Plasma levels of adipokines and insulin are associated with markers of brain atrophy and cognitive decline in the spectrum of Alzheimer's Disease.

The discovery that metabolic alterations often coexist with neurodegenerative conditions has sparked interest in the examination of metabolic regulatory factors as potential modulators of brain health. Here, we examined the role of adipokines (leptin, adiponectin, resistin, and IL6) and insulin on different markers of brain atrophy in participants on the spectrum of Alzheimer's Disease. We included 566 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with 1063 follow-up time points (average follow-up: one year); and examined the association between metabolic regulatory factors and volumetric MRI values, white matter hyperintensities, and measures of cognitive impairment. Higher leptin, resistin, IL6, and insulin were associated with markers of cerebral atrophy, such as lower total brain volume, or higher ventricular volume. Higher leptin and resistin were also associated with greater impairment in daily life activities. Higher adiponectin was associated with lower ventricle volume. There was no association between adipokines or insulin with white matter hyperintensities. Our findings indicate a co-occurrence between alterations in metabolic regulatory factors and in brain volume along the preclinical to clinical spectrum of Alzheimer's Disease. These results suggest that strategies aimed at promoting metabolic health may positively impact brain health.

Investigating the relationship between sleep disturbances and white matter hyperintensities in older adults on the Alzheimer's disease spectrum.

INTRODUCTION: While studies report that sleep disturbance can have negative effects on brain vasculature, its impact on cerebrovascular diseases such as white matter hyperintensities (WMHs) in beta-amyloid-positive older adults remains unexplored. METHODS: Sleep disturbance, WMH burden, and cognition in normal controls (NCs), and individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD), were examined at baseline and longitudinally. A total of 912 amyloid-positive participants were included (198 NC, 504 MCI, and 210 AD). RESULTS: Individuals with AD reported more sleep disturbances than NC and MCI participants. Those with sleep disturbances had more WMHs than those without sleep disturbances in the AD group. Mediation analysis revealed an effect of regional WMH burden on the relationship between sleep disturbance and future cognition. DISCUSSION: These results suggest that WMH burden and sleep disturbance increase from aging to AD. Sleep disturbance decreases cognition through increases in WMH burden. Improved sleep could mitigate the impact of WMH accumulation and cognitive decline.

The influence of APOE status on rate of cognitive decline.

BACKGROUND: Apolipoprotein (APOE) ɛ4 positivity and subjective cognitive decline (SCD) both increase risk of Alzheimer's disease (AD) development. However, few studies have examined the relationship between SCD and APOE status, especially using longitudinal data. The current study examined whether APOE is associated with the rate of cognitive change in SCD and mild cognitive impairment (MCI). METHODS: A sample of 3494 older adults (1990 normal controls, NC, 775 SCD, and 729 MCI) with a mean follow-up of 9.09 years were included from the Rush Alzheimer's Disease Center Research Sharing Hub. Linear mixed effects models examined the relationship between APOE status and cognitive change in older adults with SCD normal controls, and people with MCI. RESULTS: The presence of at least one ɛ2 allele in SCD and MCI results in cognitive change rates similar to a NC with the ɛ3ɛ3 genotype. Older adult SCD-ɛ4 individuals exhibited increased rate of cognitive decline compared to all groups, including NC-ɛ4 and MCI-ɛ4. CONCLUSION: People with SCD with at least one ɛ4 allele experience increased rates of cognitive decline compared to cognitively healthy older adults and people with MCI. These findings have important implications for treatments and interventions and can improve future research and clinical trials by targeting people in the preclinical AD phase (i.e., SCD) who also possess at least one APOE ɛ4 allele.

Beyond Hypertension: Examining Variable Blood Pressure's Role in Cognition and Brain Structure.

