Aging Brain Study Research Articles

Wearable Use in an Observational Study Among Older Adults: Adherence, Feasibility, and Effects of Clinicodemographic Factors.

IntroductionWearables have great potential to improve monitoring and delivery of physical activity interventions to older adults with downstream benefits to multisystem health and longevity; however, benefits obtained from wearables depend on their uptake and usage. Few studies have examined person-specific factors that relate to wearable adherence. We characterized adherence to using a wearable activity tracker for 30 days and examined associations between adherence and demographics, cognitive functioning, brain volumes, and technology familiarity among community-dwelling older adults.MethodsParticipants were 175 older adults enrolled in the UCSF Longitudinal Brain Aging Study who were asked to wear a FitbitTM Flex 2 during waking hours for 30 days. Sixty two of these participants were also asked to sync their devices to the Fitbit smartphone app daily to collect minute-level data. We calculated adherence to wearing the Fitbit daily (i.e., proportion of days with valid activity data) and adherence to daily device syncing (i.e., proportion of days with minute-level activity data). Participants also completed a brain MRI and in-person cognitive testing measuring memory, executive functioning, and processing speed. Spearman correlations, Wilcoxon rank sum tests, and logistic regression tested relationships between wearable adherence and clinicodemographic factors.ResultsParticipants wore the Fitbits for an average of 95% of study days and were 85% adherent to the daily syncing protocol. Greater adherence to wearing the device was related to female sex. Greater adherence to daily device syncing was related to better memory, independent of demographic factors. Wearable adherence was not significantly related to age, education, executive functioning, processing speed, brain gray matter volumes, or self-reported familiarity with technology. Participants reported little-to-no difficulty using the wearable and all reported willingness to participate in another wearable study in the future.ConclusionsOlder adults have overall high adherence to wearable use in the current study protocol. Person-specific factors, however, may represent potential barriers to equitable uptake of wearables for physical activity among older adults, including demographics and cognitive functioning. Future studies and clinical providers utilizing wearable activity trackers with older adults may benefit from implementation of reminders (e.g., texts, calls) for device use, particularly among men and individuals with memory impairment.

Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy.

Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive vs independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. Participants were 196 adults (age 73.8 ± 6.1 years) from the Harvard Aging Brain Study. Baseline Aβ burden was quantified with Pittsburgh compound B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural MRI over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aβ burden as interactive vs independent predictors of gray matter atrophy, with adjustment for age, sex, years of education, APOE ε4 status, intracranial volume (when appropriate), and their interactions with time. In subsequent models, we adjusted for markers of white matter injury to determine whether vascular risk accelerated brain atrophy independently from diffusion- and fluid-attenuated inversion recovery (FLAIR)-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aβ burden on cognitive decline. Higher vascular risk and elevated Aβ burden interacted to predict more severe atrophy in frontal and temporal lobes, thalamus, and striatum. Higher Aβ burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aβ burden. We observed an interaction between elevated vascular risk and higher Aβ burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer disease.

Metabolic Factors Are Related to Brain Amyloid Among Mexican Americans: A HABS-HD Study.

Despite the tremendous amount of research on Alzheimer's disease (AD) biomarkers, very little data is available regarding the fundamental biomarkers of AD among Mexican Americans. Here we sought to examine the link between metabolic markers and brain amyloid among Mexican Americans as compared to non-Hispanic whites from the Health & Aging Brain Study -Health Disparities (HABS-HD) cohort. PET amyloid (florbetaben) data was analyzed from 34 Mexican American and 22 non-Hispanic white participants. Glucagon (t = 3.84, p < 0.001) and insulin (t = -2.56, p = 0.02) were both significantly related to global SUVR levels among Mexican Americans. Glucagon and insulin were both related to most ROIs. No metabolic markers were significantly related to brain amyloid levels among non-Hispanic whites. Metabolic markers are related to brain amyloid burden among Mexican Americans. Given the increased risk for diabetes, additional research is needed to determine the impact of diabetes on core AD biomarkers among this underserved population.

