Cross-Omics Analysis of Fenugreek Supplementation Reveals Beneficial Effects Are Caused by Gut Microbiome Changes Not Mammalian Host Physiology.

Herbal remedies are increasing in popularity as treatments for metabolic conditions such as obesity and Type 2 Diabetes. One potential therapeutic option is fenugreek seeds (Trigonella foenum-graecum), which have been used for treating high cholesterol and Type 2 diabetes. A proposed mechanism for these benefits is through alterations in the microbiome, which impact mammalian host metabolic function. This study used untargeted metabolomics to investigate the fenugreek-induced alterations in the intestinal, liver, and serum profiles of mice fed either a 60% high-fat or low-fat control diet each with or without fenugreek supplementation (2% w/w) for 14 weeks. Metagenomic analyses of intestinal contents found significant alterations in the relative composition of the gut microbiome resulting from fenugreek supplementation. Specifically, Verrucomicrobia, a phylum containing beneficial bacteria which are correlated with health benefits, increased in relative abundance with fenugreek. Metabolomics partial least squares discriminant analysis revealed substantial fenugreek-induced changes in the large intestines. However, it was observed that while the magnitude of changes was less, significant modifications were present in the liver tissues resulting from fenugreek supplementation. Further analyses revealed metabolic processes affected by fenugreek and showed broad ranging impacts in multiple pathways, including carnitine biosynthesis, cholesterol and bile acid metabolism, and arginine biosynthesis. These pathways may play important roles in the beneficial effects of fenugreek.

What Should I Eat and Why? The Environmental, Genetic, and Behavioral Determinants of Food Choice: Summary from a Pennington Scientific Symposium.

This review details the proceedings of a Pennington Biomedical scientific symposium titled, "What Should I Eat and Why? The Environmental, Genetic, and Behavioral Determinants of Food Choice." The symposium was designed to review the literature about energy homeostasis, particularly related to food choice and feeding behaviors, from psychology to physiology. This review discusses the intrinsic determinants of food choice, including biological mechanisms (genetics), peripheral and central signals, brain correlates, and the potential role of the microbiome. This review also address the extrinsic determinants (environment) of food choice within our physical and social environments. Finally, this review reports the current treatment practices for the clinical management of eating-induced overweight and obesity. An improved understanding of these determinants will inform best practices for the clinical treatment and prevention of obesity. Strategies paired with systemic shifts in our public health policies and changes in our "obesogenic" environment will be most effective at attenuating the obesity epidemic.

Predictors of Heterogeneity in Cognitive Function: APOE-e4, Sex, Education, Depression, and Vascular Risk.

OBJECTIVE: Mild cognitive impairment and dementia are clinically heterogeneous disorders influenced by diverse risk factors. Improved characterization of the effect of multiple risk factors influence on specific cognitive functions may improve understanding of mechanisms in early cognitive change and lead to more effective interventions. METHODS: Structural equation modeling (SEM) simultaneously examined the effects of modifiable (education, depression, and metabolic/vascular risk) and nonmodifiable risk factors (age, sex, and apolipoprotein E-ɛ4 allele [APOE-e4] status) on specific cognitive domains in 461 cognitively normal older adults. RESULTS: The hypothesized model(s) provided an adequate fit for the data. Sex differences in cognition, depression, and vascular risk were found. On average, men were higher in vascular risk with generally lower cognitive performance than women; women were more likely to have depression. APOE-e4 associated with depression but not age, sex, or metabolic/vascular risk. Depression associated with lower executive attention, memory, and language performance, whereas metabolic/vascular risk associated with lower executive attention, memory, and working memory. Older age and lower education are associated with worse performance across the cognitive domains. The combined risk factors accounted for 16%-47% of the variance in the cognitive domains. CONCLUSIONS: Results highlight the combined effect of risk factors on cognitive function. Future research is needed to determine whether the multifactorial risk effects on cognition vary by sex. Precision medicine approaches that integrate neuropsychological services may improve diagnostic accuracy and earlier identification of those at risk of cognitive decline.

Fenugreek Counters the Effects of High Fat Diet on Gut Microbiota in Mice: Links to Metabolic Benefit.