Importance: Hypertension is a known risk factor for cognitive decline and structural brain changes in aging and dementia. In addition to high blood pressure (BP), individuals may also experience variable BP, meaning that their BP fluctuates between normal and high. It is currently unclear what the effects of variable BP are on cognition and brain structure. Objective: To investigate the influence of BP on cognition and brain structure in older adults. Design Setting and Participants: This longitudinal cohort study included data from the Rush Alzheimer's Disease Center Research Resource Sharing Hub (RUSH) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants from the two studies were included if they had BP measurements and either cognitive scores or MRI scans from at least one visit. Main Outcomes and Measures: Longitudinal gray matter, white matter, white matter hyperintensity volumes, postmortem neuropathology information, as well as cognitive test scores. Results: A total of 4606 participants (3429 females, mean age = 76.8) with 32776 follow-ups (mean = 7 years) from RUSH and 2114 participants (1132 females, mean age = 73.3) with 9827 follow-ups (mean = 3 years) from ADNI were included in this study. Participants were divided into one of three groups: 1) normal BP, high BP, or variable BP. Older adults with variable BP exhibited the highest rate of cognitive decline followed by high BP and then normal BP. Increased GM volume loss and WMH burden was also observed in variable BP compared to high and normal BP. With respect to post-mortem neuropathology, both variable and high BP had increased severities compared to normal BP. Importantly, results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings. Conclusion and Relevance: Limited research has examined the long-term impact of variable BP on cognition and brain structure. These findings show the importance that both high and variable BP have on cognitive decline and structural brain changes. Structural damages caused by variable BP may reduce resilience to future dementia-related pathology and increased risk of dementia. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.

Differences in Alzheimer's Disease-Related Pathology Profiles Across Apolipoprotein Groups.

The apolipoprotein (APOE) ɛ4 allele is a risk factor for Alzheimer's disease (AD), whereas the ɛ2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, white matter hyperintensities (WMHs) and APOE status in those with the ɛ2ɛ4 genotype and results are inconsistent for those with an ɛ2 allele. Alzheimer's disease neuroimaging participants were divided into 1 of 4 APOE allele profiles (E4 = ɛ4ɛ4 or ɛ3ɛ4; E2 = ɛ2ɛ2 or ɛ2ɛ3; E3 = ɛ3ɛ3; or E24 = ɛ2ɛ4). Linear mixed models examined the relationship between APOE profiles and brain changes (i.e., regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures), while controlling for age, sex, education, and diagnostic status at baseline and over time. APOE ɛ4 was associated with increased pathology, whereas ɛ2 positivity is associated with reduced baseline and lower accumulation of pathologies and neurodegeneration. APOE ɛ2ɛ4 was similar to ɛ4 (increased neurodegeneration) but with a slower rate of change. The strong associations observed between APOE and pathology show the importance of how genetic factors influence structural brain changes. These findings suggest that ɛ2ɛ4 genotype is related to increased declines associated with the ɛ4 as opposed to the protective effects of the ɛ2. These findings have important implications for initiating treatments and interventions. Given that people with the ɛ2ɛ4 genotype can expect to have increased atrophy, they should be considered (alongside those with an ɛ4) in targeted interventions to reduce brain changes that occur with AD.

Effects of virtual reality working memory task difficulty on the passive processing of irrelevant auditory stimuli.

The virtual reality (VR) environment is claimed to be highly immersive. Participants may thus be potentially unaware of their real, external world. The present study presented irrelevant auditory stimuli while participants were engaged in an easy or difficult visual working memory (WM) task within the VR environment. The difficult WM task should be immersive and require many cognitive resources, thus few will be available for the processing of task-irrelevant auditory stimuli. Sixteen young adults wore a 3D head-mounted VR device. In the easy WM task, the stimuli were nameable objects. In the difficult WM task, the stimuli were abstract objects that could not be easily named. A novel paradigm using event-related potentials (ERPs) was implemented to examine the feasibility of quantifying the extent of processing of task-irrelevant stimuli occurring outside of the VR environment. Auditory stimuli irrelevant to the WM task were presented concurrently at every 1.5 or 12 s in separate conditions. Performance on the WM task varied with task difficulty, with accuracy significantly lower during the difficult task. The auditory ERPs consisted of N1 and a later P2/P3a deflection which were larger when the auditory stimuli were presented slowly. ERPs were unaffected by task difficulty, but significant correlations were found. N1 and P2/P3a amplitudes were smallest when performance on the Easy WM task was highest. It is possible that even the easy WM task was so immersive and required many processing resources that few were available for the co-processing of the task-irrelevant auditory stimuli.

