Inflammatory cytokine levels implicated in Alzheimer's disease moderate the effects of sex on verbal memory performance.

Despite having an initial verbal memory advantage over men, women have greater rates of Alzheimer's disease and more rapid cognitive decline once diagnosed. Moreover, although Alzheimer's disease is influenced by inflammation, which itself has known sex differences, no study has investigated whether sex differences in memory are moderated by peripheral inflammatory activity. To address this issue, we analyzed data from 109 individuals (50 women, Mage = 71.62, range = 55-87) diagnosed as cognitively normal, or having mild cognitive impairment or Alzheimer's disease dementia. We then followed the sample for 12 months, as part of a longitudinal study of aging and Alzheimer's disease. At baseline, we assessed levels of the inflammatory cytokines interleukin (IL)-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in plasma. At baseline and 12 months, we assessed verbal memory using the Rey Auditory Verbal Learning Test and nonverbal memory using the Brief Visuospatial Memory Test-Revised. As hypothesized, for the full sample, women exhibited stronger verbal (but not nonverbal) memory than men. In women, but not men, higher IL-1ß at baseline related to poorer verbal learning across both time points and delayed recall at 12 months. The effect of sex on memory also differed by IL-1ß level, with women exhibiting a memory advantage both at baseline and 12 months, but only for those with low-to-moderate IL-1ß levels. Therefore, high peripheral inflammation levels may lead to a sex-specific memory vulnerability relevant for Alzheimer's disease.

A High-Intensity Exercise Boot Camp for Persons With Parkinson Disease: A Phase II, Pragmatic, Randomized Clinical Trial of Feasibility, Safety, Signal of Efficacy, and Disease Mechanisms.

BACKGROUND AND PURPOSE: The feasibility, safety, and efficacy of a high-intensity multimodal exercise program (aerobic, strengthening, and balance training) have not been well vetted in persons with Parkinson disease (PD). Thus, the primary aim was to determine whether a high-intensity multimodal exercise boot camp (HIBC) was both feasible and safe in persons with PD. The secondary aim was to determine whether the program would produce greater benefit than a usual care, low-intensity exercise program (UC). An exploratory aim was to determine whether these programs affected putative disease-modifying mechanisms. METHODS: Twenty-seven participants (19 men and 8 women) were randomized into 8 weeks of either the HIBC or UC supervised by physical therapists. For feasibility, participation, and meeting, Centers for Disease Control and Prevention (CDC) exercise guidelines were assessed. For safety, adverse events were monitored. For efficacy, the following outcome domains were assessed before and after participation: balance, motor activity, endurance and fatigue, strength, mental health, and quality of life. For disease-modifying mechanisms, circulating brain-derived neurotrophic factor (BDNF) and its genotype, superoxide dismutase, and cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-10) were monitored. RESULTS: The HIBC was better at attaining CDC guidelines (P = 0.013) and spent more minutes in higher-intensity exercise per week (P < 0.001). There were no differences in adverse events (P = 0.419). The HIBC experienced significant improvements in 7/31 outcomes versus 3/31 in the UC arm. BDNF improved significantly for both groups from pre- to posttests (Ps ≤ 0.041) and an improved anti-inflammatory was observed for both groups. DISCUSSION AND CONCLUSIONS: A high-intensity multimodal exercise boot camp was feasible and safe in persons with PD. Compared with usual care, there were no differences in adverse events. Moreover, the high-intensity multimodal exercise program produced more improvement across more domains than usual care. Our results also suggest a possible link between improvement in outcomes and an improved anti-inflammatory milieu.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A244).

Effects of Fatigue on Balance in Individuals With Parkinson Disease: Influence of Medication and Brain-Derived Neurotrophic Factor Genotype.

