bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequencing cortical microstructural changes along the Alzheimer’s disease continuum
Authors: Nir Talia M , Javid Shayan , Villalon‐Reina Julio E , Thomopoulos Sophia I , Salminen Lauren , Thompson Paul M , Jahanshad Neda
Published: December 2023

Background

Microstructural abnormalities likely precede macrostructural changes in the Alzheimer’s disease (AD) cascade. Diffusion MRI (dMRI) is sensitive to microstructural properties of brain tissue but few studies have evaluated dMRI measures in cortical gray matter where many early AD histopathological changes occur. Event‐based modeling (EBM) is a data‐driven approach for probabilistically sequencing cross‐sectional biomarkers in the order that they likely become abnormal. Here, we used EBM to examine the sequence of changes in cortical dMRI measures relative to more widely used amyloid, tau, brain volume, and cognitive biomarkers in two independent AD studies.

Method

T1w, dMRI, and amyloid‐PET (FBB/FBP) data were analyzed in 461 ADNI3 participants and 188 OASIS3 participants (Figure 1A). Some ADNI3 participants also had tau‐PET (AV‐1451) and CSF pTAU‐181 and Aβ1‐42 data. In addition to DTI, novel single‐shell adaptations of multi‐shell models, NODDI‐DTI and MAP‐AMURA, were fit to the dMRI data. 10 mean cortical dMRI measures were extracted using FreeSurfer parcellated T1w‐images (Figure 1B). T1w cortical and hippocampal volumes were also extracted, and all MRI measures harmonized using ComBat. Mean cortical amyloid‐PET SUVRs were converted to centiloids. Associations between each of 17 biomarkers (Figure 1C) and cognitive impairment (CI –MCI+Dementia– vs CN) were tested in ADNI3. Significant biomarkers were included in an ADNI3 EBM to determine event ordering.The EBM was validated in OASIS3 and used to classify clinical diagnosis.

Result

All biomarkers except DTI FA showed significant differences between CN and CI ADNI3 participants (Figure 2A). ADNI3 EBM confirmed existing AD models: CSF amyloid abnormalities preceded PET, followed by CSF pTau, while cognitive and volumetric abnormalities occurred at later stages. Changes in all dMRI biomarkers preceded CSF or PET Tau, cognitive, and volumetric abnormalities (Figure 2B). Estimated disease stages in ADNI3 distinguish dementia from CN with an AUC = 0.96 (10‐fold cross‐validation). OASIS3 disease stages, estimated using ADNI3 biomarker distributions excluding CSF measures and tau‐PET, classified diagnosis with an AUC = 0.85 (Figure 3).

Conclusion

Cortical microstructural measure abnormalities, including greater diffusivity, lower restriction and lower dispersion potentially due to neurite loss and lower dendritic arborization complexity, may precede those detectable with conventional T1w biomarkers.
Using Semi‐supervised Variational Autoencoder and Acute fMRI Changes to Predict Antidepressant Treatment Responses Among Older Adults with Depression
Authors: Wang Linghai , Lee Jihui , Mizuno Akiko , Wilson James D , Lamb Shannon , Gerlach Andrew , Wu Minjie , Aizenstein Howard J ,   Geriatric Psychiatry Neuroimaging
Published: December 2023

Background

Late‐life depression (LLD) has been consistently linked to an increased risk of dementia, with studies showing that older adults with depression have a two fold risk of developing dementia. Dementia has proven difficult to treat, yet depression has several viable treatment options, particularly antidepressants. However, the efficacy of antidepressants in LLD has proven modest as antidepressants typically achieve around a 50% remission rate and only after 4‐6 weeks of treatment. In this analysis, we investigate the effectiveness of combining fMRI data with deep learning for predicting antidepressant driven depression remission.

Method

In two LLD studies using venlafaxine (n = 51) and escitalopram or levomilnacipran (n = 29), resting state fMRI scans were collected at baseline and at day one of antidepressants. Region‐to‐region functional connectivity (FC) was calculated for each scan using the Shen50 atlas, and differential connectivity (DC) was calculated to compare baseline and day 1 FC. Clinical factors including age, race, education and cumulative illness burden and DC were used as input to a semi‐supervised variational autoencoder (VAE) to predict remission status at treatment end (Fig.1). Remission was encoded as a binary variable, defined as a final MADRS score of 10 or less after 12 weeks of treatment and subject to blinded clinician assessment. Monte Carlo cross‐validation over 30 repetitions was used to evaluate the model performance with 10% of the data held out for testing. The VAE was compared to a random forest classifier with the same cross validation methods using the area under the curve (AUC).

Result

The VAE achieved an average mean‐squared error of .005 and AUC of 0.87 on a held out test set during cross validation. The VAE outperformed the random forest classifier which achieved an average AUC of 0.68.