Progression from Subjective Cognitive Decline to Mild Cognitive Impairment or Dementia: The Role of Baseline Cognitive Performance

Background: Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression. Objective: This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia. Methods: We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT). Results: Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1–5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62]) and 122% (RAVLT 1–5; HR: 2.22 [1.55, 3.16]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1–5, RAVLT 30, and ROCFT–Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI. Conclusion: At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI.

Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease

Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022. Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined. The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin. This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

Emotional prosody recognition is impaired in Alzheimer\u2019s disease

BackgroundThe ability to understand emotions is often disturbed in patients with cognitive impairments. Right temporal lobe structures play a crucial role in emotional processing, especially the amygdala, temporal pole (TP), superior temporal sulcus (STS), and anterior cingulate (AC). Those regions are affected in early stages of Alzheimer´s disease (AD). The aim of our study was to evaluate emotional prosody recognition (EPR) in participants with amnestic mild cognitive impairment (aMCI) due to AD, AD dementia patients, and cognitively healthy controls and to measure volumes or thickness of the brain structures involved in this process. In addition, we correlated EPR score to cognitive impairment as measured by MMSE. The receiver operating characteristic (ROC) analysis was used to assess the ability of EPR tests to differentiate the control group from the aMCI and dementia groups.MethodsEighty-nine participants from the Czech Brain Aging Study: 43 aMCI due to AD, 36 AD dementia, and 23 controls, underwent Prosody Emotional Recognition Test. This experimental test included the playback of 25 sentences with neutral meaning each recorded with different emotional prosody (happiness, sadness, fear, disgust, anger). Volume of the amygdala and thickness of the TP, STS, and rostral and caudal parts of AC (RAC and CAC) were measured using FreeSurfer algorithm software. ANCOVA was used to evaluate EPR score differences. ROC analysis was used to assess the ability of EPR test to differentiate the control group from the aMCI and dementia groups. The Pearson’s correlation coefficients were calculated to explore relationships between EPR scores, structural brain measures, and MMSE.ResultsEPR was lower in the dementia and aMCI groups compared with controls. EPR total score had high sensitivity in distinguishing between not only controls and patients, but also controls and aMCI, controls and dementia, and aMCI and dementia. EPR decreased with disease severity as it correlated with MMSE. There was a significant positive correlation of EPR and thickness of the right TP, STS, and bilateral RAC.ConclusionsEPR is impaired in AD dementia and aMCI due to AD. These data suggest that the broad range of AD symptoms may include specific deficits in the emotional sphere which further complicate the patient’s quality of life.

Association between sleep parameters and longitudinal shortening of telomere length.

Background: The relationship between sleep parameters and longitudinal shortening of telomere length is unclear. This study aimed to investigate the relationship between sleep parameters and the shortening of leukocyte telomere length (LTL) over a year.Methods: Among the participants in the validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease, participants who measured both baseline and follow-up (two years later) of LTL were analyzed. They were dichotomized according to the degree of LTL attrition over two years. Clinical characteristics were compared between the faster and slower LTL shortening groups (cut-off points: −0.710 kbp, n = 119 each). Multivariable logistic regression analyses were performed to determine independent relationships between faster shortening of LTL length and sleep parameters.Results: A total of 238 participants, aged 55–88 years, were included. Participants with faster LTL shortening had a shorter duration of sleep (P = 0.013) and longer sleep latency (P = 0.007). Among the components of the PSQI, subjective measures of sleep quality, sleep latency, sleep duration, and sleep efficiency were significantly worse in participants with faster LTL shortening. Multivariate logistic regression analysis showed that sleep duration (per hour, OR = 0.831, 95% CI = 0.698–0.989), sleep latency (per minute, OR = 1.013, 95% CI = 1.002–1.024), global PSQI score (OR = 1.134, 95% CI = 1.040–1.236), shortest sleep duration (OR = 5.173, 95% CI = 1.563–17.126), and lowest sleep efficiency (OR = 7.351, 95% CI = 1.943–27.946) were independently associated with faster LTL shortening.Conclusions: Poor sleep quality, specifically short sleep duration, long sleep latency, and low sleep efficiency were associated with faster longitudinal shortening of LTL.

Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.

Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology. One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40). Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

DKI enhances the sensitivity and interpretability of age-related DTI patterns in the white matter of UK biobank participants

Studies of healthy brain aging traditionally report diffusivity patterns associated with white matter degeneration using diffusion tensor imaging (DTI), which assumes that diffusion measured at typical b-values (approximately 1000 s/mm2) is Gaussian. Diffusion kurtosis imaging (DKI) is an extension of DTI that measures non-Gaussian diffusion (kurtosis) to better capture microenvironmental processes by incorporating additional data at a higher b-value. In this study, using diffusion data (b-values of 1000 and 2000 s/mm2) from 700 UK Biobank participants aged 46–80, we investigate (1) the extent of novel information gained from adding diffusional kurtosis to diffusivity observations in aging, and (2) how conventional DTI metrics in aging compare with diffusivity metrics derived from DKI, which are corrected for kurtosis. We establish a pattern of lower kurtosis alongside higher diffusivity among older adults, with kurtosis generally being more sensitive to age than diffusivity. We also find discrepancies between diffusivity metrics derived from DTI and DKI, emphasizing the importance of accounting for non-Gaussian diffusion when interpreting age-related diffusivity patterns.

Late-Life Physical Activities Moderate the Relationship of Amyloid-β Pathology with Neurodegeneration in Individuals Without Dementia.

Physical activities (PA) have been suggested to reduce the risk of Alzheimer's disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited. We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia. This study included participants from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B positron emission tomography (PET), [18F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire. This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect. The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults.

APOEɛ4 Allele Moderates the Association Between Basal Forebrain Nuclei Volumes and Allocentric Navigation in Older Adults Without Dementia.

Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer's disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOEɛ4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures. 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1-2 = 0.039; pch4p = 0.042) and PFC (pch4ai = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p = 0.035). Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.

Racial and socioeconomic status differences in stress, posttraumatic growth, and mental health in an older adult cohort during the COVID-19 pandemic.

SummaryBackgroundThe COVID-19 pandemic has disproportionately impacted the most vulnerable and widened the health disparity gap in both physical and mental well-being. Consequentially, it is vital to understand how to best support elderly individuals, particularly Black Americans and people of low socioeconomic status, in navigating stressful situations during the COVID-19 pandemic and beyond. The aim of this study was to investigate perceived levels of stress, posttraumatic growth, coping strategies, socioeconomic status, and mental health between Black and non-Hispanic, White older adults, the majority over the age of 70. Additionally, we investigated which variables, if any, were associated with posttraumatic growth in these populations.MethodsOne hundred seventy-six community dwelling older adults (mean age = 76.30 ±8.94), part of two observational studies (The Harvard Aging Brain Study and Instrumental Activities of Daily Living Study) in Massachusetts, US, were included in this cross-sectional study. The survey, conducted from March 23, 2021 to May 13, 2021, measured perceived stress, behavioral coping strategies, posttraumatic growth, and mental health during the COVID-19 pandemic. We investigated associations with post-traumatic growth in a multiple linear regression model and examined their differences by race with t-tests, Wilcoxon rank-sum tests, and Fisher's exact tests. A second multiple linear regression model was used to examine which coping strategies were associated with posttraumatic growth.FindingsOur results indicated no significant difference between the groups in terms of mental health or stress. However, Black participants showed significantly greater posttraumatic growth compared to non-Hispanic, White participants. Additionally, the coping strategies of religion and positive reframing were found to be significantly associated with posttraumatic growth. Furthermore, even with the effects of stress and coping strategies controlled for, race remained significantly associated with posttraumatic growth.InterpretationThe COVID-19 pandemic has differentially impacted Black and non-Hispanic White older adults. These results may help encourage further analysis on geriatric psychiatry as well as understanding how cultural values and adaptations impact posttraumatic growth and mental health in diverse populations.FundingThe Harvard Aging Brain Study (HABS) has been funded by NIH-NIA P01 AG036694 (PI: Reisa Sperling). The IADL study is funded by the National Institute on Aging (R01 AG053184, PI: Gad A. Marshall).