BACKGROUND AND PURPOSE: Because falls can have deleterious consequences, it is important to understand the influence of fatigue and medications on balance in persons with Parkinson disease (PD). Thus, the purpose of this study was to investigate the effects of fatigue on balance in individuals with PD. Because brain-derived neurotrophic factor (BDNF) has been shown to be related to motor performance, we also explored its role. METHODS: A total of 27 individuals (age = 65.4 ± 8.1 years; males = 14, females = 13) with neurologist-diagnosed PD with 13 genotyped for BDNF as Val66Val, 11 as Val66Met, 2 as Met66Met (1 refused). Participants were tested both on and off medication, 1 week apart. On both days, they completed a pre- and posttest separated by a fatiguing condition. Factorial analyses of variance were performed for the following balance domains: (1) anticipatory postural responses; (2) adaptive postural responses; (3) dynamic balance; (4) sensory orientation; and (5) gait kinematics. For BDNF, t-tests were conducted comparing genotype for the pre-post difference scores in both the on and off medication states. RESULTS: There were no interactions between time (pre- and postintervention) and medication for any of the domains (Ps ≥ 0.187). Participants with BDNF Met alleles were not significantly different from Val66Val participants in balance (Ps ≥ 0.111) and response to a fatiguing condition (Ps ≥ 0.070). DISCUSSION AND CONCLUSIONS: Fatigue does not appear to have a detrimental effect on balance, and there was not a differential effect of medication in individuals with PD. These results also indicate that participants with a BDNF Met allele did not have a greater decay in function after a fatiguing condition.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A196).

Uptake of 18F-AV45 in the Putamen Provides Additional Insights into Alzheimer's Disease beyond the Cortex.

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer's disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression.

Alzheimer's Disease: Combination Therapies and Clinical Trials for Combination Therapy Development.

Alzheimer's disease (AD) is a complex multifaceted disease. Recently approved anti-amyloid monoclonal antibodies slow disease progression by approximately 30%, and combination therapy appears necessary to prevent the onset of AD or produce greater slowing of cognitive and functional decline. Combination therapies may address core features, non-specific co-pathology commonly occurring in patients with AD (e.g., inflammation), or non-AD pathologies that may co-occur with AD (e.g., α-synuclein). Combination therapies may be advanced through co-development of more than one new molecular entity or through add-on strategies including an approved agent plus a new molecular entity. Addressing add-on combination therapy is currently urgent since patients on anti-amyloid monoclonal antibodies may be included in clinical trials for experimental agents. Phase 1 information must be generated for each agent in combination drug development. Phase 2 and Phase 3 of add-on therapies may contrast the new molecular entity, the approved agent as standard of care, and the combination. More complex development programs including standard or modified combinatorial designs are required for co-development of two or more new molecular entities. Biomarkers are markedly affected by anti-amyloid monoclonal antibodies, and these effects must be anticipated in add-on trials. Examining target engagement biomarkers and comparing the magnitude and sequence of biomarker changes in those receiving more than one therapy, compared with those on monotherapy, may be informative. Using network-based medicine approaches, computational strategies may identify rational combinations using disease and drug effect network mapping.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

INTRODUCTION: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Alzheimer's disease biomarkers: correspondence between human studies and animal models.

Alzheimer's disease (AD) represents an escalating global threat as life expectancy and disease prevalence continue to increase. There is a considerable need for earlier diagnoses to improve clinical outcomes. Fluid biomarkers measured from cerebrospinal fluid (CSF) and blood, or imaging biomarkers have considerable potential to assist in the diagnosis and management of AD. An additional important utility of biomarkers is in novel therapeutic development and clinical trials to assess efficacy and side effects of therapeutic interventions. Because many biomarkers are initially examined in animal models, the extent to which markers translate from animals to humans is an important issue. The current review highlights many existing and pipeline biomarker approaches, focusing on the degree of correspondence between AD patients and animal models. The review also highlights the need for greater translational correspondence between human and animal biomarkers.

Alzheimer's disease drug development: translational neuroscience strategies.

Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.

Alzheimer's Disease: Novel Targets and Investigational Drugs for Disease Modification.

Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline of agents currently in clinical trials. Most of the target processes identified in the Common Alzheimer's Disease Research Ontology (CADRO) are represented by novel agents in trials. Inflammation and synaptic plasticity/neuroprotection are the CADRO categories with the largest number of novel candidate therapies. Within these categories, there are few overlapping targets among the test agents. Additional categories being evaluated include apolipoprotein E [Formula: see text] 4 (APOE4) effects, lipids and lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics and metabolism, vascular factors, cell death, growth factors and hormones, circadian rhythm, and epigenetic regulators. We highlight current drugs being tested within these categories and their mechanisms. Trials will be informative regarding which targets can be modulated to produce a slowing of clinical decline. Possible therapeutic combinations of agents may be suggested by trial outcomes. Biomarkers are evolving in concert with new targets and novel agents, and biomarker outcomes offer a means of supporting disease modification by the putative treatment. Identification of novel targets and development of corresponding therapeutics offer an important means of advancing new treatments for AD.