Conclusion

The VAE using DC in fMRI scans between baseline and day one shows the potential in accurately identifying responders to antidepressants as early as in one day. Our results show that acute changes to functional networks triggered by a single dose of antidepressants are promising as a means to improve patient outcomes. These results can contribute to optimizing treatment for LLD in the future.
Microglial activation interacts with amyloid‐β to drive longitudinal tau tangle accumulation and cognitive decline
Authors: Povala Guilherme , Bellaver Bruna , Lussier Firoza Z , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Aguzzoli Cristiano Schaffer , Zalzale Hussein , Soares Carolina , Abbas Sarah , Rohden Francieli , Tissot Cécile , Therriault Joseph , Bezgin Gleb , Servaes Stijn , Benedet Andrea Lessa , Stevenson Jenna , Rahmouni Nesrine , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Karikari Thomas K , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick Ali
Published: December 2023

Background

Activation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate whether baseline microglial activation impacts tau tangle deposition and cognitive decline in individuals across the AD continuum.

Method

We assessed 92 individuals from the TRIAD cohort (57 cognitively unimpaired and 35 cognitively impaired) with available baseline [11C]PBR28‐PET, a measure of microglial activation and [18F]NAV4694 Aβ‐PET, and longitudinal [18F]MK6240 Tau‐PET (mean follow‐up time = 1.93 years) and Mini‐Mental State Exam (MMSE) (mean follow‐up time = 1.84 years). We performed voxel‐wise associations using linear regressions accounting for age and sex and adjusted for multiple comparisons using Random Field Theory (RFT) (p < 0.05). We used the cuneus and superior temporal cortex as a composite ROI for [11C]PBR28‐PET and Aβ‐PET since these regions showed a higher association with longitudinal tau accumulation in the temporal meta‐ROI.

Result

Voxel‐wise analysis showed that baseline levels of [11C]PBR28‐PET alone are not sufficient to predict longitudinal tau tangle accumulation (Fig. 1a). However, the interaction between [11C]PBR28‐PET levels and Aβ burden predicted an increased accumulation of tau tangle, mainly in the cuneus, inferior frontal and lateral occipital regions (Fig. 1b).Individuals with higher baseline [11C]PBR28‐PET and Aβ‐PET levels present higher rates of longitudinal tau accumulation in the temporal meta‐ROI (β = 0.36, t = 3.46, p = 0.0009; Fig. 1c). Similarly, while [11C]PBR28‐PET levels alone did not correlate with longitudinal changes in MMSE score (β = ‐0.17, t = ‐1.69, p = 0.10), a significant interaction between [11C]PBR28‐PET and Aβ‐PET levels on MMSE annual decline was observed (β = ‐0.24, t = ‐2.25, p = 0.028; Fig. 1d).

Conclusion

We found that baseline levels of microglial activation was associated with longitudinal tau tangle accumulation and cognitive decline in individuals across the AD continuum in the presence of Aβ burden. Our results indicate that microglial activation might act potentiating the deleterious effects of Aβ on forthcoming tau tangle deposition.
The moderating effect of APOE E4 on the association of plasma biomarkers with markers of cognition and brain health in Alzheimer’s disease
Authors: Sanchez Erlan , Wilkinson Tim , Coughlan Gillian T , Baril Andree‐Ann , Binns Malcolm , Bartha Robert , Symons Sean , Hegele Robert , McLaughlin Paula , Kwan Donna , Black Sandra E. , Freedman Morris , Kvartsberg Hlin , Zetterberg Henrik , Munoz Douglas , Masellis Mario
Published: December 2023

Background

Due to low success rates in clinical trials for Alzheimer’s disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non‐carriers.

Method

Patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using Simoa assays. Composite cognitive domain scores (attention & working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post‐hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed.

Result

The APOE E4 allele moderated the association of GFAP, NfL and p‐tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p‐tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p‐tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p‐tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers.

Conclusion

Plasma biomarkers, especially GFAP and p‐tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non‐carriers in AD.
Examining the Driving Habits of Older Canadians as Captured by the COMPASS‐ND Study
Authors: Saryazdi Raheleh , Yung Stephanie , Pereira April , Naglie Gary , Rapoport Mark J. , Stasiulis Elaine , Campos Jennifer L.
Published: December 2023

Background

Driving is associated with a sense of autonomy and good quality of life in older adults. However, older adults often change their driving habits, such as regulating how often, how far, and under what conditions (e.g., time of day, weather) they drive, in part due to changes in cognition. Our study describes data from the first large‐scale Canadian cohort study to investigate differences in driving habits across cognitive groups, including cognitively healthy older adults (control), Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and Alzheimer’s Disease (AD).

Method

We analyzed data from the Comprehensive Assessment of Neurodegeneration and Dementia study (COMPASS‐ND, Chertkow et al., 2019), a population‐based study of Canadians with various cognitive and functional abilities (May 2021 Data Release). The final sample analyzed included 317 participants (55% Females, Meanage = ∼72). We report the responses for the following driving‐related questions: licensing status (no longer have license, drive with or without restrictions), driving frequency, driving distance, and driving restrictions (e.g., bad weather).

