bluuebunny/crossref_metadata_2025 huggingface dataset:
In‐vivo and post‐mortem retinal and brain pathological findings in a homozygote for the A431E PSEN1 mutation
Authors: Guzman Samuel , Koronyo‐Hamaoui Maya , Koronyo Yosef , Shi Haoshen , Hiniker Annie , Hawes Debra , Kashani Amir H , Ringman John M
Published: December 2023

Background

The neuropathology associated with PSEN1 mutations shares many features with late‐onset Alzheimer’s disease although atypical features are also seen. An important question is whether the manifestations of PSEN1 mutations are dose‐dependent. We present the neuropathological findings of a homozygote for the pathogenic A431E mutation in PSEN1 relative to heterozygotes and the finding of retinal Aβ lesions consistent with those that were topographically detected in vivo by retinal fluorescence imaging.

Methods

A homozygote for the A431E PSEN1 mutation began having symptoms at age 33 and underwent a comprehensive ophthalmic and neurologic evaluation at age 37 before passing away at age 39. Brain and eyes were collected and brain sections and retinal flatmounts and cross‐sections were processed and immunostained with 4G8 or 12F4 (anti‐Aβ), AT8 or pS396 (anti‐phosphoTau) antibodies. Retinal vascular and astrocytic markers were also assessed.

Results

Brain weight of the homozygote was 1180 grams relative to 840 and 860 grams in two heterozygotes with only mild to moderate gross atrophy appreciable relative to moderate to severe atrophy in the heterozygotes. More abundant 4G8 (Aβ) staining was appreciable in widespread brain areas in the homozygote relative to the heterozygotes with some having a “cotton wool” morphology. Conversely, neurofibrillary tangle density was markedly lower in the homozygote relative to heterozygotes in all areas assessed. Retinal in vivo imaging revealed very small, yellow deposits in the macula in both eyes that were atypical for a 37‐year‐old. These lesions correlated topographically with areas of Aβ deposits stained in post‐mortem flatmounts. In retinal cross‐section, Aβ accumulation, including vascular Aβ40 and Aβ42 deposits, pS396‐positive staining and NFTs are clearly detected, along with enhanced GFAP‐positive gliosis.

Conclusion

The neuropathological changes seen in a person homozygous for the A431E PSEN1 mutation showed an increased degree of Aβ pathology and evidence of a lesser degree of downstream pathology, possibly representing a more rapidly evolving disease with progressive disability despite a relative lack of neurodegeneration. We also demonstrated that Aβ and tau pathology occurs in the retina in this form of AD and that it can be visualized on clinical examination during life.

Funded by: P30AG066530, U01AG051218, R01AG062007
Differences in the association between midlife hypertension status and late‐life cognition and cognitive change: results from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: Gilsanz Paola , Soh Yenee , George Kristen M , Peterson Rachel , Hirst Andrew K , Mayeda Elizabeth Rose , Glymour M. Maria , Mungas Dan M. , Whitmer Rachel A.
Published: December 2023

Background

This study evaluates the association of midlife hypertension status and domain‐specific late‐life cognitive change allowing for possible differences by sex.

Method

The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort is a multi‐ethnic study of 1,712 Kaiser Permanente Northern California members age 65+ at enrollment in 2017. For 1,696 participants, we categorized the last examined clinical blood pressure measures from 1964‐1985 (mean age = 37.5) as hypotensive, normotensive, prehypertensive, or hypertensive. Verbal episodic memory and executive function were assessed using Spanish and English Neuropsychological Assessment Scales across three interview waves over 4 years and scores were z‐standardized to the baseline. Sex‐stratified linear mixed models with random intercepts estimated the associations of midlife hypertension status with domain‐specific baseline cognition and cognitive change using years since baseline as timescale. Models adjusted for age at blood pressure measurement, KHANDLE baseline age, race, ethnicity, education, practice effects, and interview mode (phone vs in‐person).

Result

A greater proportion of men than women had midlife pre‐hypertension (44% vs 31%) or hypertension (21% vs 11%) (Table 1). Among men and women, midlife hypertension status was not associated with baseline executive function or verbal episodic memory (Table 2). Compared to men with normal midlife blood pressure, those with midlife hypotension (b = ‐0.10, 95% CI: ‐0.17, ‐0.04) or midlife hypertension experienced steeper declines in executive functioning (b = ‐0.05, 95% CI: ‐0.10, ‐0.004). Among women, only midlife hypertension was associated with decline in executive function (b = ‐0.04 95% CI: ‐0.09, 0.003), though not significantly different from normotensive women. Compared to normotensive men, those with midlife hypotension (b = ‐0.17, 95%CI: ‐0.27, ‐0.07) and those with pre‐hypertension (b = ‐0.06, 95% CI: ‐0.12, ‐0.004) experienced steeper decline in verbal episodic memory. Among women, only midlife hypertension was associated with steeper declines executive function (b = ‐0.04, 95% CI: ‐0.09, 0.003), though not significantly different from normotensive women. Though effect estimates of midlife hypertension status on cognitive outcomes differed by sex, these differences were not statistically significant.

