HDXBoxeR: an R package for statistical analysis and visualization of multiple Hydrogen-Deuterium Exchange Mass-Spectrometry datasets of different protein states.

SUMMARY: Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) is a powerful protein characterization technique that provides insights into protein dynamics and flexibility at the peptide level. However, analyzing HDX-MS data presents a significant challenge due to the wealth of information it generates. Each experiment produces data for hundreds of peptides, often measured in triplicate across multiple time points. Comparisons between different protein states create distinct datasets containing thousands of peptides that require matching, rigorous statistical evaluation, and visualization. Our open-source R package, HDXBoxeR, is a comprehensive tool designed to facilitate statistical analysis and comparison of multiple sets among samples and time points for different protein states, along with data visualization. AVAILABILITY AND IMPLEMENTATION: HDXBoxeR is accessible as the R package (https://cran.r-project.org/web//packages/HDXBoxeR) and GitHub: mkajano/HDXBoxeR.

Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector.

Ubiquitination is a post-translational modification that regulates many cellular processes in eukaryotes1-4. The conventional ubiquitination cascade culminates in a covalent linkage between the C terminus of ubiquitin (Ub) and a target protein, usually on a lysine side chain1,5. Recent studies of the Legionella pneumophila SidE family of effector proteins revealed a ubiquitination method in which a phosphoribosyl ubiquitin (PR-Ub) is conjugated to a serine residue on substrates via a phosphodiester bond6-8. Here we present the crystal structure of a fragment of the SidE family member SdeA that retains ubiquitination activity, and determine the mechanism of this unique post-translational modification. The structure reveals that the catalytic module contains two distinct functional units: a phosphodiesterase domain and a mono-ADP-ribosyltransferase domain. Biochemical analysis shows that the mono-ADP-ribosyltransferase domain-mediated conversion of Ub to ADP-ribosylated Ub (ADPR-Ub) and the phosphodiesterase domain-mediated ligation of PR-Ub to substrates are two independent activities of SdeA. Furthermore, we present two crystal structures of a homologous phosphodiesterase domain from the SidE family member SdeD 9 in complexes with Ub and ADPR-Ub. The structures suggest a mechanism for how SdeA processes ADPR-Ub to PR-Ub and AMP, and conjugates PR-Ub to a serine residue in substrates. Our study establishes the molecular mechanism of phosphoribosyl-linked ubiquitination and will enable future studies of this unusual type of ubiquitination in eukaryotes.

Hippocampal Volumes in Amnestic and Non-Amnestic Mild Cognitive Impairment Types Using Two Common Methods of MCI Classification.

OBJECTIVES: Mild cognitive impairment (MCI) types may have distinct neuropathological substrates with hippocampal atrophy particularly common in amnestic MCI (aMCI). However, depending on the MCI classification criteria applied to the sample (e.g., number of abnormal test scores considered or thresholds for impairment), volumetric findings between MCI types may change. Additionally, despite increased clinical use, no prior research has examined volumetric differences in MCI types using the automated volumetric software, Neuroreader™. METHODS: The present study separately applied the Petersen/Winblad and Jak/Bondi MCI criteria to a clinical sample of older adults (N = 82) who underwent neuropsychological testing and brain MRI. Volumetric data were analyzed using Neuroreader™ and hippocampal volumes were compared between aMCI and non-amnestic MCI (naMCI). RESULTS: T-tests revealed that regardless of MCI classification criteria, hippocampal volume z-scores were significantly lower in aMCI compared to naMCI (p's < .05), and hippocampal volume z-scores significantly differed from 0 (Neuroreader™ normative mean) in the aMCI group only (p's < .05). Additionally, significant, positive correlations were found between measures of delayed recall and hippocampal z-scores in aMCI using either MCI classification criteria (p's < .05). CONCLUSIONS: We provide evidence of correlated neuroanatomical changes associated with memory performance for two commonly used neuropsychological MCI classification criteria. Future research should investigate the clinical utility of hippocampal volumes analyzed via Neuroreader™ in MCI.

Memory Performance and Quantitative Neuroimaging Software in Mild Cognitive Impairment: A Concurrent Validity Study.