White Matter Hyperintensity Trajectories in Patients With Progressive and Stable Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMH) are pathologic brain changes that are associated with increased age and cognitive decline. However, the association of WMH burden with amyloid positivity and conversion to dementia in people with mild cognitive impairment (MCI) is unclear. The aim of this study was to expand on this research by examining whether change in WMH burden over time differs in amyloid-negative (Aß-) and amyloid-positive (Aß+) people with MCI who either remain stable or convert to dementia. To examine this question, we compared regional WMH burden in 4 groups: Aß+ progressor, Aß- progressor, Aß+ stable, and Aß- stable. METHODS: Participants with MCI from the Alzheimer Disease Neuroimaging Initiative were included if they had APOE ɛ4 status and if amyloid measures were available to determine amyloid status (i.e., Aß+, or Aß-). Participants with a baseline diagnosis of MCI and who had APOE ɛ4 information and amyloid measures were included. An average of 5.7 follow-up time points per participant were included, with a total of 5,054 follow-up time points with a maximum follow-up duration of 13 years. Differences in total and regional WMH burden were examined using linear mixed-effects models. RESULTS: A total of 820 participants (55-90 years of age) were included in the study (Aß+ progressor, n = 239; Aß- progressor, n = 22; Aß+ stable, n = 343; Aß- stable, n = 216). People who were Aß- stable exhibited reduced baseline WMH compared with Aß+ progressors and people who were Aß+ stable at all regions of interest (ß belongs to 0.20-0.33, CI belongs to 0.03-0.49, p < 0.02), except deep WMH. When examining longitudinal results, compared with people who were Aß- stable, all groups had steeper accumulation in WMH burden with Aß+ progressors (ß belongs to -0.03 to 0.06, CI belongs to -0.05 to 0.09, p < 0.01) having the largest increase (i.e., largest increase in WMH accumulation over time). DISCUSSION: These results indicate that WMH accumulation contributes to conversion to dementia in older adults with MCI who are Aß+ and Aß-.

Differences in AD-related pathology profiles across APOE groups.

BACKGROUND: The apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer's disease (AD), while the e2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype and results are inconsistent for those with an e2 allele. METHODS: We analyzed Alzheimer's Disease Neuroimaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load, ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV-45), and phosphorylated tau (pTau). Participants were divided into one of four APOE allele profiles (E4=e4e4 or e3e4; E2=e2e2 or e2e3; E3=e3e3; or E24=e2e4, Fig.1). Linear mixed models examined the relationship between APOE profiles and each pathology (i.e., regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures). while controlling for age, sex, education, and diagnostic status at baseline and over time. RESULTS: APOE ε4 is associated with increased pathology while ε2 positivity is associated with reduced baseline and lower accumulation of pathologies and rates of neurodegeneration. APOE ε2ε4 is similar to ε4 (increased neurodegeneration) but with a slower rate of change. CONCLUSIONS: The strong associations observed between APOE and pathology in this study show the importance of how genetic factors influence structural brain changes. These findings suggest that ε2ε4 genotype is related to increased declines associated with the ε4 as opposed to the protective effects of the ε2. These findings have important implications for initiating treatments and interventions. Given that people who have the ε2ε4 genotype can expect to have increased atrophy, they must be included (alongside those with an ε4 profile) in targeted interventions to reduce brain changes that occur with AD.

Investigating the relationship between sleep disturbances and white matter hyperintensities in older adults on the Alzheimer's disease spectrum.

Background: While studies report that sleep disturbance can have negative effects on brain vasculature, its impact on cerebrovascular disease such as white matter hyperintensities (WMHs) in beta-amyloid positive older adults remains unexplored. Methods: Linear regressions, mixed effects models, and mediation analysis examined the crosssectional and longitudinal associations between sleep disturbance, cognition, and WMH burden, and cognition in normal controls (NCs), mild cognitive impairment (MCI), and Alzheimer's disease (AD) at baseline and longitudinally. Results: People with AD reported more sleep disturbance than NC and MCI. AD with sleep disturbance had more WMHs than AD without sleep disturbances. Mediation analysis revealed an effect of regional WMH burden on the relationship between sleep disturbance and future cognition. Conclusion: These results suggest that WMH burden and sleep disturbance increases from aging to AD. Sleep disturbance decreases cognition through increases in WMH burden. Improved sleep could mitigate the impact of WMH accumulation and cognitive decline.

Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD.

White matter hyperintensities (WMHs) are pathological changes that occur with increased age and are associated with cognitive decline. Most WMH research has not examined regional differences and focuses on a whole-brain approach. This study examined regional WMHs between normal controls (NCs), people with mild cognitive impairment (MCI), and Alzheimer's disease (AD). We also examined whether WMHs were associated with cognitive decline. Participants from the Alzheimer's Disease Neuroimaging Initiative were included if they had at least one WMH measurement and cognitive scores examining global cognition, executive functioning, and memory. Only amyloid-positive MCI and AD participants were included. A total of 1573 participants with 7381 timepoints over a maximum period of 13 years were included. Linear mixed-effects models examined group differences in WMH burden and associations between WMH burden and cognition. People with MCI and AD had increased total and regional WMHs compared to NCs. An association between WMHs and cognition was observed for global cognition, executive functioning, and memory in NCs in all regions. A steeper decline (stronger association between WMH and cognition) was observed in MCI compared to NCs for all cognitive domains in all regions. A steeper decline was observed in AD compared to NCs for global cognition in only the temporal region. A strong association is observed between all cognitive domains of interest and WMH burden in healthy aging and MCI, while those with AD only had a few associations between WMH and global cognition. These findings suggest that the WMH burden is associated with changes in cognition in healthy aging and early cognitive decline.