Conclusion

Both hypotension and hypertension 30‐50 years prior to cognitive assessments predicted accelerated cognitive decline in older men. Patterns were less consistent for women but not statistically distinguishable from associations among men.
The Effect of the COVID‐19 Pandemic on Subjective Cognitive Decline and Mood
Authors: Loor Angelique , Chapman Silvia , Joyce Jillian L. , Waltrip Leah H. , Rizer Sandra , Shagalow Shaina , Cosentino Stephanie
Published: December 2023

Background

Subjective Cognitive Decline (SCD) is being recognized as one of the earliest clinical signs of Alzheimer’s disease (AD). However, SCD is susceptible to a range of task factors (e.g., how SCD is measured) and person factors (e.g., mood). Currently, there is rising concern about the COVID‐19 pandemic’s impact on memory and mood. The purpose of this study was to investigate the effects of the pandemic on various types of SCD ratings and aspects of mood in older adults.

Methods

83 cognitively healthy older adults completed three counterbalanced 20‐item SCD questionnaires to examine SCD in general, SCD compared to 5 years ago (retrospective), and SCD compared to same‐aged peers (age‐anchored). Individuals also completed mood questionnaires that assess depression, anxiety, and apathy. After completing each SCD and mood questionnaire, participants rated the extent to which the pandemic affected their ratings using a Likert scale (range: much worse [‐2], a little worse [‐1] not changed [0], a little better [1], much better [2]). One‐sample and paired‐sample t‐tests examined pandemic effect ratings for each measure. Bivariate correlations examined pandemic effect ratings in relation to age and lifestyle features (sleep, loneliness, exercise, and social contact).

Results

One sample t‐tests revealed that age‐anchored SCD ratings were not affected by the pandemic; that is, pandemic effect ratings (mean = ‐0.11) were not significantly different from zero (p = .118). In contrast, retrospective SCD (mean = ‐0.25, p = .001) and general SCD ratings (mean = ‐0.26, p<.001) were negatively affected. Additionally, depression (p = .007), anxiety (p = .002), and apathy (p = .05) ratings were all negatively affected by the pandemic. Pandemic effect ratings for depression (r = .45; p< .001) and general SCD (r = .26; p = .018) were associated with the current quality of sleep as compared to pre‐pandemic sleep quality.

Conclusion

Age‐anchored SCD ratings are relatively resilient to the effects of the COVID‐19 pandemic. These results add to the growing evidence for using age‐anchored SCD ratings in studies of cognitive aging. Overall, these findings point to sleep quality as a potential mechanism by which older adults’ subjective cognitive experiences and mood may have been, and continue to be, affected by the pandemic.
Recruitment of Underrepresented Groups into the AHEAD Study: Strategic plan of Action
Authors: James Taryn T. , Gleason Carey E. , Gee Alexander , Gooding Diane C. , Lofton Brenda Caroll , Carter Fabu P. , Green‐Harris Gina , Norris Nia , Lawrence Sacheen L. , King Margaret F , Salazar Hector , Cardenas Cecilia , Cole Aleshia , Cronin Katherine , Carlsson Cynthia M , Bouges Shenikqua
Published: December 2023

Background

To ensure that therapies are applicable for all groups, ethnic/racial diversity in Alzheimer’s disease (AD) clinical trials is an ethical imperative. Toward this goal, we developed a recruitment model founded on 1) building trust by providing accurate and transparent information, and 2) using culturally sensitive approaches to address legitimate concerns. Our ultimate goal is to empower individuals from under‐represented groups (URG) to participate in AD research.

Method

Our group focuses on recruitment of racialized groups. Using a multistep approach (figure1), we established partnerships and created community advisory boards (CABs) comprised of leaders who effectively advocate for community needs. Research projects are presented to the CABs to determine alignment with community needs. Assessments with community leaders and advisory networks help identify opportunities to fulfill community needs. Recruitment of African Americans (AA) into the AHEAD study, a study assessing the recently approved monoclonal antibody, lecanemab in participants with preclinical AD, began by presenting the project to the Black Leaders of Brain Health (BLBH) CAB. Incorporating their input into our approach, we will structure community talks and events in a culturally appropriate manner in discussions with the larger AA community. Example, we utilized a questionnaire at an event to introduce AA participants in a biomarker study to the AHEAD study (figures 2 & 3).

Result

Feedback received from BLBH includes advocating to funders, including the NIH to fund research that reflects inclusivity and diversity. BLBH recommended building URG voices into study design by having a diverse scientific team and hiring community members to collect data. Additionally, rather than excessive compensation, researchers should speak to the study benefits both for the individual’s and the community’s health. Finally, BLBH members emphasized the need to include hopeful messages and advice to improve health, rather than merely pointing out that AA are most likely among racial groups to have the disease.

Conclusion

Recruitment models involving trust building and partnerships with groups consisting of community members of URG will be mutually beneficial for both the health researcher and the communities that they serve. This may serve as a means to tip the scale toward increased participation by URG in biomedical research.
Association of race/ethnicity with renewal to the Consent‐to‐Contact (C2C) local recruitment registry
Authors: Salazar Christian R. , Xu Yiren , Morgan Olivia M. Bernstein , Hoang Dan , Witbracht Megan G. , Gillen Daniel L , Grill Joshua D.
Published: December 2023

Background

Online recruitment registries may serve as tools for accelerating the enrollment of historically underrepresented participants in Alzheimer’s disease (AD) trials. A potential challenge, however, is retaining registry participants until they can be recruited into prospective studies. We sought to examine the association of race/ethnicity with renewal among adults over age 50 who enrolled in a local online recruitment registry.

