and cognitive function in 25 group-living female vervets (a.k.a. African green monkeys, Chlorocebus sabaeus) aged 8–29 years. Time spent in affiliative behavior decreased with age, and time spent alone correspondingly increased. Furthermore, time spent grooming others decreased with age, but the amount of grooming received did not. The number of social partners to whom individuals directed grooming also decreased with age. Grooming patterns mirrored physical activity levels, which also decreased with age. The relationship between age and grooming time was mediated, in part, by cognitive performance. Specifically, executive function significantly mediated age's effect on time spent in grooming interactions. In contrast, we did not find evidence that physical performance mediated age-related variation in social participation. Taken together, our results suggest that aging female vervets were not socially excluded but decreasingly engaged in social behavior, and that cognitive deficits may underlie this relationship. [ABSTRACT FROM AUTHOR]

Studies over the last 100 years have suggested a link between inflammation, infectious disease, and Alzheimer's Disease (AD). Understanding how the immune system changes during the development of AD may facilitate new treatments. Here, we studied an aging cohort who had been assessed for AD pathology with amyloid positron emission tomography and cognitive testing, and conducted high dimensional flow cytometry on peripheral blood mononuclear and cerebrospinal fluid cells. Participants were assigned a classification of being amyloid negative cognitively normal, amyloid positive cognitively normal (APCN), or amyloid positive mild cognitive impairment (APMCI), an early stage of AD. We observed major alterations in the peripheral innate immune system including increased myeloid and plasmacytoid dendritic cells in the blood of APMCI participants. When the adaptive immune system was examined, amyloid positive participants, regardless of cognitive status, had increased CD3+ T cells. Further analyses of CD4+ and CD8+ T cells revealed that APMCI participants had an increase in more differentiated phenotype T cells, such as effector memory and effector memory CD45RA expressing (TEMRA), compared to those with normal cognition. When T cell function was measured, we observed that T cells from APCN participants had increased IFNγ+GzB- producing cells compared to the other participants. In contrast, we demonstrate that APMCI participants had a major increase in T cells that lacked cytokine production following restimulation and expressed increased levels of PD-1 and Tox, suggesting these are exhausted cells. Rejuvenation of these cells may provide a potential treatment for AD. [ABSTRACT FROM AUTHOR]

Comparing brain structure across species and regions enables key functional insights. Leveraging publicly available data from a novel mass cytometry-based method, synaptometry by time of flight (SynTOF), we applied an unsupervised machine learning approach to conduct a comparative study of presynapse molecular abundance across three species and three brain regions. We used neural networks and their attractive properties to model complex relationships among high dimensional data to develop a unified, unsupervised framework for comparing the profile of more than 4.5 million single presynapses among normal human, macaque, and mouse samples. An extensive validation showed the feasibility of performing cross-species comparison using SynTOF profiling. Integrative analysis of the abundance of 20 presynaptic proteins revealed near-complete separation between primates and mice involving synaptic pruning, cellular energy, lipid metabolism, and neurotransmission. In addition, our analysis revealed a strong overlap between the presynaptic composition of human and macaque in the cerebral cortex and neostriatum. Our unique approach illuminates species- and region-specific variation in presynapse molecular composition. [ABSTRACT FROM AUTHOR]