Accelerated hypometabolism with disease progression associated with faster cognitive decline among amyloid positive patients.

Objective: To evaluate the progression of brain glucose metabolism among participants with biological signature of Alzheimer's disease (AD) and its relevance to cognitive decline. Method: We studied 602 amyloid positive individuals who underwent 18F-fluorodeoxyglucose PET (FDG-PET) scan, 18F-AV-45 amyloid PET (AV45-PET) scan, structural MRI scan and neuropsychological examination, including 116 cognitively normal (CN) participants, 314 participants diagnosed as mild cognitive impairment (MCI), and 172 participants diagnosed as AD dementia. The first FDG-PET scan satisfying the inclusion criteria was considered as the baseline scan. Cross-sectional analysis were conducted with the baseline FDG-PET data to compare the regional differences between diagnostic groups after adjusting confounding factors. Among these participants, 229 participants (55 CN, 139 MCI, and 35 AD dementia) had two-year follow-up FDG-PET data available. Regional glucose metabolism was computed and the progression rates of regional glucose metabolism were derived from longitudinal FDG-PET scans. Then the group differences of regional progression rates were examined to assess whether glucose metabolism deficit accelerates or becomes stable with disease progression. The association of cognitive decline rate with baseline regional glucose metabolism, and progression rate in longitudinal data, were evaluated. Results: Participants with AD dementia showed substantial glucose metabolism deficit than CN and MCI at left hippocampus, in addition to the traditionally reported frontal and parietal-temporal lobe. More substantial metabolic change was observed with the contrast AD - MCI than the contrast MCI - CN, even after adjusting time duration since cognitive symptom onset. With the longitudinal data, glucose metabolism was observed to decline the most rapidly in the AD dementia group and at a slower rate in MCI. Lower regional glucose metabolism was correlated to faster cognitive decline rate with mild-moderate correlations, and the progression rate was correlated to cognitive decline rate with moderate-large correlations. Discussion and conclusion: Hippocampus was identified to experience hypometabolism in AD pathology. Hypometabolism accelerates with disease progression toward AD dementia. FDG-PET, particularly longitudinal scans, could potentially help predict how fast cognition declines and assess the impact of treatment in interventional trials.

Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study.

BACKGROUND: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. OBJECTIVE: The goal of this study was to study human GE180 from the perspective of the previous animal observations. METHODS: With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. RESULTS: Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. CONCLUSIONS: 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

Clinical and biological relevance of glial fibrillary acidic protein in Alzheimer's disease.

INTRODUCTION: There is a tremendous need for identifying reliable blood-based biomarkers for Alzheimer's disease (AD) that are tied to the biological ATN (amyloid, tau and neurodegeneration) framework as well as clinical assessment and progression. METHODS: One hundred forty-four elderly participants underwent 18F-AV45 positron emission tomography (PET) scan, structural magnetic resonance imaging (MRI) scan, and blood sample collection. The composite standardized uptake value ratio (SUVR) was derived from 18F-AV45 PET to assess brain amyloid burden, and the hippocampal volume was determined from structural MRI scans. Plasma glial fibrillary acidic protein (GFAP), phosphorylated tau-181 (ptau-181), and neurofilament light (NfL) measured by single molecular array (SIMOA) technology were assessed with respect to ATN framework, genetic risk factor, age, clinical assessment, and future functional decline among the participants. RESULTS: Among the three plasma markers, GFAP best discriminated participants stratified by clinical diagnosis and brain amyloid status. Age was strongly associated with NfL, followed by GFAP and ptau-181 at much weaker extent. Brain amyloid was strongly associated with plasma GFAP and ptau-181 and to a lesser extent with plasma NfL. Moderate association was observed between plasma markers. Hippocampal volume was weakly associated with all three markers. Elevated GFAP and ptau-181 were associated with worse cognition, and plasma GFAP was the most predictive of future functional decline. Combining GFAP and ptau-181 together was the best model to predict brain amyloid status across all participants (AUC = 0.86) or within cognitively impaired participants (AUC = 0.93); adding NfL as an additional predictor only had a marginal improvement. CONCLUSION: Our findings indicate that GFAP is of potential clinical utility in screening amyloid pathology and predicting future cognitive decline. GFAP, NfL, and ptau-181 were moderately associated with each other, with discrepant relevance to age, sex, and AD genetic risk, suggesting their relevant but differential roles for AD assessment. The combination of GFAP with ptau-181 provides an accurate model to predict brain amyloid status, with the superior performance of GFAP over ptau-181 when the prediction is limited to cognitively impaired participants.