Fenugreek (Trigonella foenum-graecum) is an annual herbaceous plant and a staple of traditional health remedies for metabolic conditions including high cholesterol and diabetes. While the mechanisms of the beneficial actions of fenugreek remain unknown, a role for intestinal microbiota in metabolic homeostasis is likely. To determine if fenugreek utilizes intestinal bacteria to offset the adverse effects of high fat diets, C57BL/6J mice were fed control/low fat (CD) or high fat (HFD) diets each supplemented with or without 2% (w/w) fenugreek for 16 weeks. The effects of fenugreek and HFD on gut microbiota were comprehensively mapped and then statistically assessed in relation to effects on metrics of body weight, hyperlipidemia, and glucose tolerance. 16S metagenomic analyses revealed robust and significant effects of fenugreek on gut microbiota, with alterations in both alpha and beta diversity as well as taxonomic redistribution under both CD and HFD conditions. As previously reported, fenugreek attenuated HFD-induced hyperlipidemia and stabilized glucose tolerance without affecting body weight. Finally, fenugreek specifically reversed the dysbiotic effects of HFD on numerous taxa in a manner tightly correlated with overall metabolic function. Collectively, these data reinforce the essential link between gut microbiota and metabolic syndrome and suggest that the preservation of healthy populations of gut microbiota participates in the beneficial properties of fenugreek in the context of modern Western-style diets.

The db mutation improves memory in younger mice in a model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Leprdb/db) induces mixed or vascular dementia in mature to middle-aged APPΔNL/ΔNL x PS1P264L/P264L knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aß content, which we have not observed at older ages. This was unlikely to be related to altered Aß synthesis, as both ß- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1ß mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD.

Defining Dysbiosis in Disorders of Movement and Motivation.

The gut microbiota has emerged as a critical player in shaping and modulating brain function and has been shown to influence numerous behaviors, including anxiety and depression-like behaviors, sociability, and cognition. However, the effects of the gut microbiota on specific disorders associated with thalamo-cortico-basal ganglia circuits, ranging from compulsive behavior and addiction to altered sensation and motor output, are only recently being explored. Wholesale depletion and alteration of gut microbial communities in rodent models of disorders, such as Parkinson's disease, autism, and addiction, robustly affect movement and motivated behavior. A new frontier therefore lies in identifying specific microbial alterations that affect these behaviors and understanding the underlying mechanisms of action. Comparing alterations in gut microbiota across multiple basal-ganglia associated disease states allows for identification of common mechanistic pathways that may interact with distinct environmental and genetic risk factors to produce disease-specific outcomes.

Understanding heterogeneity in older adults: Latent growth curve modeling of cognitive functioning.

BACKGROUND: Clarifying relationships between specific neurocognitive functions in cognitively intact older adults can improve our understanding of mechanisms involved in cognitive decline, which may allow identification of new opportunities for intervention and earlier detection of those at increased risk of dementia. METHOD: The present study employed latent growth curve modeling to longitudinally examine the relationship between executive attention/processing speed, episodic memory, language, and working memory functioning utilizing the neuropsychological test battery from the National Alzheimer's Disease Coordinating Center. A total of 691 relatively healthy older adults (Mage = 69.07, SD = 6.49) were assessed at baseline, and 553 individuals completed three visits spanning a two-year period. RESULTS: Better cognitive performance was concomitantly associated with better functioning across domains. Subtle declines in executive attention/processing speed processes were found, while, on average, memory and language performance improved with repeated testing. Lower executive attention/processing speed performance at baseline predicted less incremental growth rate in memory. In turn, higher initial memory functioning was associated with incremental improvements in language performance. CONCLUSIONS: These results are consistent with the notion that intact executive function and attention processes are important to preserving memory functioning with advanced age, but are also the functions most susceptible to decline with age. These findings also provide further insight into the critical role of practice effects in clinical assessment practice and have implications for pharmaceutical trials. Practice effects should be routinely considered as they may give the appearance of retention of function within the cognitive domains considered to be a hallmark of Alzheimer's disease pathology.

Harnessing Gut Microbes for Mental Health: Getting From Here to There.