Background: Microtubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer's disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging. The contribution of MT instability in AD remains unknown, though it may be more proximal to neuronal dysfunction than tau accumulation. Our lab reported the first brain-penetrant MT-based PET ligand, [11C]MPC-6827, and its PET imaging with this ligand in normal rodents and non-human primates demonstrated high brain uptake and excellent pharmacokinetics. Target engagement and mechanism of action using in vitro, in vivo, and ex vivo methods were evaluated here. Methods: In vitro cell uptake assay was performed in SH-SY5Y neuronal cells with [11C]MPC-6827, with various MT stabilizing and destabilizing agents. To validate the in vitro results, wild type (WT) mice (n = 4) treated with a brain-penetrant MT stabilizing drug (EpoD) underwent microPET/CT brain imaging with [11C]MPC-6827. To determine the influence of tau protein on radiotracer binding in the absence of protein accumulation, we utilized tau knockout (KO) mice. In vivo microPET imaging, ex vivo biodistribution, and autoradiography studies were performed in tau KO and WT mice (n = 6/group) with [11C]MPC-6827. Additionally, α, β, and acetylated tubulin levels in both brain samples were determined using commercially available cytoskeleton-based MT kit and capillary electrophoresis immunoblotting assays. Results: Cell uptake demonstrated higher radioactive uptake with MT destabilizing agents and lower uptake with stabilizing agents compared to untreated cells. Similarly, acute treatment with EpoD in WT mice decreased [11C]MPC-6827 brain uptake, assessed with microPET/CT imaging. Compared to WT mice, tau KO mice expressed significantly lower β tubulin, which contains the MPC-6827 binding domain, and modestly lower levels of acetylated α tubulin, indicative of unstable MTs. In vivo imaging revealed significantly higher [11C]MPC-6827 uptake in tau KOs than WT, particularly in AD-relevant brain regions known to express high levels of tau. Ex vivo post-PET biodistribution and autoradiography confirmed the in vivo results. Conclusions: Collectively, our data indicate that [11C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [11C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies. [ABSTRACT FROM AUTHOR]

Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit. [ABSTRACT FROM AUTHOR]

Dual declines in gait speed and cognitive performance are associated with increased risk of developing dementia. Characterizing the patterns of such impairments therefore is paramount to distinguishing healthy from pathological aging. Nonhuman primates such as vervet/African green monkeys (Chlorocebus aethiops sabaeus) are important models of human neurocognitive aging, yet the trajectory of dual decline has not been characterized. We therefore (1) assessed whether cognitive and physical performance (i.e., gait speed) are lower in older aged animals; (2) explored the relationship between performance in a novel task of executive function (Wake Forest Maze Task—WFMT) and a well-established assessment of working memory (delayed response task—DR task); and (3) examined the association between baseline gait speed with executive function and working memory at 1-year follow-up. We found (1) physical and cognitive declines with age; (2) strong agreement between performance in the novel WFMT and DR task; and (3) that slow gait is associated with poor cognitive performance in both domains. Our results suggest that older aged vervets exhibit a coordinated suite of traits consistent with human aging and that slow gait may be a biomarker of cognitive decline. This integrative approach provides evidence that gait speed and cognitive function differ across the lifespan in female vervet monkeys, which advances them as a model that could be used to dissect relationships between trajectories of dual decline over time. [ABSTRACT FROM AUTHOR]

Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Introduction: High-fat diets increase risk for Alzheimer's disease, but individuals with the risk gene APOE ε4 (E4) paradoxically have improved memory soon after high fat feeding. Little is known about how dietary lipids affect CNS lipids, especially in older adults. Objectives: We analyzed the lipidomic signature of cerebrospinal fluid (CSF) in older adults who underwent both a saline and TG infusion. We further analyzed these data by E4 carrier status. Methods: Older adults (n = 21, age 67.7 ± 8.6) underwent a 5-h TG and saline infusion on different days in random crossover design; lumbar CSF was collected at the end of the infusion. Lipids were extracted using dichloromethane/methanol and 13 classes of lipids analyzed using the Lipidyzer platform consisting of an AB Sciex 5500 MS/MS QTraps system equipped with a SelexION for differential mobility spectrometry (DMS). Multiple reaction monitoring was used to target and quantify 1070 lipids in positive and negative ionization modes with and without DMS. Results: The TG infusion increased total lipids in the CSF, including the appearance of more lipids at the detection limit in the TG samples compared to saline (Chi square p < 0.0001). The infusion increased the total level of diacylglycerols and lysophosphatidylcholines and reduced dihydroceramides. Of the possible 1070 lipids detectable, we found 348 after saline and 365 after TG infusion. Analysis using MetaboAnalyst revealed 11 specific lipids that changed; five of these lipids decreased after TG infusion, and four of them differed by E4 status, but none differed by cognitive diagnosis or sex. Conclusion: These results in older adults show that blood lipids affect lipid profiles in CSF and such profiles are modified by APOE status. This suggests that how the CNS handles lipids may be important in the AD phenotype. [ABSTRACT FROM AUTHOR]