Baclofen administration alters fear extinction and GABAergic protein levels.

The investigation of GABAergic systems in learning and extinction has principally focused on ionotropic GABA(A) receptors. Less well characterized is the metabotropic GABA(B) receptor, which when activated, induces a more sustained inhibitory effect and has been implicated in regulating oscillatory activity. Few studies have been carried out utilizing GABA(B) ligands in learning, and investigations of GABA(B) in extinction have primarily focused on interactions with drugs of abuse. The current study examined changes in GABA(B) receptor function using the GABA(B) agonist baclofen (2 mg/mL) or the GABA(B) antagonist phaclofen (0.3 mg/mL) on trace cued and contextual fear conditioning and extinction. The compounds were either administered during training and throughout extinction in Experiment 1, or starting 24 h after training and throughout extinction in Experiment 2. All drugs were administered 1 mL/kg via intraperitoneal injection. These studies demonstrated that the administration of baclofen during training and extinction trials impaired animals' ability to extinguish the fear association to the CS, whereas the animals that were administered baclofen starting 24 h after training (Experiment 2) did display some extinction. Further, contextual fear extinction was impaired by baclofen in both experiments. Tissue analyses suggest the cued fear extinction deficit may be related to changes in the GABA(B2) receptor subunit in the amygdala. The data in the present investigation demonstrate that GABA(B) receptors play an important role in trace cued and contextual fear extinction, and may function differently than GABA(A) receptors in learning, memory, and extinction.

Administration of donepezil does not rescue galanin-induced spatial learning deficits.

The neuropeptide galanin inhibits the evoked release of several neurotransmitters including acetylcholine and modulates adenylate cyclase (AC) activity. Galanin has also been established to impair various forms of learning and memory in rodents. However, whether galanin produces learning deficits by inhibiting cholinergic activity or decreasing AC function has not been clearly established. The current study investigated if donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, could rescue galanin-induced Morris water task deficits in rats. The results demonstrated that donepezil did not alter the previously established deficits induced by galanin. These findings suggest that galanin-mediated spatial learning deficits may be unrelated to its modulation of the cholinergic system.

Brain functional topology differs by sex in cognitively normal older adults.

Introduction: Late onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women. Hypothesis: We hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women. Methods: We studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed. Result: Women had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men. Conclusion: Women overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD. Significance statement: Two thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes.

Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment.

Purpose: To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process. Materials and Methods: Two hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI. Results: The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10-7, right: P = 3.37 × 10-8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI. Conclusion: Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

Torpor Does Not Influence Spatial Memory in Hibernating Golden-Mantled Ground Squirrels (Spermophilus [Callospermophilus] lateralis).

AbstractMammalian hibernation in ground squirrels is characterized by periods of torpor wherein body temperature approaches ambient temperature and metabolism is reduced to as low as 1/100th of active rates. It is unclear how hibernation affects long-term spatial memory, as tremendous remodeling of neurons is associated with torpor use. Given the suspected links between remodeling and memory formation and retention, we examined long-term spatial memory retention throughout a hibernation season. Animals were trained on a Barnes maze before entering torpor. Animals were tested for memory retention once a month throughout a hibernation season. Results indicate marked variation between individuals. Some squirrels retained memory across multiple torpor bouts, while other squirrels did not. No relationship was found between the number of torpor bouts, duration of bouts, or time spent torpid on long-term memory retention. However, that some squirrels successfully retain memory suggests that the profound remodeling of dendritic spines during torpor does not always lead to memory loss.