The Link between APOE4 Presence and Neuropsychological Test Performance among Mexican Americans and Non-Hispanic Whites of the Multiethnic Health & Aging Brain Study – Health Disparities Cohort

Introduction: The APOEε4 allele is the single strongest genetic risk for late-onset Alzheimer’s disease (AD). Prior work demonstrates that not only the APOEε4 allele varies by race/ethnicity but also the risk for AD and cognitive impairment conveyed by the APOEε4 allele varies by the racial/ethnic group as well as genetic ancestry. Here, we sought to examine the link between the APOEε4 and neuropsychological functioning among Mexican Americans (MAs). Methods: Data were examined from 1,633 (852 MAs and 781 non-Hispanic Whites [NHWs]) participants of the Health & Aging Brain Study – Health Disparities (HABS-HD) and were enrolled with all requisite data to be included into the current analyses. Results: The frequency of both ε4 and ε2 alleles was significantly lower among MAs as compared to NHWs. Among MAs, APOEε4 allele presence was associated specifically with poorer immediate and delayed memory (Wechsler Memory Scale – Third Edition [WMS-III] Logical Memory and Spanish-English Verbal Learning Test [SEVLT]). Among NHWs, APOEε4 allele presence was associated with poorer immediate and delayed memory as well as worse executive functioning (Trials B) and verbal fluency (Animal naming). Discussion/Conclusion: The APOEε4 allele was associated with poorer cognition across multiple domains among NHWs; however, allele presence was specifically associated with poorer memory performance among MAs. When combined with prior work, the current findings demonstrate that the risk factors associated with cognitive dysfunction differ among MAs as compared to NHWs and require additional investigation.

Cognitive Test Scores and Progressive Cognitive Decline in the Aberdeen 1921 and 1936 Birth Cohorts.

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997–2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the −1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Targeted Suppression of Lipoprotein Receptor LSR in Astrocytes Leads to Olfactory and Memory Deficits in Mice.

Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia–neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays an important role in brain cholesterol homeostasis. Aged heterozygote Lsr+/− mice show altered brain cholesterol distribution and increased susceptibility to amyloid stress. Since LSR expression is higher in astroglia as compared to neurons, we sought to determine if astroglial LSR deficiency could lead to cognitive defects similar to those of Alzheimer’s disease (AD). Cre recombinase was activated in adult Glast-CreERT/lsrfl/fl mice by tamoxifen to induce astroglial Lsr deletion. Behavioral phenotyping of young and old astroglial Lsr KO animals revealed hyperactivity during the nocturnal period, deficits in olfactory function affecting social memory and causing possible apathy, as well as visual memory and short-term working memory problems, and deficits similar to those reported in neurodegenerative diseases, such as AD. Furthermore, GFAP staining revealed astroglial activation in the olfactory bulb. Therefore, astroglial LSR is important for working, spatial, and social memory related to sensory input, and represents a novel pathway for the study of brain aging and neurodegeneration.

Development of a Sex-Specific Risk Scoring System for the Prediction of Cognitively Normal People to Patients With Mild Cognitive Impairment (SRSS-CNMCI).