Subjective cognitive decline is a better marker for future cognitive decline in females than in males.

BACKGROUND: The identification of biomarkers for early detection of Alzheimer's disease (AD) is critical to the development of therapies and interventions targeted at symptom management and tracking the pathophysiology of disease. The endorsement of subjective cognitive decline (SCD) has emerged as a potential indicator of early change in cognitive status that may be predictive of future impairment at a time when measurable declines in neuropsychological performance cannot be detected. While there are numerous findings revealing sex differences in the prevalence of AD, there is a paucity of research examining sex differences in SCD. Therefore, the goal of this project was to determine if the relationship between the endorsement of SCD and future cognitive changes differ as a function of biological sex. METHODS: A sample of 3019 male and female healthy older adults (2188 without SCD, 831 with SCD), with a mean follow-up time of 5.7 years, were included from the Rush Alzheimer's Disease Center Research Sharing Hub. Linear regressions were performed to determine group differences in baseline cognitive scores, while linear mixed-effects models were completed to determine group differences in the rate of cognitive change over time. RESULTS: Individuals endorsing SCD had significantly lower baseline cognitive scores and increased rates of decline in all cognitive domains compared to those without SCD. Males exhibited significantly lower scores in baseline performance in global cognition, episodic memory, and perceptual speed regardless of SCD classification. Females with SCD were found to decline at significantly faster rates than both males with SCD and males and females without SCD in all cognitive domains over a maximum 15-year follow-up period. CONCLUSIONS: SCD is related to lower baseline cognitive performance and faster cognitive decline compared to those who do not endorse SCD. Females with SCD have the fastest rate of decline suggesting that SCD may be more predictive of future decline in females than in males. Targeted assessments of SCD may allow for the identification of individuals for inclusion in intervention trials, and other research studies, aiming to attenuate casual disease processes, which may ultimately aid in the mitigation of sex disparities in AD.

Effects of the Duration of a Resting-State EEG Recording in Healthy Aging and Mild Cognitive Impairment.

INTRODUCTION: The recording of resting-state EEG may provide a means to predict early cognitive decline associated with mild cognitive impairment (MCI). Previous studies have typically used very short recording times to avoid a confound with drowsiness that may occur in longer recordings. The effects of a longer recording have not however been systematically examined. METHODS: Eyes-closed resting-state EEG activity was recorded in 40 older adult participants (20 healthy older adults and 20 people with MCI). The recording period was a relatively long 6 minutes, divided into two equal 3-minute halves to determine if drowsiness will be more apparent as the recording progresses. The participants also completed standardized neuropsychological tasks that assessed global cognition (Montreal Cognitive Assessment) and memory (California Verbal Learning Test, Second Edition). A spectral analysis was performed on both short (2 seconds) and long (8 seconds) segments in both 3-minute halves. RESULTS: No differences in power density for any of the EEG frequency bands were found between the 2 halves of the study for either group. There was little evidence of increased drowsiness in the second half of the study even when frequency resolution was increased with the 8-second segmentation. Theta power density was overall larger for people with MCI compared to healthy older adults. A negative correlation was also observed between theta power and global cognition in healthy older adults. CONCLUSIONS: The present results indicate that longer resting-state EEG recording can be reliably employed without increased risk of drowsiness.

Event-Related Potential Measures of the Passive Processing of Rapidly and Slowly Presented Auditory Stimuli in MCI.

