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Humans have a remarkably high capacity and long duration memory for complex scenes. Previous research documents the neural substrates that allow for efficient categorization of scenes from other complex stimuli like objects and faces, but the spatiotemporal neural dynamics underlying scene memory at timescales relevant to working and longer-term memory are less well understood. In the present study, we used high density EEG during a visual continuous recognition task in which new, old, and scrambled scenes consisting of color outdoor photographs were presented at an average rate 0.26 Hz. Old scenes were single repeated presentations occurring within either a short-term (< 20 seconds) or longer-term intervals of between 30 sec and 3 minutes or 4 and 10 minutes. Overall recognition was far above chance, with better performance at shorter- than longer-term intervals. Sensor-level ANOVA and post-hoc pairwise comparisons of ERPs revealed three main findings: 1) occipital and parietal amplitudes distinguishing new and old from scrambled scenes; 2) frontal amplitudes distinguishing old from new scenes with a central positivity highest for hits compared to misses, false alarms and correct rejections; and 3) frontal and parietal changes from ~300 to ~600 ms distinguishing among old scenes previously encountered at short- and longer-term retention intervals. These findings reveal how distributed spatiotemporal neural changes evolve to support short- and longer-term recognition of complex scenes.

Working memory (WM) is an essential component of executive functions which depend on maintaining task-related information online for brief periods in both the presence and absence of interfering stimuli. Active maintenance occurs during the WM delay period, the time between stimulus encoding and subsequent retrieval. Previous studies have extensively documented prefrontal and posterior parietal cortex activity during the WM delay period, but the role of subcortical structures including the thalamus remains to be fully elucidated, especially in humans. Using a simultaneous electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) approach, we investigated the role of the thalamus during the WM delay period in a modified Sternberg paradigm following low and high memory load encoding of naturalistic scenes. During the delay, participants passively viewed scrambled scenes containing similar color and spatial frequency to serve as a perceptual baseline. Individual source estimation was weighted by the location of the thalamic fMRI signal relative to the WM delay period onset. The effects memory load on maintenance were observed bilaterally in thalamus with higher EEG source amplitudes in the low compared to high load condition occurring 160-390 ms after the onset of the delay period. The main finding that thalamic activation was elevated during the low compared to high condition despite similar duration of perceptual input and upcoming motor requirements suggests a capacity-limited role for sensory filtering of the thalamus during consolidation of stimuli into WM, where the highest activity occurs when fewer stimuli need to be maintained in the presence of interfering perceptual stimuli during the delay. The results are discussed in the context of theories regarding the role of the thalamus in sensory gating during working memory.

Depressed individuals are twice as likely to develop Alzheimer’s disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls ( p  < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.

Background An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p  < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p  = 0.042), higher BMIs (27.94 vs. 25.79, p  < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p  < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p  = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p  = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p  = 0.019) and p-tau (β = 3.441, p  = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + ( n  = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p  = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

Background Social isolation (SI) and loneliness are related to several negative health outcomes, including cognitive decline and dementia. While both males and females experience increased SI as a function of age, studies have found that females experience greater loneliness than males, despite males reporting more physical isolation and smaller social networks. Females, independent of SI‐status, are also at increased risk of Alzheimer’s disease (AD). These sex‐related differences in SI and AD‐risk prompted us to examine whether sex and loneliness influenced the plasma AD biomarkers in a cohort of elderly individuals. Method Participants were enrolled in the Memory Education and Research Initiative (MERI) program. MERI participants completed a neuropsychological battery, clinical and psychiatric evaluation, and blood draw. Plasma Aβ40, Aβ42, and PTau231 concentrations were determined using single‐molecule array (SIMOA) platform. Plasma Aβ42/Aβ40 ratio was calculated. MERI participants were included if they gave blood, were cognitively‐normal defined by MMSE>27, age 50 years older, and completed the Profile of Mood States scale (POMS). POMS‐Loneliness item was coded to a dichotomous variable (0‐Not Lonely; 1‐Lonely). Result A total of 459 MERI participants (mean age=71 years; 59% females) were included. There were no significant differences between males and females for education, HAM‐D total score, or MMSE, only age. A 2x2 analysis of covariance (ANCOVA) with sex (male, female) and loneliness (not lonely, lonely), and age as a covariate, revealed a significant interaction between sex and loneliness with Aβ42 (p=0.014). Lonely females had significantly lower Aβ42 than males who are lonely. The same analysis revealed a significant main effect of sex on Aβ40 (p=0.014) and PTau231 (p=0.007); females had higher Aβ40 and lower PTau231, respectively. There were no significant main effects or interactions for Plasma ratio Aβ42/Aβ40. Conclusion Cognitively‐normal females who reported being lonely, as compared with males, had lower levels of plasma Aβ42 but not lower levels of plasma Aβ42/Aβ40 ratio, a better predictor of a positive amyloid PET scan. Future studies should examine if the results reflect increased brain amyloid deposition in lonely females. If so, interventions that mitigate loneliness may reduce overall risk for AD in females.