Method

Study participants enrolled in the University of California, Irvine Consent‐to‐Contract (C2C) registry, a local online registry designed to improve recruitment into AD studies. At enrollment, participants completed an online structured questionnaire to assess sociodemographic characteristics, source of recruitment and self‐reported medical history. Research attitudes were assessed with the 7‐item Research Attitude Questionnaire (RAQ). We examined the frequency of participant completion of annual renewal within 15 months from initial enrollment to the registry. To evaluate the association of race/ethnicity with first‐year renewal, we used ordinal logistic regression models that were adjusted for age, sex, educational attainment, number of chronic conditions and research attitudes.

Result

Among 3,065 included C2C participants, the average age at enrollment was 66 years, 87% (n = 2,658) were Non‐Hispanic (NH) White, 6% (n = 191) were Hispanic/Latino, 6% (n = 180) were NH) Asian, and 1% (n = 36) were NH Black. Compared to NH Whites, Hispanics/Latinos exhibited a 40% lower odds of renewal (adjusted Odds Ratio [aOR] = 0.60, 95% Confidence Interval [CI]: 0.44 ‐ 0.82), 32% lower odds of renewal for NH Asians (aOR = 0.68, 95% CI: 0.50 ‐ 0.93) and 16% lower odds for NH Blacks (aOR = 0.84, 95% CI: 0.43‐1.66). Higher age, more years of education, and better research attitudes was associated with higher odds of first‐year renewal in the fully adjusted model.

Conclusion

Underrepresented populations may be at greater risk for loss to follow‐up in online recruitment registries. Future research addressing potential barriers to continued participation and interventions to improve retention will be critical to maximize the impact of registries.
Atrophy in brainstem nuclei with early Alzheimer’s Disease pathology, a biomarker for identification of at risk individuals?
Authors: Mueller Susanne G
Published: December 2023

Background

Autopsy studies suggest that AD‐related tau pathology may affect the brainstem already in adolescence/young adulthood suggesting that it could be a biomarker for the identification of at risk individuals in the preclinical stage. The overall goal was to investigate a. if a newly developed method for the segmentation of internal brainstem structures from T1 and T2 weighted MRIs can be used to identify subjects with volume losses in brainstem nuclei known to be affected by tau pathology, and b. if these brainstem volume losses affect cognition.

Method

The age‐adjusted Total Cognition Composite Score (CCS) and T1 and T2 weighted images were obtained from 675 participants in the Human Connectome Project of typical Aging. The T1 and T2 image intensities were recalibrated and a T1/T2 image calculated. The brainstem was extracted from these 3 images, and k‐means clustering used to identify five brainstem tissue types (Figure 1). The five tissue maps were warped onto a brainstem tissue template on which 48 structures were labeled. Jacobian determinant (JD) maps were calculated and the mean JD from these rois extracted. Linear regression with the mean roi JD as dependent and age as independent variable were used to generate a 675×48 matrix where residuals >2 SD above the fit line were set to 1 (larger than age‐average), those >2 SD below to ‐1 (smaller than age‐average) and all others to 0. Hierarchical clustering analysis with the 675×48 matrix as input was used to identify different brainstem atrophy patterns.

Result

The cluster analysis identified 11 clusters. 31 individuals (mean(SD) age: 56.2(16.2), range:36‐100) were assigned to Cluster 8. This cluster had the most rois (n = 17) with significant volume loss (Figure 2 for detailed results) and the 31 individuals the lowest CCS score compared to those assigned to other clusters (98.2(19.5) vs.109.6(15.2), p = 0.003).

Conclusion

The new brainstem segmentation identified a subgroup with lower cognitive performance and widespread volume loss exceeding that in their age cohort in brainstem nuclei known to be affected by AD. Additional studies will be necessary to determine if individuals showing this specific brainstem atrophy pattern are indeed at risk to develop AD in their later life.
Marital status associated with excess ADRD mortality among Californians during the COVID‐19 pandemic
Authors: DeVost Michelle A , Chen Yea‐Hung , Charpignon Marie‐Laure , Wells Whitney M , Kiang Mathew V , Mooney Alyssa C , Riley Alicia R , Glymour M. Maria , Chen Ruijia
Published: December 2023

Background

Social support shapes the health of older adults with Alzheimer’s disease and related dementias (ADRD), and marital status is linked to ADRD risk and all‐cause mortality. During the Covid‐19 pandemic, older adults with ADRD may have been particularly reliant on key social ties such as spouses. We estimated excess ADRD mortality by marital status among older Californians during the pandemic.