ObjectiveWe aimed to develop a sex-specific risk scoring system, abbreviated as SRSS-CNMCI, for the prediction of the conversion of cognitively normal (CN) people into patients with Mild Cognitive Impairment (MCI) to provide a reliable tool for the prevention of MCI.MethodsCN at baseline participants 61–90 years of age were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database with at least one follow-up. Multivariable Cox proportional hazards models were used to identify the major risk factors associated with the conversion from CN to MCI and to develop the SRSS-CNMCI. Receiver operating characteristic (ROC) curve analysis was used to determine risk cutoff points corresponding to an optimal prediction. The results were externally validated, including evaluation of the discrimination and calibration in the Harvard Aging Brain Study (HABS) database.ResultsA total of 471 participants, including 240 female (51%) and 231 male participants (49%) aged from 61 to 90 years, were included in the study cohort. The final multivariable models and the SRSS-CNMCI included age, APOE e4, mini mental state examination (MMSE) and clinical dementia rating (CDR). The C-statistics of the SRSS-CNMCI were 0.902 in the female subgroup and 0.911 in the male subgroup. The cutoff point of high and low risks was 33% in the female subgroup, indicating that more than 33% female participants were considered to have a high risk, and more than 9% participants were considered to have a high risk in the male subgroup. The SRSS-CNMCI performed well in the external cohort: the C-statistics were 0.950 in the female subgroup and 0.965 in the male subgroup.ConclusionThe SRSS-CNMCI performs well in various cohorts and provides an accurate prediction and a generalization.

Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure.

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at least in isolation) to draw strong reverse inferences about white matter microstructure, but based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users. Therefore, this paper will briefly discuss the complex biophysical underpinnings of these measures in the context of crossing fibers, provide some intuitive “thought experiments” to highlight how conventional interpretations can lead to incorrect conclusions, and suggest that future studies refrain from using (over-interpreting) FA, AD, and RD values as standalone biomarkers of cerebral white matter microstructure.

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease.

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

Memory Binding Test and Its Associations With Hippocampal Volume Across the Cognitive Continuum Preceding Dementia.

Innovative memory paradigms have been introduced to capture subtle memory changes in early Alzheimer's disease (AD). We aimed to examine the associations between different indexes of the challenging Memory Binding Test (MBT) and hippocampal volume (HV) in a sample of individuals with subjective cognitive decline (SCD; n = 50), amnestic mild cognitive impairment (aMCI) due to AD (n = 31), and cognitively normal (CN) older adults (n = 29) recruited from the Czech Brain Aging Study, in contrast to traditional verbal memory tests. Both MBT free and cued recall scores in immediate and delayed recall conditions were associated with lower HV in both SCD and aMCI due to AD, whereas in traditional verbal memory tests only delayed recall scores were associated with lower HV. In SCD, the associations with lower HV in the immediate recall covered specific cued recall indexes only. In conclusion, the MBT is a promising test for detecting subtle hippocampal-associated memory decline during the predementia continuum.

Serum neurofilament light chain level as a predictor of cognitive stage transition

BackgroundNeurofilament light chain (NFL) level has been suggested as a blood-based biomarker for neurodegeneration in dementia. However, the association between baseline NFL levels and cognitive stage transition or cortical thickness is unclear. This study aimed to investigate whether baseline NFL levels are associated with cognitive stage transition or cortical thickness in mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants.MethodsThis study analyzed data on participants from the independent validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE-V) study. Among the participants of KBASE-V study, 53 MCI and 146 CU participants who were followed up for ≥ 2 years and had data on the serum NFL levels were eligible for inclusion in this study. Participants were classified into three groups according to baseline serum NFL levels of low, middle, or high.ResultsThe Kaplan–Meier analysis showed association between the serum NFL tertiles and risk of cognitive stage transition in MCI (P = 0.002) and CU (P = 0.028) participants, analyzed separately. The same is true upon analysis of MCI and CU participants together (P < 0.001). In MCI participants, the highest serum NFL tertile and amyloid-beta positivity were independent predictors for cognitive stage transition after adjusting for covariates. For CU participants, only amyloid-beta positivity was identified to be an independent predictor.ConclusionThe study shows that higher serum NFL tertile levels correlate with increased risk of cognitive stage transition in both MCI and CU participants. Serum NFL levels were negatively correlated with the mean cortical thickness of the whole-brain and specific brain regions.