An elevated neutrophil-lymphocyte ratio (NLR) has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. We explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and NYU Center for Brain Health (CBH). Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau ), as well as the trajectories of these CSF measures obtained longitudinally. A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p<0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p<0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p<0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009) (Table 1). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau . In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p<0.001), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort (Figure 1). In both cohorts, the same associations observed in the cross-sectional analyses were observed after incoporating longitudinal CSF data (Figure 2). We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD-biomarkers may occur as part of immunosenescence.

Background An elevated neutrophil‐lymphocyte ratio (NLR) has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Method We explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and NYU Center for Brain Health (CBH). Specifically, we examined associations between the NLR and cross‐sectional measures of amyloid‐β42 (Aβ42), total tau (t‐tau), and phosphorylated tau181 (p‐tau181), as well as the trajectories of these CSF measures obtained longitudinally. Result A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p<0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p<0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p<0.001), and a greater percentage of Aβ‐positivity (34.2% vs. 20.0%, p = 0.009) (Table 1). In the ADNI cohort, we found cross‐sectional associations between the NLR and CSF Aβ42 (β = ‐12.193, p = 0.021), but not t‐tau or p‐tau181. In the NYU cohort, we found cross‐sectional associations between the NLR and CSF t‐tau (β = 26.812, p = 0.019) and p‐tau181 (β = 3.441, p<0.001), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t‐tau (β = 100.476, p = 0.037) compared to Aβ‐ subjects or the non‐stratified cohort (Figure 1). In both cohorts, the same associations observed in the cross‐sectional analyses were observed after incoporating longitudinal CSF data (Figure 2). Conclusion We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t‐tau and p‐tau181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD‐biomarkers may occur as part of immunosenescence.

Working memory (WM) is the temporary storage of information to accomplish a future goal. The WM delay period is the time after encoding but before retrieval when information is being maintained, typically in the absence of relevant stimuli. Understanding how the brain supports maintenance during the delay period, and how neural activity and connectivity are related to memory is critical for advancing both basic knowledge as well as informing declines in memory and cognition related to neurodegenerative diseases and healthy aging. An open question in the field of WM research is how information is stored during this delay period. One theory suggests persistent neural activity supports the storage of information while another theory suggests rapid synaptic weight changes (i.e., an activity-silent mechanism). While support exists for both theories, numerous confounds complicate the experiments designed to distinguish between these two theories. Most notably, studies typically use simple stimuli with short, predictable, unfilled delay periods, with few studies examining this open question using complex visual stimuli. For this dissertation four EEG experiments were conducted to answer three questions: 1) Does the type of maintenance technique used during the delay period modulate the neural activity for complex visual stimuli? 2) What are the load-dependent delay activity and connectivity patterns associated with maintenance of complex visual stimuli? And 3) How do patterns of delay activity and connectivity change when attention is sustained during unpredictable delay period durations?In the first set of experiments, we examined the role of rehearsal in maintaining complex visual stimuli. We looked at the impact of rehearsal versus suppression of rehearsal using novel naturalistic scenes that contained semantic content and phase-scrambled scenes that lacked semantic content. The benefit of rehearsal was associated with increases in theta and alpha band amplitude, but only when the stimuli lacked semantic content. The overall pattern of change in amplitude was similar for rehearsal and suppression of rehearsal, regardless of the type of stimulus.In the second set of experiments, we examined the role of attention in maintaining complex visual stimuli. We used a similar set of stimuli to the first experiments, employing a load manipulation (low load-2 images, high load-5 images) while perceptual interference was present. While increasing the WM load, particularly with complex stimuli, places a greater demand on attentional resources, interfering stimuli may compete for the available resources. This was confirmed in the examination of theta and alpha amplitude, as amplitude was reduced for the high WM load as compared with the low WM load. We also analyzed functional connectivity to identify the underlying brain networks that facilitated performance for the low load condition and identified three supporting networks, including a frontal- posterior temporal network that is responsible for filtering the interfering stimuli. Additionally, in a separate experiment using similar stimuli, we randomly varied the delay interval (short-2 sec, medium-5 sec, and long-9 sec) from trial to trial, which ensured sustained attention throughout the delay period because participants did not know when the delay period would end and the probe would appear. The delay activity associated with complex visual stimuli suggests a pattern of transient delay activity for medium and long delay periods, regardless of load, with an early increase in event-related synchronous activity (ERS) in alpha and lower beta activity (until 2-3 secs) followed by an extended period of event-related desynchronous (ERD) in alpha and beta band activity, in parietal and parieto-occipital regions. Sustained delay activity (i.e., ERS in alpha activity followed by a return to baseline) was only observed for the short delay interval (~2 sec). Our results suggest that the pattern of ERS reflects an early period of goal setting, in which attention is focused inward to prevent interference. As the delay interval increases, the pattern of ERD reflects ongoing maintenance and associations with stored semantic knowledge.Finally, we compared the underlying brain networks that supported maintenance across all experiments using connectivity measures. This comparison identified a different frontoparietal network that is implicated in cognitive control and was found to be involved in both effortful maintenance (i.e., for stimuli lacking semantic content) as well as maintenance that places an increased demand on attentional resources (e.g., interference present or increased intervals). These results provide some support for the persistent delay activity hypothesis, as there were changes in delay activity from baseline throughout the delay period in all experiments, regardless of maintenance technique, WM load or delay period interval. Furthermore, the delay period connectivity analyses for all experiments implicate fronto-parietal and temporal networks in supporting maintenance and suggest a flexible role of attention (e.g., filtering of interfering stimuli, control over attention) that varies based on task demands. Together, these delay activity and connectivity findings inform the ongoing debate about the neural dynamics that support visual WM.