Method

Using California monthly mortality data from January 2016 to February 2020, we built autoregressive integrated moving average time series models to estimate the number of expected deaths with ADRD as a final or contributing cause between March 2020 and December 2022, stratified by marital status and age group. We obtained population estimates from the US Census’ American Community Survey. We calculated cumulative and monthly excess deaths per 100,000 living individuals and relative risk ratios (by dividing the number of observed deaths by the number expected). We simulated models 10,000 times to estimate 95% prediction intervals (PIs) for cumulative measures of excess.

Result

Among older Californians who died with ADRD during the study period, 7% were 65‐74, 26% were 75‐84, and 67% were 85+ (Table 1). Compared to people who were divorced, never married, or widowed, married people experienced the lowest spikes in per capita excess mortality associated with ADRD during the 2020 winter surge, regardless of age group (Figure 1). Among people who were 75 years and older, married people had the fewest estimated cumulative excess deaths per 100,000 population (1385, 95%PI: (1033, 1746)) compared to divorced (3217 (2294, 4155)), never married (2621 (1777, 3471)), and widowed people (2156 (770, 3560) (Table 1), although prediction intervals overlapped.

Conclusion

Being married may have protected against excess ADRD mortality during the pandemic among older Californians. The link between marital status and ADRD mortality risk likely reflects several mechanisms: social and emotional support; instrumental support to adhere to safety protocols during contagious outbreaks; caregiving and practical assistance with the activities of daily living; access to a broader social network that may include adult children; and advocacy to ensure appropriate medical care and support.
The relationship of intraindividual variability on mobile cognitive testing with age and frontotemporal dementia disease severity
Authors: Sanderson‐Cimino Mark E. , Clark Annie L , Wise Amy B. , Dhanam Sreya , Taylor Jack C , Paolillo Emily W. , Heuer Hilary W. , Hassenstab Jason J. , Kramer Joel H. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Staffaroni Adam M. ,   ALLFTD Consortium
Published: December 2023

Background

There has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity.

Method

Participants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses.

Result

Greater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p = .02) tasks; a positive but non‐significant association was seen with memory testing (p = .16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (𝛃 = .39, p = .004) than those with CDR®+NACC‐FTLD’s of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (𝛃 = .85, p<.001) and Go/No‐go tasks (𝛃 = .51, p = .007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (𝛃 = .27, p<.001) and Go/no‐go (𝛃 = .23, p<.001) tasks.

Conclusion

Increased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted.
Frailty, Brain Aging and Alzheimer’s Disease Brain Signatures: Longitudinal Associations from Middle to Old Age
Authors: Franz Carol E , Buchholz Erik , Reynolds Chandra A. , Hunt Jack F.V. , Schroeder Angelica , Cortes Isaac , Kremen William S.
Published: December 2023

Background

Frailty—feelings of weakness, fatigue, and lack of physiological resiliency—places older adults at increased risk for Alzheimer’s Disease (AD) and related dementias. A possible mechanism underlying these associations may be the effects of frailty on brain aging prior to old age.

Method

A prospective observational study of approximately 502 community‐based men of predominantly European ancestry without dementia at baseline, from the Vietnam Era Twin Study of Aging (VETSA). Frailty index and MRI imaging were collected at three waves at average ages 56, 62, and 68. We created frailty index (FI) scores using 37 items from previously validated cumulative deficit model indices. Imaging measures included brain‐age (BA; Cole et al. 2018), as well as a validated thickness/hippocampal volume AD‐signature (CTS), and a novel gray matter mean diffusivity AD‐signature (MDS), both weighted averages of MRI‐based morphometry or diffusivity in eight AD‐related brain regions. Different longitudinal models were tested using structural equation modeling in Mplus. Models were adjusted for age, race/ethnicity, education, and smoking.

Result

FI was highly correlated over time (range rs = 0.69 to 0.77), as were the brain signatures (range rs = 0.52 to 0.85). The best fitting model was the simplex/auto‐regressive model with correlated random intercepts. Figures 1‐3 show significant associations in the covariate‐adjusted models. FI is significantly associated with brain‐age and the cortical thickness/hippocampal volume AD‐signature random intercepts but not the mean diffusivity signature. Associations attenuate when smoking is added to the model. Moreover, when the cortical thickness/hippocampal volume and mean diffusivity AD‐signatures are adjusted for brain‐age then the associations further attenuate and are no longer significant. No cross‐lag associations were significant.

Conclusion

The results are striking given the relatively young age of the sample. Across middle age, frailty was associated with worse brain age and a smaller cortical thickness/hippocampal volume AD‐signature. These associations do not appear to be causal, rather biological aging processes running in parallel. Combined with recent evidence showing associations between frailty and AD‐related biomarkers, the results suggest frailty is not just a geriatric disease and support the need for early intervention in biological aging.
The temporal relationship between physical activity, mood, and sleep in older adults via a lead‐lag analysis
Authors: Colina Adrian Noriega , Ai Meishan , Bao Shania Fock Ka , Kramer Arthur F , Geddes Maiya R.
Published: December 2023

Background

Physical Activity, sleep, and mood are key modifiable lifestyle behaviours that are individually associated with lower cognitive decline [1]. Prior research suggests there may be a tridirectionally relationship among these three behaviours. The temporal relationship among these behaviours is unknown. Using an Ecological Momentary Assessment (ECA) and a time series analysis we aim to understand the temporal and longitudinal relationship among these factors.

