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.

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.

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.

Sex differences in risk factors, burden, and outcomes of cerebrovascular disease in Alzheimer's disease populations.

BACKGROUND: White matter hyperintensities (WMHs) are associated with cognitive decline and progression to mild cognitive impairment (MCI) and dementia. It remains unclear if sex differences influence WMH progression or the relationship between WMH and cognition. METHODS: Linear mixed models examined the relationship between risk factors, WMHs, and cognition in males and females. RESULTS: Males exhibited increased WMH progression in occipital, but lower progression in frontal, total, and deep than females. For males, history of hypertension was the strongest contributor, while in females, the vascular composite was the strongest contributor to WMH burden. WMH burden was more strongly associated with decreases in global cognition, executive functioning, memory, and functional activities in females than males. DISCUSSION: Controlling vascular risk factors may reduce WMH in both males and females. For males, targeting hypertension may be most important to reduce WMHs. The results have implications for therapies/interventions targeting cerebrovascular pathology and subsequent cognitive decline. HIGHLIGHTS: Hypertension is the main vascular risk factor associated with WMH in males A combination of vascular risk factors contributes to WMH burden in females Only small WMH burden differences were observed between sexes Females' cognition was more negatively impacted by WMH burden than males Females with WMHs may have less resilience to future pathology.

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.

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-.

Hippocampal grading provides higher classification accuracy for those in the AD trajectory than hippocampal volume.

Much research has focused on neurodegeneration in aging and Alzheimer's disease (AD). We developed Scoring by Nonlocal Image Patch Estimator (SNIPE), a non-local patch-based measure of anatomical similarity and hippocampal segmentation to measure hippocampal change. While SNIPE shows enhanced predictive power over hippocampal volume, it is unknown whether SNIPE is more strongly associated with group differences between normal controls (NC), early MCI (eMCI), late (lMCI), and AD than hippocampal volume. Alzheimer's Disease Neuroimaging Initiative older adults were included in the first analyses (N = 1666, 513 NCs, 269 eMCI, 556 lMCI, and 328 AD). Sub-analyses investigated amyloid positive individuals (N = 834; 179 NC, 148 eMCI, 298 lMCI, and 209 AD) to determine accuracy in those on the AD trajectory. We compared SNIPE grading, SNIPE volume, and Freesurfer volume as features in seven different machine learning techniques classifying participants into their correct cohort using 10-fold cross-validation. The best model was then validated in the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). SNIPE grading provided the highest classification accuracy for all classifications in both the full and amyloid positive sample. When classifying NC:AD, SNIPE grading provided an 89% accuracy (full sample) and 87% (amyloid positive sample). Freesurfer volume provided much lower accuracies of 65% (full sample) and 46% (amyloid positive sample). In the AIBL validation cohort, SNIPE grading provided a 90% classification accuracy for NC:AD. These findings suggest SNIPE grading provides increased classification accuracy over both SNIPE and Freesurfer volume. SNIPE grading offers promise to accurately identify people with and without 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.

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.

The use of hippocampal grading as a biomarker for preclinical and prodromal Alzheimer's disease.

Hippocampal changes are associated with increased age and cognitive decline due to mild cognitive impairment (MCI) and Alzheimer's disease (AD). These associations are often observed only in the later stages of decline. This study examined if hippocampal grading, a method measuring local morphological similarity of the hippocampus to cognitively normal controls (NCs) and AD participants, is associated with cognition in NCs, subjective cognitive decline (SCD), early (eMCI), late (lMCI), and AD. A total of 1620 Alzheimer's Disease Neuroimaging Initiative participants were examined (495 NC, 262 eMCI, 545 lMCI, and 318 AD) because they had baseline MRIs and Alzheimer's disease Assessment Scale (ADAS-13) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. In a sub-analysis, NCs with episodic memory scores (as measured by Rey Auditory Verbal Learning Test, RAVLT) were divided into those with subjective cognitive decline (SCD+; 103) and those without (SCD-; 390). Linear regressions evaluated the influence of hippocampal grading on cognition in preclinical and prodromal AD. Lower global cognition, as measured by increased ADAS-13, was associated with hippocampal grading: NC (p < .001), eMCI (p < .05), lMCI (p < .05), and AD (p = .01). Lower global cognition as measured increased CDR-SB was associated with hippocampal grading in lMCI (p < .05) and AD (p < .001). Lower RAVLT performance was associated with hippocampal grading in SCD- (p < .05) and SCD+ (p < .05). These findings suggest that hippocampal grading is associated with global cognition in NC, eMCI, lMCI, and AD. Early changes in episodic memory during pre-clinical AD are associated with changes in hippocampal grading. Hippocampal grading may be sensitive to progressive changes early in the disease course.

Racial differences in white matter hyperintensity burden in older adults.

White matter hyperintensities (WMHs) may be one of the earliest pathological changes in aging. Race differences in WMH burden has been conflicting. This study examined if race influences WMHs and whether these differences are influenced by vascular risk factors. Alzheimer's Disease Neuroimaging Initiative participants were included if they had a baseline MRI, diagnosis, and WMH measurements. Ninety-one Blacks and 1937 Whites were included. Using bootstrap re-sampling, 91 Whites were randomly sampled and matched to Blacks based on age, sex, education, and diagnosis 1000 times. Linear models examined the influence of race on baseline WMHs, and change of WMHs over time, with and without vascular factors. Vascular risk factors had higher prevalence in Blacks than Whites. When not including vascular factors, Blacks had greater frontal, parietal, deep, and total WMH burden compared to Whites. There were no race differences in longitudinal progression of WMH accumulation. After controlling for vascular factors, only overall longitudinal parietal WMH group differences remained significant, suggesting that vascular factors contribute to racial group differences observed in WMHs.