Result

Most participants across all groups reported that they have a driver’s license without restrictions, including the AD group (AD: ∼61%, remaining groups: >90%). The following analyses only included current drivers. In terms of the frequency of driving and the distance travelled, as expected, the AD group drove the least often and the shortest distances. The most frequent restriction types selected by all groups were bad weather and nighttime driving. The number of restriction types increased with the severity of cognitive decline. Interestingly, driving restrictions reported by the SCD group more closely approximated the cognitively impaired groups (MCI and AD) than the control group.

Conclusion

Although many of the AD group participants still had a license, they also reported the greatest number of driving restrictions. Further, the SCD group and MCI group were quite similar in their responses for several items, indicating that even SCD may be associated with differences in driving habits. Implications of driving‐related limitations include reduced independence, socialization, participation, and access to resources (e.g., medical care, groceries).
Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum
Authors: Sibahi Ahmad , Rosa‐Neto Pedro , Tardif Christine L , Cassidy Clifford
Published: December 2023

Background

Noradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.

Method

This study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.

Result

Consistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p<0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p<0.0001; MMSE score: t(254) = 4.30, p<0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (<27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).

Conclusion

While cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.
Effect of SUVR reference region selection on sampled iterative local approximation estimates of amyloid onset age
Authors: Teague Jordan P , De Chavez Elena Ruiz , Irizarry‐Pagan Erica E , Cody Karly Alex , Asthana Sanjay , Johnson Sterling C , Christian Bradley T. , Langhough Rebecca E , Betthauser Tobey J
Published: December 2023

Background

Amyloid PET imaging quantifies Aβ plaques informing longitudinal modeling methods such as sampled iterative local approximation (SILA) that provide individualized estimated amyloid onset age (EAOA). EAOA is defined as the transition to abnormal Aβ accumulation that occurs in Alzheimer’s disease. This work investigates the effect of SUVR reference region selection on EAOA by comparing DVR‐trained versus SUVR‐trained SILA models with three different SUVR reference regions.

Method

N = 585 participants (mean (SD) baseline age = 66.40 (7.89) years, 512 unimpaired, 44 MCI, 28 dementia, 1 unknown) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center underwent T1‐weighted MRI and dynamic 11C‐Pittsburgh Compound B (PiB) amyloid PET imaging (0‐70 minutes after bolus injection). Reconstructed dynamic PET time series were processed and quantified using MR‐guided imaging pipelines optimized for DVR (Logan, k2’ = 0.149 min−1, cerebellum gray matter (CBLM‐GM) reference region) and SUVR (50‐70 min frames) quantification with CBLM‐GM, whole cerebellum (WHOLE‐CBLM), or subcortical white matter (WM) as a reference region. Mean cortical PiB DVR and SUVR were each calculated by averaging across eight bilateral ROIs. Group‐based trajectory modeling was applied to longitudinal DVR data to establish an amyloid positivity (A+) threshold (DVR>1.14; equivalent to 14 centiloids). LME was used to define the relationship between DVR and SUVR and translate the DVR threshold to SUVR (SUVRCBLM GM>1.28; SUVRWHOLE CBLM>1.07; SUVRWM>0.68). Within‐person paired differences between EAOADVR and EAOASUVR_REFERENCE_REGION are reported as (mean; [95% CI]).

Result

EAOA derived from DVR and SUVR were compared for n = 198 (34%) DVR A+ participants. Amyloid vs. age data are shown for each quantification approach in Figure 1. EAOASUVR‐WHOLE‐CBLM (‐1.29 years; [‐1.51, ‐1.08]) had the highest agreement with EAOADVR compared to EAOASUVR‐CBLM‐GM (‐1.44 years; [‐1.75, ‐1.12]) and EAOASUVR‐WM (‐0.67 years; [‐2.13, 0.79]; Figure 2). EAOA variability was highest for DVR>1.8 where fewer longitudinal observations were available for model training.

Conclusion

SUVR with whole cerebellum as a reference region resulted in the smallest difference in EAOA compared to DVR from the SILA model. Future work is ongoing to define SUVR thresholds that will optimize agreement with DVR‐trained EAOA results for harmonization of temporal estimates.
Pathologic Features of Asymptomatic Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy Neuropathologic Change (LATE‐NC)
Authors: Culhane Jessica E. , Mock Charles , Chan Kwun Chuen Gary , Chen Yen‐Chi , Kukull Walter A.
Published: December 2023

Background

LATE‐NC is a newly‐defined TDP‐43 proteinopathy that is common in older adults and associated with amnestic dementia syndrome. To our knowledge, no prior study has studied individuals resilient to LATE‐NC (participants with Stage 2 or 3 LATE‐NC but no cognitive impairment at autopsy). The extensive autopsy dataset at the National Alzheimer’s Coordinator Center (NACC) uniquely positions us to examine these rare individuals. To determine if asymptomatic participants have lower levels of other neuropathologic diseases, we compared neuropathologic features against participants with clinical dementia.