OBJECTIVE: This study examined the relationship between patient performance on multiple memory measures and regional brain volumes using an FDA-cleared quantitative volumetric analysis program - Neuroreader™. METHOD: Ninety-two patients diagnosed with mild cognitive impairment (MCI) by a clinical neuropsychologist completed cognitive evaluations and underwent MR Neuroreader™ within 1 year of testing. Select brain regions were correlated with three widely used memory tests. Regression analyses were conducted to determine if using more than one memory measures would better predict hippocampal z-scores and to explore the added value of recognition memory to prediction models. RESULTS: Memory performances were most strongly correlated with hippocampal volumes than other brain regions. After controlling for encoding/Immediate Recall standard scores, statistically significant correlations emerged between Delayed Recall and hippocampal volumes (rs ranging from .348 to .490). Regression analysis revealed that evaluating memory performance across multiple memory measures is a better predictor of hippocampal volume than individual memory performances. Recognition memory did not add further predictive utility to regression analyses. CONCLUSIONS: This study provides support for use of MR Neuroreader™ hippocampal volumes as a clinically informative biomarker associated with memory performance, which is a critical diagnostic feature of MCI phenotype.

Neuropsychological presentation of colpocephaly and porencephaly with symptom onset in adulthood.

Colpocephaly is a form of congenital ventriculomegaly while porencephaly describes any full-thickness defect within the brain which usually presents as a cystic structure. Postulated aetologies include intrauterine/perinatal injuries, genetic disorders, and morphogenesis error. Colopocephaly and porencephaly is typically diagnosed in infancy while diagnosis in adulthood is exceptionally rare. We report a case of co-existence of colpocephaly with porencephaly diagnosed incidentally in a 54-year-old male presenting with subtle cognitive and neurologic abnormalities. Neuropsychological assessment revealed weaknesses in executive functions, processing speed, and language.To our knowledge, this is the only reported case of dual incidental findings of porencephaly and colpocephaly in an adult.

Two functionally distinct E2/E3 pairs coordinate sequential ubiquitination of a common substrate in Caenorhabditis elegans development.

Ubiquitination, the crucial posttranslational modification that regulates the eukaryotic proteome, is carried out by a trio of enzymes, known as E1 [ubiquitin (Ub)-activating enzyme], E2 (Ub-conjugating enzyme), and E3 (Ub ligase). Although most E2s can work with any of the three mechanistically distinct classes of E3s, the E2 UBCH7 is unable to function with really interesting new gene (RING)-type E3s, thereby restricting it to homologous to E6AP C-terminus (HECT) and RING-in-between-RING (RBR) E3s. The Caenorhabditis elegans UBCH7 homolog, UBC-18, plays a critical role in developmental processes through its cooperation with the RBR E3 ARI-1 (HHARI in humans). We discovered that another E2, ubc-3, interacts genetically with ubc-18 in an unbiased genome-wide RNAi screen in C. elegans These two E2s have nonoverlapping biochemical activities, and each is dedicated to distinct classes of E3s. UBC-3 is the ortholog of CDC34 that functions specifically with Cullin-RING E3 ligases, such as SCF (Skp1-Cullin-F-box). Our genetic and biochemical studies show that UBCH7 (UBC-18) and the RBR E3 HHARI (ARI-1) coordinate with CDC34 (UBC-3) and an SCF E3 complex to ubiquitinate a common substrate, a SKP1-related protein. We show that UBCH7/HHARI primes the substrate with a single Ub in the presence of CUL-1, and that CDC34 is required to build chains onto the Ub-primed substrate. Our study reveals that the association and coordination of two distinct E2/E3 pairs play essential roles in a developmental pathway and suggests that cooperative action among E3s is a conserved feature from worms to humans.

Characterization and Structural Insights into Selective E1-E2 Interactions in the Human and Plasmodium falciparum SUMO Conjugation Systems.