Method

We performed a 10‐day lead‐lag analysis using Moderate‐to‐Vigorous Physical Activity (MVPA) and sleep as measured by a 24‐hour wrist‐worn accelerometer, and a self‐assessed daily mood scale on 30 community dwelling older adults who participated in a behavioural study to enhance physical activity in sedentary individuals (Clinicaltrials.gov identifier: NCT04315363). Participants were included if they did not exercise more than 150 minutes of MVPA per week (International Physical Activity Questionnaire) and were sitting more than 8 hours per day (Marshall Sitting Questionnaire). We examine each variable separately for auto‐correlative relationships for different timepoints of the same variable. The temporal dynamics are calculated from the rank‐order of the lead‐lag coefficients. The relationships between different timepoints of mood, MVPA, and sleep are examined through cross‐correlations.

Results

Autocorrelations showed that mood presented seasonality with baseline mood positively correlated to the subsequent day’s mood (r = +.571, p = .037) and negatively correlated with mood at day 7 (r = ‐.330, p = 0.27) and day 8 (r = ‐.248, p = .013). The temporal dynamics identified mood (B = +.602), preceding MVPA time (B = ‐.001), and sleep time (B = ‐.276) (Figure 1). Furthermore, cross‐correlations demonstrated that mood was positively correlated to MVPA at the same time point (r = ‐.605) and also that previous day mood predicted next day’s MVPA (r = ‐.629). Cross‐correlations confirmed that MVPA (r = ‐.507) and mood (r = ‐.504) predicted next day’s sleep time.

Conclusion

Improved mood precedes the increase in MVPA and sleep time in sedentary older adults. Understanding temporal dynamics between mood, sleep time, and MVPA, can help develop better interventions targeting increase in physical activity in older adults.

Reference:

[1] 2020 Report of the Lancet Commission. https://doi.org/10.1016/S0140‐6736(20)30367‐6.
Occupational complexity with people and late‐life cognitive decline: Does it vary by level of occupational prestige?
Authors: Soh Yenee , Lee Catherine , Peterson Rachel , Whitmer Rachel A. , Glymour M. Maria , Gilsanz Paola
Published: December 2023

Background

Prior evidence suggests engaging in intellectually challenging activities (e.g., complex work environments) in midlife is associated with favorable late‐life cognition. Substantial evidence exists for the relationship between occupational complexity with people (i.e., occupations with strong social engagement) and favorable cognitive function. Complex occupations often have high prestige, which may provide higher‐quality social interactions, and may be particularly beneficial for cognition. It remains unclear whether cognitive benefits conferred by occupational complexity varies across levels of occupational prestige.

Method

The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort includes community‐dwelling participants aged 65+ years in Northern California. For self‐reported main lifetime occupation, occupational complexity scores (from the Dictionary of Occupational Titles) for people (range: 0‐8) and Hodge‐Siegel‐Rossi occupational prestige scores (range: 9‐82) were coded. Executive function and verbal episodic memory were assessed 3 times across 4 years with the Spanish and English Neuropsychological Assessment Scales. Linear mixed‐effects models were estimated for associations between occupational complexity with people (in tertiles) and domain‐specific cognitive decline (z‐standardized), stratified by tertiles of occupational prestige (high: 57‐82; medium: 47‐56; low: 14‐46). Models adjusted for baseline age, years since baseline, race/ethnicity, sex, educational attainment, maternal education, practice effects, and interview mode.

Result

Among 1,529 participants (mean age = 76.0 years), 58.9% were female, 24.4% identified as Asian, 26.6% Black, 19.9% Latino, 29.0% White, 49.6% had a college degree or higher, and 21.3% had maternal education >12 years (Table 1). Among those with highest occupational prestige, highest complexity with people was associated with higher baseline executive function (β[95%CI] 0.34 [0.13,0.56] SD units). Among those with medium occupational prestige, no significant associations were found. Among those with lowest occupational prestige, highest complexity with people was associated with higher baseline executive function (0.31[0.07, 0.54]) and verbal episodic memory (0.29[0.03, 0.55]). No associations were found for cognitive decline (Table 2).

Conclusion

Within a diverse cohort, we found that higher occupational complexity with people was associated with better baseline cognition among those with highest and lowest occupational prestige, but not for those with middle prestige. Further investigation is needed to disentangle how occupational complexity may differentially impact individuals in different types of occupations.
Acoustic speech metrics that differentiate primary progressive aphasia variants depend on language typology
Authors: Elvira‐García Wendy , Marrero‐Aguiar Victoria , Borras‐Comes Joan , Rubio‐Guerra Sara , Marques‐Kiderle Sonia Karin , Montagut Núria , Faixa Carlota , Auge Laura , Rodriguez Camille Wagner , Grasso Stephanie M , Lleo Alberto , Illán‐Gala Ignacio , Santos‐Santos Miguel A
Published: December 2023

Background

Primary Progressive Aphasia (PPA) variants can be distinguished using acoustic speech measures. In particular, the syllabic pairwise‐variability‐index (syll‐PVI), which computes syllable duration differences between unstressed and stressed adjacent syllables, can differentiate between the logopenic (lvPPA) and non‐fluent (nfvPPA) variants in English.