Method

We included autopsied participants from NACC’s Uniform Data Set whose last visit was within two years of death or had clinical dementia at their last visit. Participants were excluded if they had rare neuropathologic diseases or were not evaluated for each neuropathologic feature. For asymptomatic (normal cognition, 75+ years old, stage 2 or 3 LATE‐NC) individuals, we calculated the odds of having non‐LATE pathologic features against a control group (stage 2 or 3 LATE‐NC, clinical dementia), adjusting for age at death, sex, education, and presence of APOE e4 allele(s). Features included Alzheimer’s pathology (amyloid plaques and neurofibrillary tangles) vascular pathology (number of infarcts and microinfarcts; severity of arteriosclerosis, atherosclerosis, and cerebral amyloid angiopathy), and Lewy body disease (LBD) staging.

Result

Of participants who met inclusion criteria, 20 were asymptomatic and 505 were controls. In unadjusted analyses, asymptomatic participants had lower severity of amyloid plaques, tau tangles, LBD, microinfarcts, and arteriosclerosis, and were less likely to have an APOE e4 allele. In adjusted logistic regression analysis, associations remained only for tau tangles, LBD, and APOE. Interestingly, we found no association of asymptomatic LATE‐NC with amyloid plaques (Thal phase or CERAD score).

Conclusion

Resilience to LATE‐NC is associated with lower odds of other neuropathologic disease, including neurofibrillary tangles and Lewy bodies. This supports prior research indicating an interactive effect of multiple neuropathologic diseases on risk of dementia. Severity of amyloid plaques was not associated with risk of dementia in participants with LATE‐NC, indicating that amyloid‐reducing therapies may not be an effective way to prevent LATE symptoms.
Association of birth weight with incident dementia: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study
Authors: Emanuel Olivia M , Lee Mark , Lutsey Pamela L. , Sullivan Kevin J , Groechel Renee C. , Mosley Thomas H. , Schneider Andrea LC , Wong Dean F. , Gottesman Rebecca F.
Published: December 2023

Background

Early life factors, such as birth weight (BW), may have long‐term health consequences, but the importance of these factors in dementia risk is poorly understood. Our objective was to prospectively examine the association of BW with dementia incidence over mid‐ to late‐adulthood in the ARIC study. We hypothesized that participants who report lower BW experience more incident dementia than participants who report normal BW, and this association may differ by race.

Method

10,789 participants who were dementia‐free at ARIC baseline (Visit 1: 1987‐1989; ages 45‐64) and followed through 2019 were included. Participants were asked their BW through standard interviews at Visit 4 (1996‐1998), but if unable to recall, they selected their BW category: low (<5.5 lbs.), medium (normal) (5.5‐9.0 lbs.), or high (>9.0 lbs.), and to identify if they were premature (yes/no). Adjudicated dementia cases from baseline through 2019 were classified using in‐person cognitive evaluations, informant interviews, and phone assessments as well as hospitalization codes and death certificate codes. The associations between having high or low (vs medium) BW and dementia, or premature birth status and dementia were investigated using Cox proportional hazards models, with testing for interaction by race.

Result

Our overall population was 54 yo at baseline, 56% female, and 20% Black; 2,255 dementia cases were identified over a median of 28.2 years. Participants who reported a low BW had 1.2 times (95% CI 1.02, 1.41) increased risk of incident dementia compared to those with medium BW in demographic‐ and APOE‐adjusted models (Table 1). This association was no longer significant when the model additionally adjusted for vascular risk factors. The risk for dementia was not increased among participants who reported having been born premature (vs not premature). When stratified by race, the risk of incident dementia was elevated in Black participants reporting high (vs medium) BW, but not in White participants reporting high BW (p‐interaction = 0.006) (Table 2).

Conclusion

In this cohort, low BW was associated with risk of dementia in minimally adjusted models. The association was attenuated after accounting for vascular risk factors. High BW was associated with risk of dementia in Black participants only.
INCREASED CATALASE ACTIVITY IN AGING ADULTS WITH DOWN SYNDROME: ASSOCIATIONS WITH AGE AND COGNITIVE DECLINE
Authors: Sarno Tamires Alves , Cordeiro Augusto Magno Tranquezi , Pereira Cícero Augusto Costa , Talib Leda Leme , Forlenza Orestes Vicente
Published: December 2023

Background

The aging process in Down syndrome (DS) is associated with a high prevalence of dementia, which is regarded as a variant form of early‐onset Alzheimer’s disease (AD). In addition to the central role played by amyloid pathology, DS‐dementia (DS‐D) may also be related to abnormal regulation of oxidative stress. The copper/zinc‐dependent superoxide dismutase (SOD1) gene is also located on chromosome 21, and studies have suggested an association of SOD1 overexpression with disrupted redox homeostasis. We hypothesize that such abnormalities may be further related to cognitive decline in DS.

Method

30 aging adults with DS were enrolled to the study, of whom 14 were cognitively stable (DS‐S) and 16 had evidence of cognitive decline (DS‐D). Two comparison groups were constituted with euploid volunteers, i.e., 30 age‐matched, cognitively healthy subjects (euploid controls, EU‐C); and 60 MCI and AD patients (EU‐MCI‐AD). We used an enzymatic assay to determine catalase activity.