One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke. [ABSTRACT FROM AUTHOR]

Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism-such as insulin resistance in obesity, type 2 diabetes and AD-and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy. [ABSTRACT FROM AUTHOR]

Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis. [ABSTRACT FROM AUTHOR]

An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in Alzheimer's disease may contribute to the disease pathophysiology and clinical symptoms. It has long been known that insulin is essential for energy metabolism in the periphery. In the past 2 decades, convergent findings have begun to demonstrate that insulin also plays a role in energy metabolism and other aspects of CNS function. Investigators reported 20 years ago that insulin and insulin receptors were densely but selectively expressed in the brain, including the medial temporal regions that support the formation of memory. It has recently been demonstrated that insulin-sensitive glucose transporters are localised to the same regions supporting memory and that insulin plays a role in memory functions. Collectively, these findings suggest that insulin may contribute to normal cognitive functioning and that insulin abnormalities may exacerbate cognitive impairments, such as those associated with Alzheimer's disease. Insulin may also play a role in regulating the amyloid precursor protein and its derivative β-amyloid (Aβ), which is associated with senile plaques, a neuropathological hallmark of Alzheimer's disease. It has been proposed that insulin can accelerate the intracellular trafficking of Aβ and interfere with its degradation. These findings are consistent with the notion that insulin abnormalities may potentially influence levels of Aβ in the brains of patients with Alzheimer's disease. The increased occurrence of insulin resistance in Alzheimer's disease and the numerous mechanisms through which insulin may affect clinical and pathological aspects of the disease suggest that improving insulin effectiveness may have therapeutic benefit for patients with Alzheimer's disease. The thiazolidinedione rosiglitazone has been shown to have a potent insulin-sensitising action that appears to be mediated through the peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ agonists, such as rosiglitazone, also have anti-inflammatory effects that may be of therapeutic benefit in patients with Alzheimer's disease. This review presents evidence suggesting that insulin resistance plays a role in the pathophysiology and clinical symptoms of Alzheimer's disease. Based on this evidence, we propose that treatment of insulin resistance may reduce the risk or retard the development of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Erratum to: GeroScience (2021) 43:1303-1315 https://doi.org/10.1007/s11357-021-00338-w The original version of this article unfortunately contained an error in the funding section. The original articles can be found online at https://doi.org/10.1007/s11357-021-00338-w. Funding This work was supported by several mechanisms, including the following: National Institutes of Health (NIH) R01HL087103 (CAS), NIH RF1AG058829 (CAS and SC), P30 AG049638 (SC), T35OD010946 (PI Kavanagh), Intramural Grant from the Department of Pathology, Wake Forest School of Medicine (CAS), Wake Forest Claude Pepper Older Americans Independence Center grant P30 AG21332 (SK), Vervet Research Colony (P40-OD010965) (MJ), and the Wake Forest Clinical and Translational Science Institute (NCATS UL1TR001420). [Extracted from the article]

The article discusses two studies which characterized amyloid-related brain insulin resistance in animal models of, and patients with, Alzheimer's disease (AD). Results show that exendin-4, a glucagon-like peptide 1 receptor agonist, ameliorates pathology and symptoms in a mouse model of AD, suggesting a novel therapeutic approach to AD. It also demonstrated that defective insulin signalling is a characteristic feature of the AD brain.

The article discusses the studies which characterized insulin signalling in human brain tissue or animal models in Alzheimer disease (AD). According to the study of Talbot, defective insulin signalling was AD brain's characteristic property, which confirms that phosphorylation of insulin receptor substrate 1 exists in the AD brain. It adds that the two studies of Bomfim, propose that glucagon-like peptide 1 (GLP-1) receptor agonists have efficacy which elevated insulin levels in the brain.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike. [ABSTRACT FROM AUTHOR]