Method

We analysed 5 repetitions of 5 multisyllabic words in a cohort of 37 patients (7 svPPA, 14 lvPPA, 16 nfvPPA) and 15 healthy controls. Data were annotated in Praat (manually revised) and metrics computed in R by means of Generalized Linear Mixed Models. The temporal parameters analysed were speech rate (number of sounds per second), average syllable duration (mean duration of each syllable for each word), and syll‐PVI (the normalized difference in duration between the stressed syllable of a word and the preceding one). Four speech language pathologists with extensive clinical experience with PPA performed blinded independent ratings of apraxia of speech severity in a subset of 31 participants.

Result

Syllable duration behaves as expected, the control group had the smallest average syllable duration for the five polysyllabic words, followed by the lvPPA, nfvPPA and svPPA groups. The durations are longer in nfvPPA compared to lvPPA (Cohen’s d = 2.249, p = 0.02). Speech rate shows similar results; the largest difference is found between lvPPA and nfPPA, however it does not reach significance (Cohen’s d = 1.434, p = 0.07). Regarding syll‐PVI, nfvPPA tend to have the value closest to 0 (as expected due to greater presence of apraxia of speech), but the effect size does not reach significance for any word. Mean apraxia of speech severity showed higher correlation with syllable duration (spearman coef = 0.290, p = 0.11) than syll‐PVI (spearman coef = ‐0.073, p = 0.69).

Conclusion

Syllable duration, and not syll‐PVI, can distinguish lvPPA and nfvPPA in Spanish. This is probably due to a typological difference between English (a prototypical stress‐timed language) and Spanish (a prototypical syllable‐timed language) given that the syllabic‐PVI computes differences between duration of unstressed and stressed syllables and those differences are smaller in syllable‐timed languages. Our results highlight the necessity of considering language particularities in the development of speech and language clinical measures.
Development and implementation of plasma P‐tau immunoassays
Authors: Karikari Thomas K
Published: December 2023

Background

Multiple advances in plasma biomarkers have been reported in recent times, one of these being the development of plasma p‐tau assays.

Methods

In this invited presentation as part of the Perspectives Session on “Advances in plasma Alzheimer’s disease biomarkers,” I will provide an expert review of the current state of analytical development of plasma p‐tau biomarkers.

Results

Specifically, I will discuss the biochemical and molecular bases of why specific p‐tau forms are accessible in blood whilst others are not, as well as why these blood p‐tau markers tend to associate predominantly with brain amyloid but not tau pathology. Furthermore, I will highlight new discoveries in the development of biofluid‐based tau markers (both phosphorylated and non‐phosphorylated) that associate with neurofibrillary tangle pathology. Other aspects of my talk will focus on associations of the novel biomarker plasma brain‐derived tau with AD‐signature neurodegeneration. Additionally, I will discuss how newly improved preanalytical handling protocols enable plasma biomarker measurements in remote and resource‐limited settings, towards democratizing access to diagnostics.

Conclusion

Finally, I will discuss and suggest solutions to challenges around cut‐off generation, inter‐laboratory and inter‐assay measurements.
Modernizing AD clinical trials: why are we designing studies for disease modifying treatments using the symptomatic treatment paradigm?
Authors: Dickson Samuel P. , Mallinckrodt Craig , Wassom Mitchell , Nicodemus‐Johnson Jessie , Knowlton Newman , Hennessey Sean , Hendrix Suzanne B.
Published: December 2023

Background

Until the accelerated approvals of aducanumab and lecanemab, the only approved drugs for Alzheimer’s disease (AD) were symptomatic treatments, which showed relatively large improvements but did not alter disease progression. Multiple decades of designing and analyzing trials for symptomatic treatments have optimized the process for acetyl cholinesterase inhibitors and NMDA receptor antagonists, but this paradigm is not optimal for disease‐modifying therapies. As the AD research community continues to transition towards treatments with the potential to alter disease progression, significant course corrections in the design and analysis of clinical trials are required to ensure that treatments with the largest potential for impact do not fail because they’re being evaluated out of context.

Method

Several design aspects from AD clinical trials are evaluated in the context of disease‐modifying treatments, including the expected effect size, patient population, outcomes, multiplicity adjustments, trial duration, use of biomarkers, and timing of visits. We use publicly available trial results to demonstrate that both the clinical trial process and public interpretation of data will result in costly losses unless significant improvements are accepted and implemented

Result

In the context of donepezil’s expected 3‐point change on ADAS‐cog over 6 months, the results for lecanemab (1.5 points over 18 months) seem small, yet lecanemab improvements can be reasonably expected to match donepezil after three years of treatment and continue to increase. Symptomatic treatments were required to demonstrate significant improvement on multiple outcomes, but disease‐modifying treatments should address the underlying disease process. Trials of aducanumab, donanemab, and lecanemab show consistent disease modification of 5 to 6 months less progression over 18 months when outcomes are converted to units of time and combined. This time‐converted composite (which may include biomarkers) can show consistent results earlier in the disease course, allowing prodromal and early AD patients to be studied with greater success.