Result

As compared to euploid controls, catalase activity was increased in DS irrespective of the presence of cognitive decline (p<0.004). This finding was also observed when the DS group was stratified according to the presence of cognitive decline (EU‐C vs. DS‐S, p<0.001; EU‐C vs. DS‐D, p<0.01). Catalase activity was also increased among cognitively stable DS as compared to MCI‐AD (DS‐S vs. EU‐MCI‐AD, p<0.027).

When the DS group was stratified by age (18‐34y, 35‐49y, and ≥ 50y), catalase activity was found to be increased in younger and middle‐aged DS‐S as compared to EU‐C (18‐34y, p<0.01; 35‐49y, p<0.01) and in middle‐aged DS‐S as compared to SD‐D (35‐49y: p< 0.03).

Conclusion

Our preliminary findings suggest a systemic pro‐oxidant status in DS, evidenced by the increased catalase activity, presumably as a physiological compensation for redox imbalance due to the upregulation of SOD1 (data not shown). Furthermore, antioxidant defense functions decline with aging in the DS carrying. Thus, catalase could be a predictive biomarker candidate for AD.
The Built Environment’s Role in Supporting Dementia Inclusive Communities: A Case Study of Canterbury‐Bankstown City
Authors: Karamacoska Diana , Shatnawi Eman , Caballero Gabriela , Woodward Jeannette , Vu Thi Hang , Pham Ho Trong Nhan , Morrison Nicky , Siette Joyce , Steiner‐Lim Genevieve Z. , DiGiacomo Michelle , Dadich Ann ,   Canterbury‐Bankstown Dementia Alliance
Published: December 2023

Background

Inclusive and enabling cities are fundamental to the wellbeing of people impacted by dementia. How we implement these ideals in multicultural communities through the built environment remains understudied. The experience of place must be considered in the context of dementia‐friendly community (DFC) models to fully enable people experiencing dementia to remain autonomous, integrated, and connected. This study aimed to explore how diverse individuals with dementia perceive the built environment and its impacts on everyday activities using a mixed methods approach.

Method

This study was set in Canterbury‐Bankstown, New South Wales, Australia where a high proportion of people impacted by dementia speak English, Arabic, and/or Vietnamese. Seventeen people experiencing dementia, their care partners, and former carers (English: n = 7; Arabic: n = 5; Vietnamese: n = 5) were recruited for a semi‐structured interview, and two of these dyads (English: n = 1; Vietnamese n = 1) audited a local shopping centre and hospital using the DFC‐environmental assessment tool (DFC‐EAT). Interviews and audits were conducted in‐language with bilingual researchers, who then transcribed the data into English for analysis. Similarities and differences were identified across the interview transcripts and audit data to identify issues with the existing built environment and improvement opportunities.

Result

We found that participants would limit or avoid going outdoors for everyday activities because of safety concerns (especially when using paths and carparks). Furthermore, overwhelming indoor experiences were characterised by unfamiliar designs and fittings (particularly with bathroom facilities), unsupported movement and way‐finding due to excessive or insufficient signage, poor lighting, and high noise. Participants recommended greater access to door‐to‐door transport that caters to people experiencing dementia, establishing quiet resting areas, and improving navigation through signage that uses standardised symbols (e.g., for toilet facilities).

Conclusion

People experiencing dementia and carers reported an array of issues concerning built environment design and accessibility features that excluded them from everyday activities. These findings were translated into an implementation plan that informed the City of Canterbury‐Bankstown Council’s community planning efforts and the shopping centre’s facility operations. Critical areas for improvement in the built environment would benefit from co‐design practices that are inclusive and representative of the community.
Biobanking best practices for research, Banner Sun Health Research Institute Brain and Body Donation Program standards and journey
Authors: Serrano Geidy E
Published: December 2023

The Arizona Study of Aging and Neurodegenerative Disease (AZSAND)/Brain and Body Donation Program (BBDP) is a unique clinicopathological study of aging and neurodegenerative disease based in Sun City, AZ since 1987. The BBDP has made rapid autopsy a priority, with a constitutive 24‐7 rapid autopsy team and a 3.0‐hour median postmortem interval for the entire collection. Tissue quality is correspondingly high, with a median RNA Integrity Number (RIN) for frozen brain tissue of 8.9. The current holdings include fixed and frozen brain and body tissue, as well as biofluids from more than 850 Alzheimer’s Disease (AD) cases, 250 Parkinson’s Disease (PD) cases and more than 350 elderly control subjects. The program supports and leads national and international research focused on AD, AD related dementias and other debilitating neurodegenerative diseases. It provides basic scientists with de‐identified annual comprehensive standardized cognitive, motor, and non‐motor assessments data and neuropathologically characterized human samples that are suitable for the elucidation of the molecular mechanisms of disease and novel therapeutic targets. The BBDP is committed to distributing human samples and accompanying clinicopathological data to as many researchers as possible. All collected data are available to researchers through the program’s website https://www.brainandbodydonationregistration.org/ and personalized consultations.
Neurophysiological changes associated with plasma p‐tau represent functional effects of amyloid accumulation and are modulated by APOE.
Authors: Ranasinghe Kamalini G , Rojas Julio C. , Casaletto Kaitlin B. , Kudo Kiwamu , Syed Faatimah , La Joie Renaud , Chan Brandon , Lago Argentina Lario , Miller Bruce L , Vossel Keith , Kramer Joel H. , Boxer Adam L. , Rankin Katherine P , Rabinovici Gil D. , Nagarajan Srikantan S
Published: December 2023