Alterations of GABA B receptors in the APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive decline of memory and cognitive function. The disease is characterized by the presence of amyloid plaques, tau tangles, altered inflammatory signaling, and alterations in numerous neurotransmitter signaling systems, including γ-aminobutyric acid (GABA). Given the extensive role of GABA in regulating neuronal activity, a careful investigation of GABA-related changes is needed. Further, given persistent inflammation has been demonstrated to drive AD pathology, the presence of GABA B receptor expressed on glia that serve a role regulation of the immune response adds to potential implications of altered GABA in AD. There has not previously been a systematic evaluation of GABA-related changes in an amyloid model of AD that specifically focuses on examining changes in GABA B receptors. In the present study, we examined alterations in several GABA-specific targets in the APP/PS1 mouse model at different ages. In the 4-month-old cohort, no significant deficits in spatial learning and memory or alterations in any of the GABAergic targets were observed compared with wild-type controls. However, we identified significant alterations in several GABA-related targets in the 6-month-old cohort that exhibited spatial learning deficits that include changes in glutamic acid decarboxylase 65, GABA transporter type 3, and GABA B receptors protein and mRNA levels. This was the same cohort at which learning and memory deficits and significant amyloid pathology was observed. Overall, our study provides evidence of altered GABAergic signaling in an amyloid model of AD at a time point consistent with AD-related deficits.

Dietary Strawberries Improve Cardiometabolic Risks in Adults with Obesity and Elevated Serum LDL Cholesterol in a Randomized Controlled Crossover Trial.

Background and aims: Dietary berries, such as strawberries, are rich in bioactive compounds and have been shown to lower cardiometabolic risk. We examined the effects of two dietary achievable doses of strawberries on glycemic control and lipid profiles in obese adults with elevated serum LDL cholesterol (LDL-C). Methods: In this 14-week randomized controlled crossover study, participants were assigned to one of the three arms for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or two-and-a -half servings (high dose: 32 g strawberry powder/day). Participants were instructed to follow their usual diet and lifestyle while refraining from consuming other berries and related products throughout the study interval. Blood samples, anthropometric measures, blood pressure, and dietary and physical activity data were collected at baseline and at the end of each four-week phase of intervention. Results: In total, 33 participants completed all three phases of the trial [(mean ± SD): Age: 53 ± 13 y; BMI: 33 ± 3.0 kg/m2). Findings revealed significant reductions in fasting insulin (p = 0.0002) and homeostatic model of assessment of insulin resistance (p = 0.0003) following the high dose strawberry phase when compared to the low dose strawberry and control phases. Glucose and conventional lipid profiles did not differ among the phases. Nuclear magnetic resonance-determined particle concentrations of total VLDL and chylomicrons, small VLDL, and total and small LDL were significantly decreased after the high dose strawberry phase, compared to control and low dose phases (all p < 0.0001). Among the biomarkers of inflammation and adipokines measured, only serum PAI-1 showed a decrease after the high dose strawberry phase (p = 0.002). Conclusions: These data suggest that consuming strawberries at two-and-a-half servings for four weeks significantly improves insulin resistance, lipid particle profiles, and serum PAI-1 in obese adults with elevated serum LDL-C.

Altered theta rhythm and hippocampal-cortical interactions underlie working memory deficits in a hyperglycemia risk factor model of Alzheimer's disease.

Diabetes mellitus is a metabolic disease associated with dysregulated glucose and insulin levels and an increased risk of developing Alzheimer's disease (AD) later in life. It is thought that chronic hyperglycemia leads to neuroinflammation and tau hyperphosphorylation in the hippocampus leading to cognitive decline, but effects on hippocampal network activity are unknown. A sustained hyperglycemic state was induced in otherwise healthy animals and subjects were then tested on a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex (ACC). Hyperglycemic animals performed worse on long delay trials and had multiple electrophysiological differences throughout the task. We found increased delta power and decreased theta power in the hippocampus, which led to altered theta/delta ratios at the end of the delay period. Cross frequency coupling was significantly higher in multiple bands and delay period hippocampus-ACC theta coherence was elevated, revealing hypersynchrony. The highest coherence values appeared long delays on error trials for STZ animals, the opposite of what was observed in controls, where lower delay period coherence was associated with errors. Consistent with previous investigations, we found increases in phosphorylated tau in STZ animals' hippocampus and cortex, which might account for the observed oscillatory and cognitive changes.