Much research effort is currently devoted to the development of a simple, low-cost method to determine early signs of Alzheimer's disease (AD) pathology. The present study employs a simple paradigm in which event-related potentials (ERPs) were recorded to a single auditory stimulus that was presented rapidly or very slowly while the participant was engaged in a visual task. A multi-channel EEG was recorded in 20 healthy older adults and 20 people with mild cognitive impairment (MCI). In two different conditions, a single 80 dB sound pressure level (SPL) auditory stimulus was presented every 1.5 s (fast condition) or every 12.0 s (slow condition). Participants were instructed to watch a silent video and ignore the auditory stimuli. Auditory processing thus occurred passively. When the auditory stimuli were presented rapidly (every 1.5 s), N1 and P2 amplitudes did not differ between the two groups. When the stimuli were presented very slowly, the amplitude of N1 and P2 increased in both groups and their latencies were prolonged. The amplitude of N1 did not significantly differ between the two groups. However, the subsequent positivity was reduced in people with MCI compared to healthy older adults. This late positivity in the slow condition may reflect a delayed P2 or a summation of a composite P2 + P3a. In people with MCI, the priority of processing may not be switched from the visual task to the potentially much more relevant auditory input. ERPs offer promise as a means to identify the pathology underlying cognitive impairment associated with MCI.

Event-related potential evidence that very slowly presented auditory stimuli are passively processed differently in younger and older adults.

The occurrence of a very infrequent and unattended auditory stimulus is highly salient and may result in an interruption of the frontoparietal network controlling processing priorities. Research has suggested that older adults may be unable to compute the level of salience of unattended stimulus inputs. A multi-channel EEG was recorded in 20 younger adults and 20 older adults. In different conditions, a single 80 dB SPL auditory stimulus was presented relatively rapidly, every 1.5 s or very slowly, every 12.0 s. Participants ignored the auditory stimuli while watching a silent video. When the stimuli were presented rapidly, group differences were not observed for the amplitudes of N1 and P2, which peaked at 100 and 180 ms respectively. When stimuli were presented very slowly, their amplitudes were much enhanced for younger adults, but did not increase for older adults. The failure to observe a large increase in the amplitude of N1 and P2 in older adults for very slowly presented auditory stimuli provides strong evidence of a dysfunction of the salience network in this group.

The influence of different types of auditory change on processes associated with the switching of attention in younger and older adults.

Potentially highly relevant but unattended auditory stimuli may result in attention capture. The detection of stimulus change is associated with two event-related potentials: the deviant-related negativity (DRN), whose amplitude varies with the extent of change, and the P3a, which is elicited only by stimuli deemed to be highly relevant. In the present study, younger adults (aged 18-30 years) and older adults (aged 65-73 years) were presented with to-be-ignored auditory stimuli while engaged in a visual task. The auditory stimuli consisted of frequently presented standards and six different rarely presented deviants. In older adults, the amplitude of the DRN varied with the extent of deviance: it was significantly larger to the white noise and environmental sound deviants. A large P3a was elicited by these in younger adults but was much reduced in older adults. The DRN results suggest that older adults are able to compute saliency level of unattended stimulus input at an early stage of processing. However, the attenuated P3a results in older adults suggest that a potentially highly salient stimulus is not given sufficient priority to result in a switch of attention from current cognitive demands.

Event-related potentials associated with auditory attention capture in younger and older adults.

A deviant-related negativity (DRN), mismatch negativity (MMN), and P3a are electrophysiological measures thought to reflect processes involved in the involuntary switching of attention to a task-irrelevant stimulus. The purpose of this article was to determine whether healthy older adults involuntarily detect unattended auditory stimuli as efficiently as younger adults. To test this, 20 younger adults (aged 18-30 years) and 20 older adults (aged 65+ years) were presented with to-be-ignored auditory sequences consisting of frequently presented 80 dB SPL standards and rarely presented increments (+10 dB) and decrements (-20 dB). The MMN to the decrement did not differ between the 2 groups. On the other hand, the DRN to the increment was significantly reduced in the older adults. Importantly, the P3a was also significantly reduced in the older adults. This reduced P3a may reflect a deficit in the involuntary shift of attention from current cognitive demands to a potentially more critical event.

The influence of working memory performance on event-related potentials in young and older adults.

Variations in brain activation may lead to individual differences in working memory (WM) performance. Such differences may account for contradictory findings in the literature relating to age-related changes in neural activation during WM tasks. In the present study, 39 young adults (aged 18-30) and 34 older adults (aged 65+) completed an n-back task while their electroencephalography, accuracy, and reaction time was recorded. They were then categorized as high or low performers. High performers had larger P3b and parietal P200 amplitudes and smaller parietal N200 amplitudes than low performers. High-performing older adults exhibited larger parietal P200 amplitudes than low-performing older adults, and similar P3bs to young adults during the 2-back. Low-performing older adults, in contrast, exhibited smaller parietal P3bs than young adults during the 2-back. These findings suggest that brain activity during a WM task is influenced by individual differences in performance level. Moreover, some older adults can maintain high WM performance and capacity through recruitment of additional brain regions.