Background

Alzheimer disease (AD) is defined by the presence of cerebral amyloid‐β plaques and tau neurofibrillary tangles (NFT). Neurophysiological manifestations which depict the functional changes of neurons and circuits, demonstrate that amyloid‐β and tau have distinct effects—high cerebral amyloid‐β burden is associated with increased neural oscillatory activity while high tau burden with decreased activity. With the recent proliferation of fluid biomarkers, plasma p‐tau181 is known to reflect accumulation of amyloid‐β as well as tau, detected from molecular imaging and neuropathological analyses. It remains unknown whether the neurophysiological consequences of soluble p‐tau reflects the effects of amyloid‐β or those of NFT.

Method

We used multimodal imaging combining magnetoencephalography (MEG) to cross‐sectionally study the spectral signatures and positron emission tomography with Aβ binding tracers to define the global amyloid burden in early‐stage neuropathological spectrum including Aβ+ cognitively‐unimpaired (CU, n = 9), Aβ+ mild‐cognitive‐impairment (MCI, n = 20), and Aβ‐negative CU controls (n = 45). Plasma p‐tau181 and neurofilament light (NFL) were measured with Simoa. Using statistical mixed models we examined the associations of neural oscillatory signatures with plasma p‐tau181 and NFL.

Result

The characteristic oscillatory signature of increased delta‐theta and reduced alpha spectrum were detectable even in the earliest stages of global amyloid accumulation (Aβ+CU vs. Aβ‐CU; Fig.1). Increased p‐tau181 was associated with increased spectral signatures across the frequency spectrum in Aβ+ individuals (Fig.2). These positive correlations were more robust within delta‐theta (2‐7Hz) than alpha (8‐12 Hz) spectrum. Plasma NFL in Aβ+ individuals, in contrast, was associated with reduced spectral signatures. We also found APOE‐ɛ4 carriers have greater degree of neurodegeneration which modulated the associations between p‐tau181 and neural oscillations (Fig.3).

Conclusion

Previous neurophysiological studies have demonstrated that Aβ accumulation is associated with increased oscillatory activity while tau accumulation is associated with reduced oscillatory activity. Positive correlations of p‐tau181 across the spectrum is therefore consistent with the effects of Aβ accumulation and not with tau accumulation. Plasm NFL may represent early effects of neurodegeneration. Collectively our findings indicate that p‐tau181 reflects earliest functional effects of Aβ rather than tau and have implications for the interpretation of plasma p‐tau along the AT(N) stages.
Applying the Boot Camp Translation Method to Increase Alzheimer’s Disease Awareness in the Houston Hispanic/Latino Community
Authors: Arroyo‐Miranda Mirna L , Martinez Michelle N
Published: December 2023

Background

Despite increased risk for Alzheimer’s disease and related dementias (ADRD), Hispanics/Latinos (H/Ls) continue to be underrepresented in ADRD research. H/Ls comprise over 40% of the population in the Houston, Texas, metropolitan area. We engaged Houston H/L middle‐ and older‐age community members through a “Boot Camp Translation” (BCT), a community engaged strategy, to co‐create culturally‐responsive materials on ADRD awareness and risk reduction.

Method

Twenty ADRD stakeholder organizations yielded 12 participants 35 y/o and older (Median age: 50 y/o). Participants met in three, 4‐hour virtual sessions and several phone conferences from February to June 2021. After an informative kick‐off session on ADRD clinical manifestations, epidemiology and risk reduction, participants answered these questions throughout the process: 1) main message(s) on AD for the Houston H/L community, 2) targeted audience, and 3) best method(s) to convey the message. After the process, BCT participants were invited to become part of a Community Action Board (CAB).

Result

Nine adults completed the BCT process. Compared to baseline, participants demonstrated improved subjective understanding and objective knowledge of ADRD at the end of the process. Local messaging centered around brain health to reduce AD stigma, importance of geriatric education for care providers, and self‐care in caregiving. Targeted audiences were the general H/L population across the lifespan, care providers and caregivers. Dissemination strategies focused on family and intergenerational relationships, with imagery and colors reflecting the diversity and vibrancy of the Houston H/L community. Final products included a “telenovela‐style” educational video series, and other graphic/ printed materials. Four of the nine participants remain active in the CAB at one year post BCT.