Protein modification by small ubiquitin-related modifiers (SUMOs) is essential and conserved in the malaria parasite, Plasmodium falciparum. We have previously shown that interactions between the SUMO E1-activating and E2-conjugating enzyme in P. falciparum are distinct compared with human, suggesting a potential target for development of parasite-specific inhibitors of SUMOylation. The parasite asexual trophozoite stage is susceptible to iron-induced oxidative stress and is subsequently a target for many of the current anti-malarial drugs. Here, we provide evidence that SUMOylation plays a role in the parasite response to oxidative stress during red blood cell stages, indicative of a protective role seen in other organisms. Using x-ray crystallography, we solved the structure of the human SUMO E1 ubiquitin fold domain in complex with the E2, Ubc9. The interface defined in this structure guided in silico modeling, mutagenesis, and in vitro biochemical studies of the P. falciparum SUMO E1 and E2 enzymes, resulting in the identification of surface residues that explain species-specific interactions. Our findings suggest that parasite-specific inhibitors of SUMOylation could be developed and used in combination therapies with drugs that induce oxidative stress.

Cognitive Workload and Fatigue in a Vigilance Dual Task: Miss Errors, False Alarms, and the Effect of Wearing Biometric Sensors While Working.

The effects of workload, fatigue, and practice on the performance of cognitive tasks are often intertwined. Previous research has shown that these influences can be separated with the two cusp catastrophe models. This study expanded an earlier investigation of the two models for workload and fatigue in a vigilance task to include a wider range of bifurcation variables that could affect the elasticity versus rigidity of the operator in response to workload and added performance variability resulting from fatigue. The study also responded to a concern in the literature that performance on cognitive tasks can be complicated by adaptive responses to artificial task situations and thus distort underlying cognitive events. Therefore, we also explored whether wearing biometric sensors, frequently used in workload studies, can affect performance dynamics. Participants were 279 undergraduates who responded to target stimuli that appeared on a simulated security camera display at three rates of speed while completing a secondary task. Participants worked alone, in pairs, or in pairs wearing GSR sensors. Results supported the efficacy of the two models and isolated the impact of wearing sensors on the fatigue process. The strongest control variables across both the workload and fatigue models were field independence, anxiety, indecisiveness, inflexibility, secondary task completion, working in pairs, and wearing the sensors. The contributing effect of wearing sensors could possibly extend to other types of wearable technologies.

E2-mediated small ubiquitin-like modifier (SUMO) modification of thymine DNA glycosylase is efficient but not selective for the enzyme-product complex.

Thymine DNA glycosylase (TDG) initiates the repair of G·T mismatches that arise by deamination of 5-methylcytosine (mC), and it excises 5-formylcytosine and 5-carboxylcytosine, oxidized forms of mC. TDG functions in active DNA demethylation and is essential for embryonic development. TDG forms a tight enzyme-product complex with abasic DNA, which severely impedes enzymatic turnover. Modification of TDG by small ubiquitin-like modifier (SUMO) proteins weakens its binding to abasic DNA. It was proposed that sumoylation of product-bound TDG regulates product release, with SUMO conjugation and deconjugation needed for each catalytic cycle, but this model remains unsubstantiated. We examined the efficiency and specificity of TDG sumoylation using in vitro assays with purified E1 and E2 enzymes, finding that TDG is modified efficiently by SUMO-1 and SUMO-2. Remarkably, we observed similar modification rates for free TDG and TDG bound to abasic or undamaged DNA. To examine the conjugation step directly, we determined modification rates (kobs) using preformed E2∼SUMO-1 thioester. The hyperbolic dependence of kobs on TDG concentration gives kmax = 1.6 min(-1) and K1/2 = 0.55 µM, suggesting that E2∼SUMO-1 has higher affinity for TDG than for the SUMO targets RanGAP1 and p53 (peptide). Whereas sumoylation substantially weakens TDG binding to DNA, TDG∼SUMO-1 still binds relatively tightly to AP-DNA (Kd ∼50 nM). Although E2∼SUMO-1 exhibits no specificity for product-bound TDG, the relatively high conjugation efficiency raises the possibility that E2-mediated sumoylation could stimulate product release in vivo. This and other implications for the biological role and mechanism of TDG sumoylation are discussed.

Improved Cardiorespiratory Fitness Is Associated with Increased Cortical Thickness in Mild Cognitive Impairment.