Conclusion

The current message sent by recent approvals is that only sponsors with resources to field clinical trials with thousands of patients have a chance of gaining regulatory approval. By modernizing clinical trials, more sponsors will have a better chance of success, meaning better treatments available to more patients sooner.
Assessment of quantitative susceptibility mapping (QSM) and oxygen extraction fraction (OEF) in the spectrum of Alzheimer’s disease clinical presentations
Authors: Hosseini Seyyed Ali , Servaes Stijn , Therriault Joseph , Tissot Cécile , Rahmouni Nesrine , Macedo Arthur C. , Lussier Firoza Z , Stevenson Jenna , Wang Yi‐Ting , Arias Jaime Fernandez , Aumont Etienne , Socualaya Kely Quispialaya , Nazneen Tahnia , Stevenson Alyssa , Gauthier Serge , Pascoal Tharick A. , Rosa‐Neto Pedro
Published: December 2023

Background

Different methods have been proposed to assess vascular dysfunction in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitively unimpaired (CU) subjects including quantitative susceptibility mapping (QSM), and recently oxygen extraction fraction (OEF). QSM is sensitive to the presence of iron and is a non‐invasive MR approach to measure local tissue susceptibility with high spatial resolution. OEF is a measure of the percentage of oxygen taken from the brain’s blood supply and relates directly to brain oxygen metabolism. Here, we aimed to examine QSM (Figure1) and OEF (Figure1) potential in differentiating AD, MCI, and CU.

Method

A cohort of 310 subjects with AD (n = 48), MCI (n = 80), and CU (n = 182) were recruited. All the patients received 3D gradient‐recalled echo sequence MRI. All QSM images were constructed by MEDI+0 and OEF images were constructed by QSM+qBOLD model with CCTV (Temporal clustering, tissue composition, and total variation). Eighty‐two various brain regions of interest (ROI) and 6 Braak ROI were investigated in the current study. ANOVA and Posthoc least significant difference (LSD) tests were implemented for each ROI over AD, MCI, and CU.

Result

Over Braak ROI analysis, the ANOVA test showed that the average susceptibility of QSM with Braak 4 ROI is significantly different (p<0.001). LSD test showed that Braak 4 ROI of QSM is significantly different between AD vs. MCI and AD vs. CU (p<0.001). Braak 2 ROI of OEF was significantly different between AD vs. MCI and AD vs. CU (p = 0.21 and p = 0.32, respectively). Over brain ROI, the ANOVA test showed QSM right and left posterior cingulate and right Caudate were significantly different (p<0.001). Besides, these ROIs were significantly different between AD vs. MCI and AD vs. CU, according to the LSD test. Over brain ROI, OEF right Caudate was significantly different (p<0.001) followed by left Caudate and Right transverse temporal with p = 0.002 based on the ANOVA test. However, right and left Caudate were just significantly different between AD vs. CU (p<0.001) based on the LSD test (Table 1 and 2).

Conclusion

QSM and OEF are affordable non‐invasive MR approaches to assess vascular dysfunction in the spectrum of clinical presentations of AD.
Hippocampal Enlargement and White Matter Hyperintensities in Obstructive Sleep Apnea Patients
Authors: Mula Manasa , Mathew Alex , Das Sandhitsu R. , Nasrallah Ilya M. , Bryan R N , Detre John A. , Benzinger Tammie L.S. , Wolk David A. , Hanlon Alexandra , Lozano Alicia , Moelter Steven , Chi Luqi , Davis Eric M , Cheng Cindy , Bhamidipati Abhinav , Gooneratne Nalaka , Richards Kathy C
Published: December 2023

Background

Obstructive sleep apnea (OSA), which results from recurrent collapses of the upper airway system, affects around 27% of the geriatric population with mild cognitive impairment (MCI) and causes intermittent hypoxia and sleep fragmentation (Mubashir et al., 2019). Prior research suggests that OSA results in brain ischemic preconditioning, causing hippocampal enlargement due to adaptive hippocampal neurogenesis (Rosenzweig et al., 2013). OSA has also been linked to increased white matter hyperintensities (WMHs) through hypoxic‐ ischemic injury, which contribute to cognitive decline in dementias such as Alzheimer’s disease (Zacharias et al., 2021). Previous research necessitates studying the effects of apnea in an elderly population with MCI.

Method

In the Memories2 study, subjects aged 55‐85 underwent a polysomnography and were assigned to the no OSA (OSA‐) group if their apnea‐hypopnea index (AHI) was <5 events/hour or to the OSA (OSA+) group if their AHI was ≥15. Amnestic MCI status was determined with a neuropsychological battery using standard criteria. The subjects received an optional MRI, in which hippocampal and WMH volumetry were derived from a T1‐weighted structural scan and a whole‐brain fluid‐attenuated inversion recovery (FLAIR) scan, respectively. Statistical analyses (two‐sample t‐tests and Wilcoxon‐Mann‐Whitney test) were performed to understand group differences in hippocampal volume and WMH at baseline. Hippocampal volume data (N = 131) was obtained for 67 OSA+ and 64 OSA‐ subjects. WMH data (N = 129) was obtained for 66 OSA+ and 63 OSA‐ subjects.

Result

OSA+ subjects had significantly greater right hippocampal volume (p = 0.0374) and left hippocampal volume (0.0336) than the OSA‐ subjects. OSA+ subjects also had higher levels of white matter hyperintensities as compared to the OSA‐ subjects (p = 0.0340) (Table 1).

Conclusion

Increased WMH burden is suggestive of hypoxic‐ischemic injury and supports the hypothesis that hippocampal enlargement may be a response to intermittent hypoxia in OSA. These findings reveal the need for early evaluation for sleep apnea. The future direction of this work includes analyzing the group differences adjusting for covariates, detecting and verifying outliers, and rerunning analyses with the complete baseline data. Future data from the Memories2 study will examine the effects of OSA treatment in MCI patients using continuous positive airway pressure (CPAP).
Associations of antipsychotic medication use with mortality, stroke, and myocardial infarction among long‐term nursing home Medicare beneficiaries
Authors: Okhravi Hamid , Fang Fang , Sheehan Brynn E
Published: December 2023

Background

In 2005, the Food and Drug Administration issued a black box warning regarding increased mortality and cardiovascular accidents with the off‐label use of antipsychotic medication (APM) in patients with dementia. To improve the quality of care for patients with dementia in nursing homes (NH), in early 2012, the Centers for Medicare & Medicaid Services launched the National Partnership (NP) aimed at combatting the excessive use of APM. Within five years of the partnership, the number of antipsychotic prescriptions in NHs decreased by 34%. The objective of the present study was to examine how APM use has impacted other outcomes, including mortality and major cardiovascular events such as stroke and myocardial infarction (MI) among NH residents with dementia.

Method

We analyzed Medicare data on a sample of 611,773 long‐term NH residents with dementia, aged 50 years and older, from 2011 through 2016. Residents who had received hospice care during the time period were excluded. Cross‐sectional (by year) logistic regressions were conducted to examine the associations of APM use with death, stroke, and MI in the years 2011‐2016. Regression models were adjusted for demographic and co‐morbidity indicators.

Result

Logistic regressions (see results in Table 1) revealed that NH residents prescribed APM had a significantly higher probability of death compared to non‐users from 2011 through 2015. However, in 2016, the probability of death was lower among APM users than non‐users, although the association was weak. Additionally, NH residents who were on APM were less likely to have a stroke or MI than non‐users from 2011 through 2016.

Conclusion

Current study findings suggest that APM use is likely associated with a heightened probability of death among long‐term NH residents, which is consistent with previous literature. The finding that APM use is negatively associated with stroke and MI is inconsistent with prevailing understandings that APM use would lead to higher risks of these outcomes. The shift in the likelihood of death in 2016, and negative associations with stroke and MI warrant further investigation as to the possible contributing factors of death and cardiovascular events in NH residents on antipsychotic medications.
Online abridged behavioral neurology training for specialists in Latin America: EduBrainLat
Authors: Escudero Stefanie Danielle Pina , Franco Teresita Ramos , Archila Oscar Robles , Renteria Miguel E. , Ibanez Agustin , Slachevsky Andrea , Yokoyama Jennifer S.
Published: December 2023

Background

Currently, dementia training is only offered in a few large medical centers in a handful of Latin America ́s biggest cities. Reduced access and the heterogeneous quality of dementia education for clinicians hinder the diagnosis and treatment of neurodegeneration in Latin America.

Aim

This project aims to fill the education gaps and increase specialist´s diagnostic and therapeutic skills in neurodegenerative diseases through an interactive online Spanish‐language pilot program tailored for Latin America.

Methods

We put together a 108 hour curriculum formed by four modules: basic aspects of behavioral neurology, neurobehavioral and neuropsychiatric syndromes,treatment, and other aspects of neurodegenerative diseases. It was delivered by 35 brain health experts and reviewers that coolaborate with the Global Brain Health Institute in at the University of California, San Francisco to a pilot group formed by 35 geriatricians, neurologists and psychiatrists from six Latin American Countries (Peru, Mexico, Chile, Colombia, Ecuador, and Venezuela). An initial and final evaluations were performed with the Spanish‐dementia knowledge assessment scale (Carnes et al, 2021), the Frontotemporal Dementia Knowledge Scale (Magrath et al 2021) and clinical cases. In addition, short evaluations submitted by professor were answered before and after each class. Separately, we requested feedback from the students about the course.

Results

Comparing the overall scores between the initial and final evaluation, there was a 7% increase in the Geriatrician´s score, 4% in Neurologists´ score and 9% in the Psychiatrist’s score. The greatest increase was in Frontotemporal Dementia Knowledge. (Figures 1 and 2). The topics with the worse baseline scores were clinical evaluation attention, executive functions, and atypical Alzheimer´s Disease. We observed an increase in knowledge after every class. Most of the feedback brought to light that there were many topics that specialists had not had the opportunity to learn before such as sleep in neurodegeneration, traumatic encephalopathy, and atypical dementia syndromes.

Conclusion

It is imperative to find ways of bringing education to regions where dementia prevalence is increasing, and specialist do not have enough knowledge. Online programs are feasible and effective strategies to close educational gaps.