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 Associated With Lower Baseline Cognition and Increased Rate of Cognitive Decline.

OBJECTIVES: Subjective cognitive decline (SCD) is a known risk factor for Alzheimer's disease. However, little research has examined whether healthy older adults with SCD (SCD+) exhibit lower cognition and increased rates of cognitive decline compared to those without SCD (SCD-). The goal of this study was to examine if cognitive change over a 15-year period differs between SCD+ and SCD-. METHOD: 3,019 cognitively normal older adults (831 SCD+) from 3 Rush Alzheimer's Disease Center cohort studies were followed annually for up to a maximum of 15 years. Due to attrition, the average follow-up time was 5.7 years. Cognition was measured using z-scores of global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory. Linear mixed-effects models investigated whether SCD was associated with cognitive change. RESULTS: Both baseline cognition and cognitive change over time differed between SCD+ and SCD-. People with SCD+ exhibited lower baseline scores and a steeper decline in global cognition, episodic memory, semantic memory, and perceptual speed. People with SCD+ did not differ from SCD- in baseline visuospatial ability or working memory but exhibited increased change over time in those two domains compared to SCD-. DISCUSSION: The observed results reveal that older adults with SCD+ have lower baseline cognition and steeper declines in cognition over time compared to SCD-. Older adults with SCD may be aware of subtle cognitive declines that occur over time in global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory compared to those without SCD.

White matter hyperintensity load varies depending on subjective cognitive decline criteria.

Increased age and cognitive impairment is associated with an increase in cerebrovascular pathology often measured as white matter hyperintensities (WMHs) on MRI. Whether WMH burden differs between cognitively unimpaired older adults with subjective cognitive decline (SCD +) and without subjective cognitive decline (SCD -) remains conflicting, and could be related to the methods used to identify SCD. Our goal was to examine if four common SCD classification methods are associated with different WMH accumulation patterns between SCD + and SCD - . A total of 535 cognitively unimpaired older adults with 1353 time points from the Alzheimer's Disease Neuroimaging Initiative were included in this study. SCD was operationalized using four different methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry. Linear mixed-effects models were used to investigate the associations between SCD and overall and regional WMH burden. Overall temporal WMH burden differences were only observed with the Worry questionnaire. Higher WMH burden change over time was observed in SCD + compared to SCD - in the temporal and parietal regions using the CCI (temporal, p = .01; parietal p = .02) and ECog (temporal, p = .02; parietal p = .01). For both the ECog + Worry and Worry questionnaire, change in WMH burden over time was increased in SCD + compared to SCD - for overall, frontal, temporal, and parietal WMH burden (p < .05). These results show that WMH burden differs between SCD + and SCD - depending on the questionnaire and the approach (regional/global) used to measure WMHs. The various methods used to define SCD may reflect different types of underlying pathologies.

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.

White matter lesions may be an early marker for age-related cognitive decline.

BACKGROUND: Research suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. This project examines the association between these factors and their relationship to cognitive decline in cognitively unimpaired older adults without subjective cognitive decline. METHODS: A total of 230 subjects with cerebrospinal fluid (CSF) Aß42, CSF pTau181, white matter lesions (WMLs) used as a proxy of CSVD, and cognitive scores from the Alzheimer's Disease Neuroimaging Initiative were included. Associations between each factor and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models. RESULTS: At baseline, there was an inverse association between WML load and Aß42 (t = -4.20, p <.001). There was no association between WML load and pTau (t = 0.32, p = 0.75), nor with Aß42 and pTau (t = 0.51, p =.61). Correcting for age, sex and education, baseline WML load was associated with baseline ADAS-13 scores (t = 2.59, p =.01) and lower follow-up executive functioning (t = -2.84, p =.005). Baseline Aß42 was associated with executive function at baseline (t = 3.58, p<.004) but not at follow-up (t = 1.05, p = 0.30), nor with ADAS-13 at baseline (t = -0.24, p = 0.81) or follow-up (t = 0.09, p = 0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up. CONCLUSION: Both baseline Aß42 and WML load are associated with some baseline cognition scores, but only baseline WML load is associated with follow-up executive functioning. This finding suggests that WMLs may be one of the earliest clinical manifestations that contributes to future cognitive decline in cognitively healthy older adults. Given that healthy older adults with WMLs exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMLs.

Regional brain atrophy and cognitive decline depend on definition of subjective cognitive decline.

BACKGROUND: People with subjective cognitive decline (SCD) may be at increased risk for Alzheimer's disease (AD). However, not all studies have observed this increased risk. This project examined whether four common methods of defining SCD yields different patterns of atrophy and future cognitive decline between cognitively normal older adults with (SCD+ ) and without SCD (SCD-). METHODS: Data from 273 Alzheimer's Disease Neuroimaging Initiative cognitively normal older adults were examined. To operationalize SCD we used four common methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry. Voxel-based logistic regressions were applied to deformation-based morphology results to determine if regional atrophy between SCD- and SCD+ differed by SCD definition. Linear mixed-effects models were used to evaluate differences in future cognitive decline. RESULTS: Results varied between the four methods of defining SCD. Left hippocampal grading was more similar to AD in SCD+ than SCD- when using the CCI (p = .041) and Worry (p = .021) definitions. The right (p=.008) and left (p=.003) superior temporal regions had smaller volumes in SCD+ than SCD-, but only with the ECog. SCD+ was associated with greater future cognitive decline measured by Alzheimer's Disease Assessment Scale, but only with the CCI definition. In contrast, only the ECog definition of SCD was associated with future decline on the Montreal Cognitive Assessment. CONCLUSION: These findings suggest that the various methods used to differentiate between SCD- and SCD+ influence whether volume differences and findings of cognitive decline are observed between groups in this retrospective analysis.

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.