Cortical atrophy is a biomarker of Alzheimer's disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (V̇O2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. V̇O2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (V̇O2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved V̇O2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI.

Estimating Appropriate Lag Length for Synchronized Physiological Time Series: The Electrodermal Response.

Physiological synchronization of autonomic arousal between people is thought to be an important component of work team dynamics, therapist-client relationships, and other interpersonal dynamics. This article examines concepts and mathematical models of synchronization that could be relevant to work teams. Before it is possible to deploy nonlinear modeling, however, it is necessary to develop a strategy for determining appropriate lag lengths. If a measurement at time 2 is a function of itself at time 1 and a coupling effect from another source, what is the appropriate amount of real time that should be allowed to elapse between the two measurements in order to observe the coupling effect? This study examined four strategies for doing so. In the experiment, 78 undergraduates worked in pairs to perform a vigilance dual task for 90 min while galvanic skin responses (GSR) were recorded. Lags based on mutual entropy and the natural rate criteria produced corroborating results, whereas strategies based on a critical decline in the linear autocorrelation (max r/e) and Theiler's W did not produce usable results for this situation. Some connections were uncovered between linear autocorrelation strength and lag based on mutual entropy with performance on the tasks and subjective ratings of workload.

Catastrophe models for cognitive workload and fatigue in N-back tasks.

N-back tasks place a heavy load on working memory, and thus make good candidates for studying cognitive workload and fatigue (CWLF). This study extended previous work on CWLF which separated the two phenomena with two cusp catastrophe models. Participants were 113 undergraduates who completed 2-back and 3-back tasks with both auditory and visual stimuli simultaneously. Task data were complemented by several measures hypothesized to be related to cognitive elasticity and compensatory abilities and the NASA TLX ratings of subjective workload. The adjusted R2 was .980 for the workload model, which indicated a highly accurate prediction with six bifurcation (elasticity versus rigidity) effects: algebra flexibility, TLX performance, effort, and frustration; and psychosocial measures of inflexibility and monitoring. There were also two cognitive load effects (asymmetry): 2 vs. 3-back and TLX temporal demands. The adjusted R2 was .454 for the fatigue model, which contained two bifurcation variables indicating the amount of work done, and algebra flexibility as the compensatory ability variable. Both cusp models were stronger than the next best linear alternative model. The study makes an important step forward by uncovering an apparently complete model for workload, finding the role of subjective workload in the context of performance dynamics, and finding CWLF dynamics in yet another type of memory-intensive task. The results were also consistent with the developing notion that performance deficits induced by workload and deficits induced by fatigue result from the impact of the task on the workspace and executive functions of working memory respectively.

Identification of biochemically distinct properties of the small ubiquitin-related modifier (SUMO) conjugation pathway in Plasmodium falciparum.

Small ubiquitin-related modifiers (SUMOs) are post-translationally conjugated to other proteins and are thereby essential regulators of a wide range of cellular processes. Sumoylation, and enzymes of the sumoylation pathway, are conserved in the malaria causing parasite, Plasmodium falciparum. However, the specific functions of sumoylation in P. falciparum, and the degree of functional conservation between enzymes of the human and P. falciparum sumoylation pathways, have not been characterized. Here, we demonstrate that sumoylation levels peak during midstages of the intra-erythrocyte developmental cycle, concomitant with hemoglobin consumption and elevated oxidative stress. In vitro studies revealed that P. falciparum E1- and E2-conjugating enzymes interact effectively to recognize and modify RanGAP1, a model mammalian SUMO substrate. However, in heterologous reactions, P. falciparum E1 and E2 enzymes failed to interact with cognate human E2 and E1 partners, respectively, to modify RanGAP1. Structural analysis, binding studies, and functional assays revealed divergent amino acid residues within the E1-E2 binding interface that define organism-specific enzyme interactions. Our studies identify sumoylation as a potentially important regulator of oxidative stress response during the P. falciparum intra-erythrocyte developmental cycle, and define E1 and E2 interactions as a promising target for development of parasite-specific inhibitors of sumoylation and parasite replication.