Conclusion

Boot Camp Translation is an effective way to build community trust, and design culturally relevant AD messaging. Experience was positive overall; participants developed a sense of ownership of the process, and created an atmosphere of cooperation and solidarity.
Neuropathological characterization of PiB binding in postmortem striatum in Down syndrome
Authors: Rouanet Jeremy P. , Shamas Tamara , Ngo Kim Chan , Phelan Brenna , Pascual Jesse R. , Andrews Elizabeth J. , Phelan Michael J. , Ikonomovic Milos D , Head Elizabeth ,   Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS)
Published: December 2023

Background

Amyloid‐beta plaques form in the brain throughout life in people with Down syndrome (DS) and are one of the hallmarks of Alzheimer disease (AD) neuropathology. The regional progression of amyloid buildup in DS is similar to that of late onset AD (LOAD) in the neurotypical population. The development of positron emission tomography (PET) ligands like Pittsburgh Compound B (PiB) has allowed researchers and clinicians to visualize and track amyloid accumulation in the brain throughout life. Using this technology, a unique pattern emerges in people with DS, where the earliest and strongest PiB PET retention is in the striatum, unlike LOAD but similar to autosomal dominant AD. Frontal cortex PiB PET retention is similar in all groups. We used a fluorescent derivative of PiB, cyano‐PiB (CN‐PiB), to investigate PiB labeling postmortem in DS striatum. We hypothesized that striatal CN‐PiB load increases with age and is greater than in the frontal cortex, similar to observations from PiB PET studies of adults with DS.

Method

We conducted CN‐PiB labeling in postmortem striatum and frontal cortex from 44 cases with DS ages ranging from 42 to 70 years (25F/19M, mean PMI 7.4 hours). Whole slide imaging and automated image analysis were used to derive individual plaque‐level information regarding load, size, and distribution of CN‐PiB+ plaques in DS with age.

Result

CN‐PiB labeled plaques in both the striatum and frontal cortex were also positive for amyloid‐beta antibodies targeting epitopes 1‐16, 17‐24, and x‐42. Preliminary data suggest that striatal CN‐PiB load (median = 2.3%) is not higher compared to the frontal cortex in DS (median = 10%). Striatal CN‐PiB load did not change with age from 42 to 70 years, suggesting an early saturation (IQR = 3.5%).

Conclusion

CN‐PiB labeled amyloid‐beta plaque load in the striatum in DS is comparable to conventional neuropathologic analysis and does not differ from frontal cortical load. Other aspects of PiB‐binding or pathologies may contribute to the early and prominent striatal PiB PET retention reported in DS. It will be important in future studies to include younger cases with DS.
Elevated Carotid Pulse Wave Velocity is associated with Cognitive Impairment and Cerebral Amyloid Deposition: A Phase‐Contrast MRI Study
Authors: Tang Jianing , Pahlavian Soroush Heidari , Joe Elizabeth B , Terner Jamie , Braskie Meredith N , Marmarelis Vasilis , Chui Helena C , Yan Lirong
Published: December 2023

Background

Previous studies have indicated that arterial stiffness could play an important role in the AD pathology. Arterial stiffness is typically measured by pulse wave velocity (PWV) from central and peripheral arteries. Recent work has introduced a two‐minute robust MRI method to measure carotid PWV (cPWV) using a single‐slice oblique‐sagittal phase‐contrast MRI(OS PC‐MRI)[Pahlavian SH et al, JCBFM 2021]. This study aims to evaluate cPWV measured by OS PC‐MRI as a sensitive imaging marker of AD by studying the association of cPWV with cognitive performance and amyloid pathology.

Method

Twenty‐three elderly volunteers (13 female, 72.6 ± 7.1 years) participated in the study and underwent cognitive and functional assessments including Clinical Dementia Rating (CDR, n = 23), Mini‐Mental State Exam (MMSE, n = 21), and Montreal Cognitive Assessment (MoCA, n = 23) and F18‐florbetaben amyloid‐PET scans (n = 14). A retrospectively gated single‐slice 2D OS PC‐MRI was performed on each participant at 3T to assess cPWV. The correlations between cPWV vs cognitive measures and cerebral amyloid were calculated across subjects using Pearson or Spearman’s correlation coefficients.

Result

Table 1 lists the demographic and clinical information of participants. cPWV showed significant negative correlations with both MoCA (Figure 1a) and MMSE (Figure 1b) (cPWV vs. MoCA: r = ‐0.57, p = 0.0044; cPWV vs. MMSE: r = ‐0.74, p < 0.001;), and correlations remained significant after controlling for age, gender, years of education (cPWV vs. MoCA:r = ‐0.70, p < 0.001; cPWV vs. MMSE: r = ‐0.75, p < 0.001). Participants were further separated into two groups (CRD = 0: n = 12; CDR> = 0.5: n = 11) based on their CDR scores. cPWV values were significantly higher in the group with CDR> = 0.5 without and with correcting for age, sex, and educational level (p = 0.0019, p = 0.015) (Figure 1c). Individuals who presented with amyloid pathology had higher cPWV compared to the ones without amyloid pathology (p = 0.038) (Figure 2), which indicates cPWV may be closely linked to amyloid pathology in AD.