An open question in the working memory (WM) field is how information is kept online during the WM delay period. Maintenance of simple stimuli in WM is supported by connectivity between frontal and parietal brain regions. How does delay period activity and connectivity support WM of complex stimuli? Twenty-two participants completed a modified Sternberg WM task with complex stimuli and were told to remember either 2 (low-load) or 5 (high-load) scenes while 32-channel scalp EEG was recorded. During the 6-sec delay period 6 phase-scrambled scenes were presented, which served as interference. While increasing the WM load, particularly with complex stimuli, places a greater demand on attentional resources, interfering stimuli may hijack the available resources. This was confirmed in the examination of theta and alpha amplitude, as amplitude was reduced for the high WM load as compared with the low WM load across frontal, central, and parietal regions. Delay period connectivity was assessed with phase-locking value (PLV). We identified 3 supporting networks that facilitated performance for the low-load condition: 1) increased PLV between left frontal and right posterior temporal in the theta and alpha bands; 2) increased PLV between right anterior temporal and left central in the alpha and lower beta bands; and 3) increased PLV between left anterior temporal and left posterior temporal in theta, alpha, and lower beta bands for the low-load condition. These results suggest that these brain networks facilitated the low-load WM by filtering of interference and the use of verbal rehearsal during the delay period. Competing Interest Statement The authors have declared no competing interest.

Rehearsal during working memory (WM) maintenance facilitates retrieval. Less is known about how rehearsal modulates WM delay activity. In the present study, 44 participants completed a Sternberg Task with either intact novel scenes or phase-scrambled scenes, which had similar color and spatial frequency but lacked semantic content. During each condition participants generated a descriptive label and covertly rehearsed or suppressed (repeated 'the') during the delay. This was easy in the former but more difficult in the later condition where scenes lacked semantic content. Behavioral performance and EEG delay activity was analyzed as a function of maintenance strategy. Performance during WM revealed a benefit of rehearsal for phase-scrambled but not intact scenes. Examination of the absolute amplitude revealed three underlying sources of activity for rehearsal, including the left anterior temporal (TAL), left and midline parietal regions. Increases in alpha and theta activity in TAL were correlated with improvement in performance on WM with rehearsal only when labeling was not automatic (i.e. phase-scrambled scenes), which may reflect differences in labeling and rehearsal (i.e. semantic associations vs. shallow labels). We conclude that rehearsal only benefits memory for visual stimuli that lack semantic information, and that this is correlated with changes in alpha and theta rhythms. Competing Interest Statement The authors have declared no competing interest. Footnotes * Additional supplemental methods and results, new figures, and a more extensive discussion of the salient findings.