The performance-variability paradox, financial decision making, and the curious case of negative Hurst exponents.

This study examined the relationship between performance variability and actual performance of financial decision makers who were working under experimental conditions of increasing workload and fatigue. The rescaled range statistic, also known as the Hurst exponent (H) was used as an index of variability. Although H is defined as having a range between 0 and 1, 45% of the 172 time series generated by undergraduates were negative. Participants in the study chose the optimum investment out of sets of 3 to 5 options that were presented a series of 350 displays. The sets of options varied in both the complexity of the options and number of options under simultaneous consideration. One experimental condition required participants to make their choices within 15 sec, and the other condition required them to choose within 7.5 sec. Results showed that (a) negative H was possible and not a result of psychometric error; (b) negative H was associated with negative autocorrelations in a time series. (c) H was the best predictor of performance of the variables studied; (d) three other significant predictors were scores on an anagrams test and ratings of physical demands and performance demands; (e) persistence as evidenced by the autocorrelations was associated with ratings of greater time pressure. It was concluded, furthermore, that persistence and overall performance were correlated, that 'healthy' variability only exists within a limited range, and other individual differences related to ability and resistance to stress or fatigue are also involved in the prediction of performance.

Cognitively normal individuals with AD parents may be at risk for developing aging-related cortical thinning patterns characteristic of AD.

Children of Alzheimer's disease (AD) patients are at heightened risk of developing AD due to genetic influences, including the apolipoprotein E4 (ApoE4) allele. In this study, we assessed the earliest cortical changes associated with AD in 71 cognitively healthy, adult children of AD patients (AD offspring) as compared with 69 with no family history of AD (non-AD offspring). Cortical thickness measures were obtained using FreeSurfer from 1.5T magnetic resonance (MR) scans. ApoE genotyping was obtained. Primary analyses examined family history and ApoeE4 effects on cortical thickness. Secondary analyses examined age effects within groups. All comparisons were adjusted using False Discovery Rate at a significance threshold of p<0.05. There were no statistically significant differences between family history and ApoE4 groups. Within AD offspring, increasing age was related to reduced cortical thickness (atrophy) over large areas of the precuneus, superior frontal and superior temporal gyri, starting at around age 60. Further, these patterns existed within female and maternal AD offspring, but were absent in male and paternal AD offspring. Within non-AD offspring, negative correlations existed over small regions of the superior temporal, insula and lingual cortices. These results suggest that as AD offspring age, cortical atrophy is more prominent, particularly if the parent with AD is mother or if the AD offspring is female.

Neurocognitive Profiles in Patients With Persisting Cognitive Symptoms Associated With COVID-19.

OBJECTIVE: A subset of individuals with coronavirus disease 2019 (COVID-19) appears to develop persisting cognitive and medical symptoms. Research in the acute stages of illness, generally utilizing cognitive screening measures or case reports, suggests presence of deficits in attention and executive function. This observational study investigated cognitive functioning among individuals with persistent cognitive complaints about 5.5 months after COVID-19 infection. METHODS: Patients with polymerase chain reaction confirmed COVID-19 and persistent cognitive complaints underwent comprehensive in-person neuropsychological evaluations. Patients with prior neurological disorders were excluded. When diagnosed, 40% required hospitalization, 15% were in an intensive care unit, 10% needed mechanical ventilation, and 10% experienced delirium. RESULTS: This sample was predominately women (90%), White non-Hispanic (70%), with average education of 15 years. Mild cognitive deficits were seen on tests involving attention and processing speed or executive function. Seventy percent of patients were diagnosed with a mood disorder prior to COVID-19 infection. At the time of testing, 35%-40% endorsed moderate to severe mood symptoms and 85% noted significant fatigue as measured by the Fatigue Severity Scale. CONCLUSIONS: The pattern of cognitive deficits, although mild, is consistent with prior research at the acute stage of the illness. These findings suggest that psychological factors and other persisting symptoms (e.g., sleep, fatigue) may play a significant role in subjective cognitive complaints in patients with persisting complaints post COVID-19 who did not require intensive treatment. These patients would likely benefit from resources to manage persisting or new mood symptoms and compensatory strategies for the cognitive inefficiencies they experience.