Conclusion

This study demonstrates that elevated carotid PWV is associated with cognitive impairment and amyloid pathology in elderly adults. Longitudinal studies are necessary to determine whether cPWV contributes to accumulation of amyloid in brain parenchyma or results from deposition of amyloid in cerebral blood vessels.
Association of focal epilepsy in Alzheimer’s disease with tau, amyloid, and neurodegeneration
Authors: Lam Alice D , Jacobs Heidi I.L. , Thibault Emma G. , Mayblyum Danielle V. , Hsieh Stephanie , Pellerin Kyle R , Buss Stephanie S. , Sarkis Rani A , Johnson Keith A. , Sperling Reisa A.
Published: December 2023

Background

Network hyperexcitability has emerged as an important contributor to cognitive dysfunction and clinical progression in Alzheimer’s disease (AD), with work in animal AD models supporting a mechanistic, feed‐forward link between neuronal hyperexcitability and amyloid and tau pathology. Seizures are a quintessential manifestation of network hyperexcitability in AD. AD is associated with a 2‐3‐fold increased risk of developing epilepsy, and epilepsy in AD is most often a focal, unilateral temporal lobe epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then focal unitemporal hyperexcitability in individuals with AD and epilepsy would be associated with increased deposition of tau and/or amyloid within the epileptogenic hemisphere.

Method

We studied eight individuals with early clinical stages of AD who developed focal epilepsy early in the course of AD. All individuals underwent overnight scalp EEG, 3T structural brain MRI, and PET imaging with 11C‐PiB and 18F‐MK‐6240. We performed region‐of‐interest based imaging analyses and calculated asymmetry indices (AI) as: 200 * (Ipsilateral ‐ Contralateral) / (Ipsilateral + Contralateral), where ipsilateral and contralateral are relative to the epileptogenic hemisphere.

Result

Tau deposition was asymmetrically increased within the epileptogenic hemisphere. Individuals with a higher global tau burden showed asymmetrically increased tau in the lateral temporal lobe, medial and lateral parietal lobes, and frontal lobes of the epileptogenic hemisphere, while those with a lower global tau burden demonstrated a highly focal, discrete tau accumulation within the lateral temporal lobe. Amyloid deposition was also increased within the epileptogenic hemisphere, particularly in the lateral temporal, medial and lateral parietal, and frontal regions, though the magnitude of amyloid AI was lower than that of tau AI. We also found increased cortical atrophy in the lateral temporal and lateral parietal regions of the epileptogenic hemisphere.

Conclusion

Our study reveals a spatial association between focal epilepsy and asymmetries in tau and amyloid deposition and cortical atrophy in early clinical stages of AD. While historically, individuals with AD and epilepsy have been excluded from most studies in AD, our findings demonstrate that studying these individuals can provide unique insights on mechanisms that underlie the clinical and pathologic heterogeneity of AD.
Age of dementia onset and death in chronic traumatic encephalopathy
Authors: Ryder Megan H. , Abdolmohammadi Bobak , Daneshvar Daniel H , Martin Brett M , Palmisano Joseph N , Alvarez Victor E. , Huber Bertrand R. , Tripodis Yorghos , Stein Thor D. , Alosco Michael L , McKee Ann C. , Mez Jesse B.
Published: December 2023

Background

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. The clinical presentation of CTE can include cognitive impairment, with progression to dementia. Currently, CTE can only be definitively diagnosed postmortem; most reports of the associated clinical syndrome come from retrospective informant interviews. In this setting, characterizing the clinical course can be biased because donors may have died from causes unrelated to CTE. To minimize this selection pressure and more accurately report average age of dementia and death in CTE, we identified brain donors with high stage CTE who died from neurodegenerative disease.

Method

Donors with RHI exposure from contact sports and/or military service were eligible for the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank. CTE neuropathological diagnosis and staging were assessed using validated criteria. Dementia diagnosis was determined by clinical consensus and dementia onset age was defined as the age that informants first reported functional impairment on a standardized scale of activities of daily living (Functional Activities Questionnaire, FAQ). Causes of death were determined from medical records, death certificate review, and informant interviews. Donors with a neuropathological diagnosis of high stage CTE (III or IV) and a neurodegenerative cause of death were included in the current study.

Result

186 donors met inclusion criteria. Football was the most common type of RHI exposure (172; 92.5%). Mean age of dementia onset was 70.2 (SD = 7.4; range = 48‐93) and the mean age of death was 77.1 (SD = 7.8; range = 54‐97). Mean time from dementia diagnosis to death was 6.9 years (SD = 4.6; range = 0‐24). 136 donors (73.1%) had other comorbid neurodegenerative diseases, including 84 (45.4%) with Alzheimer’s disease, 58 (31.2%) with Lewy body disease, and 28 (15.1%) with frontotemporal lobar degeneration. Compared to donors with CTE and comorbid neurodegenerative diseases, donors with CTE but without comorbid neurodegenerative diseases did not significantly differ in age at dementia onset, age at death, and time from dementia diagnosis to death.

Conclusion

Among brain donors with high stage CTE who died from neurodegenerative disease, approximately 75% had late onset‐dementia (i.e., age of dementia onset >65 years) and died within 10 years of dementia diagnosis.