There has been an explosion of interest in the study of microorganisms inhabiting the gastrointestinal tract (gut microbiota) and their impact on host health and physiology. Accumulating data suggest that altered communication between gut microbiota and host systems could participate in disorders such as obesity, diabetes mellitus, and autoimmune disorders as well as neuropsychiatric disorders, including autism, anxiety, and major depressive disorders. The conceptual development of the microbiome-gut-brain axis has facilitated understanding of the complex and bidirectional networks between gastrointestinal microbiota and their host, highlighting potential mechanisms through which this environment influences central nervous system physiology. Communication pathways between gut microbiota and the central nervous system could include autonomic, neuroendocrine, enteric, and immune systems, with pathology resulting in disruption to neurotransmitter balance, increases in chronic inflammation, or exacerbated hypothalamic-pituitary-adrenal axis activity. However, uncertainty remains regarding the generalizability of controlled animal studies to the more multifaceted pattern of human pathophysiology, especially with regard to the therapeutic potential for neuropsychiatric health. This narrative review summarizes current understanding of gut microbial influence over physiological function, with an emphasis on neurobehavioral and neurological impairment based on growing understanding of the gut-brain axis. Experimental and clinical data regarding means of therapeutic manipulation of gut microbiota as a novel treatment option for mental health are described, and important knowledge gaps are identified and discussed.

Fenugreek supplementation during high-fat feeding improves specific markers of metabolic health.

To assess the metabolically beneficial effects of fenugreek (Trigonella foenum-graecum), C57BL/6J mice were fed a low- or high-fat diet for 16 weeks with or without 2% (w/w) fenugreek supplementation. Body weight, body composition, energy expenditure, food intake, and insulin/glucose tolerance were measured regularly, and tissues were collected for histological and biochemical analysis after 16 weeks of diet exposure. Fenugreek did not alter body weight, fat mass, or food intake in either group, but did transiently improve glucose tolerance in high fat-fed mice. Fenugreek also significantly improved high-density lipoprotein to low-density lipoprotein ratios in high fat-fed mice without affecting circulating total cholesterol, triglycerides, or glycerol levels. Fenugreek decreased hepatic expression of fatty acid-binding protein 4 and increased subcutaneous inguinal adipose tissue expression of adiponectin, but did not prevent hepatic steatosis. Notably, fenugreek was not as effective at improving glucose tolerance as was four days of voluntary wheel running. Overall, our results demonstrate that fenugreek promotes metabolic resiliency via significant and selected effects on glucose regulation, hyperlipidemia, and adipose pathology; but may not be as effective as behavioral modifications at preventing the adverse metabolic consequences of a high fat diet.

Myeloid-specific deletion of NOX2 prevents the metabolic and neurologic consequences of high fat diet.

High fat diet-induced obesity is associated with inflammatory and oxidative signaling in macrophages that likely participates in metabolic and physiologic impairment. One key factor that could drive pathologic changes in macrophages is the pro-inflammatory, pro-oxidant enzyme NADPH oxidase. However, NADPH oxidase is a pleiotropic enzyme with both pathologic and physiologic functions, ruling out indiscriminant NADPH oxidase inhibition as a viable therapy. To determine if targeted inhibition of monocyte/macrophage NADPH oxidase could mitigate obesity pathology, we generated mice that lack the NADPH oxidase catalytic subunit NOX2 in myeloid lineage cells. C57Bl/6 control (NOX2-FL) and myeloid-deficient NOX2 (mNOX2-KO) mice were given high fat diet for 16 weeks, and subject to comprehensive metabolic, behavioral, and biochemical analyses. Data show that mNOX2-KO mice had lower body weight, delayed adiposity, attenuated visceral inflammation, and decreased macrophage infiltration and cell injury in visceral adipose relative to control NOX2-FL mice. Moreover, the effects of high fat diet on glucose regulation and circulating lipids were attenuated in mNOX2-KO mice. Finally, memory was impaired and markers of brain injury increased in NOX2-FL, but not mNOX2-KO mice. Collectively, these data indicate that NOX2 signaling in macrophages participates in the pathogenesis of obesity, and reinforce a key role for macrophage inflammation in diet-induced metabolic and neurologic decline. Development of macrophage/immune-specific NOX-based therapies could thus potentially be used to preserve metabolic and neurologic function in the context of obesity.

Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion.

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA GABA neurons that coexpress the neuropeptide galanin (LHA Gal ). These LHA Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA Gal neurons may represent a subpopulation of LHA GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA Gal or LHA GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA Gal or LHA GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA GABA neurons increased overall chow consumption. Additionally, LHA Gal or LHA GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA GABA neurons induced compulsive-like locomotor behavior; while LHA Gal neurons induced locomotor activity without compulsivity. Thus, LHA Gal neurons define a subpopulation of LHA GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified.SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHA GABA neurons is heterogeneous and largely undefined. Here we introduce LHA Gal neurons as a subset of LHA GABA neurons that lack direct innervation of the ventral tegmental area (VTA). LHA Gal neurons are sufficient to drive motivated feeding and locomotor activity similar to LHA GABA neurons, but without inducing compulsive-like behaviors, which we propose to require direct VTA innervation. Our study integrates galanin-expressing LHA neurons into our current understanding of the neuronal circuits and molecular mechanisms of the LHA that contribute to motivated feeding behaviors.

Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice.

Maternal obesity is known to predispose offspring to metabolic and neurodevelopmental abnormalities. While the mechanisms underlying these phenomena are unclear, high fat diets dramatically alter intestinal microbiota, and gut microbiota can impact physiological function. To determine if maternal diet-induced gut dysbiosis can disrupt offspring neurobehavioral function, we transplanted high fat diet- (HFD) or control low fat diet-associated (CD) gut microbiota to conventionally-housed female mice. Recipient mice were then bred and the behavioral phenotype of male and female offspring was tracked. While maternal behavior was unaffected, neonatal offspring from HFD dams vocalized less upon maternal separation than pups from CD dams. Furthermore, weaned male offspring from HFD dams had significant and selective disruptions in exploratory, cognitive, and stereotypical/compulsive behavior compared to male offspring from CD dams; while female offspring from HFD dams had increases in body weight and adiposity. 16S metagenomic analyses confirmed establishment of divergent microbiota in CD and HFD dams, with alterations in diversity and taxonomic distribution throughout pregnancy and lactation. Likewise, significant alterations in gut microbial diversity and distribution were noted in offspring from HFD dams compared to CD dams, and in males compared to females. Regression analyses of behavioral performance against differentially represented taxa suggest that decreased representation of specific members of the Firmicutes phylum predict behavioral decline in male offspring. Collectively, these data establish that high fat diet-induced maternal dysbiosis is sufficient to disrupt behavioral function in murine offspring in a sex-specific manner. Thus these data reinforce the essential link between maternal diet and neurologic programming in offspring and suggest that intestinal dysbiosis could link unhealthy modern diets to the increased prevalence of neurodevelopmental and childhood disorders.

Apolipoprotein E Genotype Linked to Spatial Gait Characteristics: Predictors of Cognitive Dual Task Gait Change.

BACKGROUND: Developing measures to detect preclinical Alzheimer's Disease is vital, as prodromal stage interventions may prove more efficacious in altering the disease's trajectory. Gait changes may serve as a useful clinical heuristic that precedes cognitive decline. This study provides the first systematic investigation of gait characteristics relationship with relevant demographic, physical, genetic (Apolipoprotein E genotype), and health risk factors in non-demented older adults during a cognitive-load dual task walking condition. METHODS: The GAITRite system provided objective measurement of gait characteristics in APOE-e4 "carriers" (n = 75) and "non-carriers" (n = 224). Analyses examined stride length and step time gait characteristics during simple and dual-task (spelling five-letter words backwards) conditions in relation to demographic, physical, genetic, and health risk factors. RESULTS: Slower step time and shorter stride length associated with older age, greater health risk, and worse physical performance (ps < .05). Men and women differed in height, gait characteristics, health risk factors and global cognition (ps < .05). APOE-e4 associated with a higher likelihood of hypercholesterolemia and overall illness index scores (ps < .05). No genotype-sex interactions on gait were found. APOE-e4 was linked to shorter stride length and greater dual-task related disturbances in stride length. CONCLUSIONS: Stride length has been linked to heightened fall risk, attention decrements and structural brain changes in older adults. Our results indicate that stride length is a useful behavioral marker of cognitive change that is associated with genetic risk for AD. Sex disparities in motor decline may be a function of health risk factors.

Elevated adiponectin prevents HIV protease inhibitor toxicity and preserves cerebrovascular homeostasis in mice.

HIV protease inhibitors are key components of HIV antiretroviral therapies, which are fundamental in the treatment of HIV infection. However, the protease inhibitors are well-known to induce metabolic dysfunction which can in turn escalate the complications of HIV, including HIV associated neurocognitive disorders. As experimental and epidemiological data support a therapeutic role for adiponectin in both metabolic and neurologic homeostasis, this study was designed to determine if increased adiponectin could prevent the detrimental effects of protease inhibitors in mice. Adult male wild type (WT) and adiponectin-overexpressing (ADTg) mice were thus subjected to a 4-week regimen of lopinavir/ritonavir, followed by comprehensive metabolic, neurobehavioral, and neurochemical analyses. Data show that lopinavir/ritonavir-induced lipodystrophy, hypoadiponectinemia, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia were attenuated in ADTg mice. Furthermore, cognitive function and blood-brain barrier integrity were preserved, while loss of cerebrovascular markers and white matter injury were prevented in ADTg mice. Finally, lopinavir/ritonavir caused significant increases in expression of markers of brain inflammation and decreases in synaptic markers in WT, but not in ADTg mice. Collectively, these data reinforce the pathophysiologic link from metabolic dysfunction to loss of cerebrovascular and cognitive homeostasis; and suggest that preservation and/or replacement of adiponectin could prevent these key aspects of HIV protease inhibitor-induced toxicity in clinical settings.

Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain.

Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTOR(ser2448), AKT(thr308) and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight into the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions.

Effects of Ghrelin on the Proteolytic Pathways of Alzheimer's Disease Neuronal Cells.

Ghrelin is an orexigenic hormone with a role in the onset and progression of neurodegenerative disorders. It has been recently associated to Alzheimer's disease (AD) for its neuroprotective and anti-apoptotic activity. In the present study, we dissected the effect of ghrelin treatment on the two major intracellular proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy, in cellular models of AD (namely SH-SY5Y neuroblastoma cells stably transfected with either the wild-type AßPP gene or the 717 valine-to-glycine AßPP-mutated gene). Ghrelin showed a growth-promoting effect on neuronal cells inducing also time-dependent modifications of the growth hormone secretagogue receptor type 1 (GHS-R1) expression. Interestingly, we demonstrated for the first time that ghrelin was able to activate the proteasome in neural cells playing also a role in the interplay between the UPS and autophagy. Our data provide a novel mechanism by which circulating hormones control neural homeostasis through the regulation of proteolytic pathways implicated in AD.

Adipose-specific ablation of Nrf2 transiently delayed high-fat diet-induced obesity by altering glucose, lipid and energy metabolism of male mice.

Nuclear factor E2-related factor 2 (NRF2) is a well-known master controller of the cellular adaptive antioxidant and detoxification response. Recent studies demonstrated altered glucose, lipid and energy metabolism in mice with a global Nrf2 knockout. In the present study, we aim to determine the effects of an adipose-specific ablation of Nrf2 (ASAN) on diet-induced obesity (DIO) in male mice. The 6-week-old adipose-specific Nrf2 knockout (NK) and its Nrf2 control (NC) mice were fed with either control diet (CD) or high-fat diet (HFD) for 14 weeks. NK mice exhibited transiently delayed body weight (BW) growth from week 5 to week 11 of HFD feeding, higher daily physical activity levels and preferential use of fat over carbohydrates as a source of energy at week 8 of the CD-feeding period. After 14 weeks of feeding, NK mice showed comparable results with NC mice with respect to the overall BW and body fat content, but exhibited reduced blood glucose, reduced number but increased size of adipocytes, accompanied with elevated expression of many genes and proteins in the visceral fat related to glucose, lipid and energy metabolism (e.g. Fgf21, Pgc1a). These results indicated that NRF2 is an important mediator for glucose, lipid and energy metabolism in adipose tissue, and ASAN could have beneficial effect for prevention of DIO during the early development of mice.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.

Longitudinal assessment of neuropsychological and temporal/spatial gait characteristics of elderly fallers: taking it all in stride.

Gait abnormalities are linked to cognitive decline and an increased fall risk within older adults. The present study addressed gaps from cross-sectional studies in the literature by longitudinally examining the interplay between temporal and spatial aspects of gait, cognitive function, age, and lower-extremity strength in elderly "fallers" and "non-fallers". Gait characteristics, neuropsychological and physical test performance were examined at two time points spaced a year apart in cognitively intact individuals aged 60 and older (N = 416). Mixed-model repeated-measure ANCOVAs examined temporal (step time) and spatial (stride length) gait characteristics during a simple and cognitive-load walking task in fallers as compared to non-fallers. Fallers consistently demonstrated significant alterations in spatial, but not temporal, aspects of gait as compared to non-fallers during both walking tasks. Step time became slower as stride length shortened amongst all participants during the dual task. Shorter strides and slower step times during the dual task were both predicted by worse executive attention/processing speed performance. In summary, divided attention significantly impacts spatial aspects of gait in "fallers", suggesting stride length changes may precede declines in other neuropsychological and gait characteristics, thereby selectively increasing fall risk. Our results indicate that multimodal intervention approaches that integrate physical and cognitive remediation strategies may increase the effectiveness of fall risk interventions.