Cullin-independent recognition of HHARI substrates by a dynamic RBR catalytic domain.

RING-between-RING (RBR) E3 ligases mediate ubiquitin transfer through an obligate E3-ubiquitin thioester intermediate prior to substrate ubiquitination. Although RBRs share a conserved catalytic module, substrate recruitment mechanisms remain enigmatic, and the relevant domains have yet to be identified for any member of the class. Here we characterize the interaction between the auto-inhibited RBR, HHARI (AriH1), and its target protein, 4EHP, using a combination of XL-MS, HDX-MS, NMR, and biochemical studies. The results show that (1) a di-aromatic surface on the catalytic HHARI Rcat domain forms a binding platform for substrates and (2) a phosphomimetic mutation on the auto-inhibitory Ariadne domain of HHARI promotes release and reorientation of Rcat for transthiolation and substrate modification. The findings identify a direct binding interaction between a RING-between-RING ligase and its substrate and suggest a general model for RBR substrate recognition.

Characterization of RING-Between-RING E3 Ubiquitin Transfer Mechanisms.

Protein ubiquitination is an essential posttranslational modification that regulates nearly all cellular processes. E3 ligases catalyze the final transfer of ubiquitin (Ub) onto substrates and thus are important temporal regulators of ubiquitin modifications in the cell. E3s are classified by their distinct transfer mechanisms. RING E3s act as scaffolds to facilitate the transfer of Ub from E2-conjugating enzymes directly onto substrates, while HECT E3s form an E3~Ub thioester intermediate prior to Ub transfer. A third class, RING-Between-RING (RBR) E3s, are classified as RING/HECT hybrids based on their ability to engage the E2~Ub conjugate via a RING1 domain while subsequently forming an obligate E3~Ub intermediate prior to substrate modification. RBRs comprise the smallest class of E3s, consisting of only 14 family members in humans, yet their dysfunction has been associated with neurodegenerative diseases, susceptibility to infection, inflammation, and cancer. Additionally, their activity is suppressed by auto-inhibitory domains that block their catalytic activity, suggesting their regulation has important cellular consequences. Here, we identify technical hurdles faced in studying RBR E3s and provide protocols and guidelines to overcome these challenges.

Differential 5-year brain atrophy rates in cognitively declining and stable APOE-ε4 elders.

OBJECTIVE: The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for late-onset Alzheimer's disease. Many ε4 carriers, however, never develop Alzheimer's disease. The purpose of this study is to characterize the variability in phenotypic expression of the ε4 allele, as measured by the longitudinal trajectory of cognitive test scores and MRI brain volumes, in cognitively intact elders. METHOD: Healthy older adults, ages 65-85, participated in a 5-year longitudinal study that included structural MRI and cognitive testing administered at baseline and at 1.5 and 5 years postenrollment. Participants included 22 ε4 noncarriers, 15 ε4 carriers who experienced a decline in cognition over the 5-year interval, and 11 ε4 carriers who remained cognitively stable. RESULTS: No baseline cognitive or volumetric group differences were observed. Compared to noncarriers, declining ε4 carriers had significantly greater rates of atrophy in left (p = .001, Cohen's d = .691) and right (p = .003, d = .622) cortical gray matter, left (p = .003, d = .625) and right (p = .020, d = .492) hippocampi, and greater expansion of the right inferior lateral ventricle (p < .001, d = .751) over 5 years. CONCLUSIONS: This study illustrates the variability in phenotypic expression of the ε4 allele related to neurodegeneration. Specifically, only those individuals who exhibited longitudinal declines in cognitive function experienced concomitant changes in brain volume. Future research is needed to better understand the biological and lifestyle factors that may influence the expression of the ε4 allele. (PsycINFO Database Record

Exercise Training and Functional Connectivity Changes in Mild Cognitive Impairment and Healthy Elders.

BACKGROUND: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer's disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. OBJECTIVE: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. METHODS: Sixteen MCI and 16 healthy elders (age range = 60-88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. RESULTS: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. CONCLUSION: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated.