bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Among Depression, Stress, Resilience, and Alzheimer’s Disease Biomarkers in Older Adults Following a Major Societal Stressor
Authors: Burling Jessa , Mimmack Kayden J. , Gagliardi Geoffroy Pierre , Quiroz Yakeel T. , Marshall Gad A , Vannini Patrizia , Gatchel Jennifer
Published: December 2023

Background

Better predicting depression following a stressor like COVID‐19 would help identify vulnerable individuals who might benefit the most from early intervention. We examined change in depressive symptoms relative to the onset of COVID‐19 and longitudinal trajectories of depressive symptoms post‐pandemic‐onset. As a secondary objective, we examined associations of these changes with stress, resilience, and in vivo AD biomarkers.

Method

Data were analyzed from 101 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study, a longitudinal observational cohort study. Depressive symptoms are assessed annually with the 30‐item Geriatric Depression Scale (GDS), and for these analyses, participants had no/mild self‐reported depression (GDS<11) at the last pre‐COVID examination. GDS‐delta scores were computed using the mean of the post‐COVID‐onset scores subtracted by the last pre‐COVID examination for participants. Levels of resilience (Connor‐Davidson Resilience scale) and stress (Perceived Stress Scale) were assessed within a year after pandemic onset. Cortical amyloid (PiB) and entorhinal (EC) and inferior temporal (IT) tau (FTP) were analyzed using pre‐pandemic acquisition (mean 1.6 years to pandemic onset). We used linear models to predict GDS‐delta and linear mixed effects models to predict GDS trajectory post‐COVID onset from resilience, stress, and the interaction of each with AD biomarkers (PiB and FTP).

Results

GDS‐delta was predicted by resilience (t = ‐4.69, p<0.001) and stress (t = 3.51, p<0.001) such that those with lower resilience and higher stress experienced higher GDS‐delta. EC tau, but not IT tau or cortical amyloid, interacted with stress to predict GDS‐deltas (EC tau*stress: t = 2.04; p = 0.04) indicating that those with higher levels of EC tau and stress experienced higher GDS‐delta. For post‐pandemic‐onset GDS trajectory, no significant longitudinal associations were observed, but there was a marginal interaction between EC‐tau*stress in predicting greater GDS trajectories (t = ‐1.79, p = 0.08).

Conclusion

Results suggest that change in depressive symptoms in elders following a societal stressor is associated with lower resilience and higher stress; this may be exacerbated by concurrent EC tau pathology. Moreover, elevated depressive symptoms in the years following onset of a societal stressor can be partially predicted by increased EC tau and stress, highlighting a vulnerable population who may benefit from preventive interventions throughout a major stressor.
Abeta and Tau impair retromer‐mediated cargo trafficking via distinct mechanisms
Authors: Ye Hui , Arya Vanuli , Shulman Joshua M
Published: December 2023

Background

Evidence from neuronal pathology and experimental models suggest that endolysosomal dysfunction may contribute to Alzheimer’s Disease (AD) pathogenesis, however it is unclear how Aβ and Tau directly affect endolysosomal dynamics, partially due to a lack of reporters. The retromer, including VPS35, VPS26, and VPS29, is a conserved protein complex responsible for recycling proteins within the endolysosomal pathway. Retromer regulates Tau phosphorylation and pathogenic processing of the amyloid precursor protein. Cation‐independent Mannose 6‐phosphate receptor (CIMPR) is a well‐established retromer cargo, with a WLM motif recognized by the retromer for retrieval.

Method

To track retromer‐dependent protein trafficking in vivo, I have cloned the cytoplasmic tail of CIMPR carrying the WLM motif into a pUAST‐attb vector and generated a transgenic fly line (UAS‐CIMPR‐WLM). A transgenic line carrying CIMPR, but having WLM mutated to AAA, has also been developed as a negative control (UAS‐CIMPR‐AAA). I examined the CIMPR reporter in Vps35 and Vps29 mutants, as well as established Drosophila AD models during aging.

Result

The protein level of CIMPR‐WLM was reduced by genetic ablation of Vps35, possibly due to promoted degradation. Expressed in young Vps29 mutant brains, CIMPR‐WLM showed an increased colocalization with a late endosomal/lysosomal marker Arl8, indicating a promoted delivery of retromer cargoes into the lysosome. Further, neuronal expression of CIMPR‐WLM exhibited a punctate distribution, which was abolished when WLM was mutated to AAA. Altogether, my data suggested that CIMPR‐WLM worked as a retromer‐dependent reporter. While the reporter was broadly enriched within neuropil regions in control animals (Elav>CIMPR), neuronally expression of Aβ (Elav> Aβ+CIMPR) led to a striking redistribution of CIMPR, shifting from neuropil to enrichment in soma, and forming large perinuclear puncta. Moreover, the retromer reporter was mislocalized in brains from 1‐day‐old Elav> Aβ animals, and this result did not significantly change with aging. Interestingly, Elav>Tau+CIMPR animals showed no noticeable effects on the distribution of CIMPR‐WLM on day 1, but caused a similar redistribution of CIMPR‐WLM to the perinuclei region at day 30.

Conclusion

The CIMPR‐WLM reporter requires the retromer for proper cellular localization. Our findings are consistent with the notion that Aβ and Tau affect endosomal sorting, but likely via distinct mechanisms.
An accelerated rate of Beta‐amyloid Measured with [C‐11]PiB in Down Syndrome compared to Neurotypical Populations
Authors: McVea Andrew K , DiFilippo Alexandra H , McLachlan Max , Murali Dhanabalan , Zammit Matthew D , Johnson Sterling C , Betthauser Tobey J , Stone Charles K , Tudorascu Dana , Laymon Charles M , Klunk William E , Cohen Ann D. , Handen Benjamin L. , Christian Bradley T.
Published: December 2023

Background

Down syndrome (DS) is characterized by a higher risk and earlier onset of beta‐amyloid (Aβ) plaque accumulation and Alzheimer’s disease (AD). The triplication of chromosome 21 containing the amyloid precursor protein (APP) gene is implicated in this process and in this study we compare the accumulation rates of Aβ between DS and neurotypical (NT) populations quantified by longitudinal [C‐11]PiB imaged at the same site to minimize experimental variation.

Methods

Individuals with three or more [C‐11]PiB scans spanning eleven years our site with at least one Aβ+ (global SUVR>1.40) and Aβ‐ [C‐11]PiB scan were selected. 12 of 74 DS and 15 of 246 NT participants fit these criteria. An identical imaging procedure was conducted for all participants imaged on either an ECAT HR+ or Biograph mCT PET scanner 50‐70 minutes post‐injection. Reconstructed PET images were summed and spatially normalized into template space and converted into 50‐70min SUVR images using a cerebellar grey matter reference region. Global SUVR composed of grey matter regions from the AAL atlas was used as a metric for Aβ deposition. SUVR data were fit against age with a logistic growth curve (f(t) = NS+K/(1+e(‐r(t‐t50)))) to determine Aβ accumulation as subjects transitioned to Aβ+. The rate of accumulation was found using the slope of the curve at Aβ positivity threshold based on the model fit. Our model fixed NS = 1.12, the average baseline SUVR of all Aβ‐ subject scans (n = 491), and K = 1.28, the highest specific binding in any participant.

Results

Plotting [C‐11]PiB SUVR against age provides visual comparisons of cohorts (Fig 1) and transforming the x‐axis to amyloid chronicity (t = 0 at Aβ+) illustrates differences in accumulation rates between groups (Fig 2). The average rate of amyloid accumulation (ΔSUVR/yr) when becoming Aβ+ in the DS cohort is 0.071(0.021) versus 0.043(0.009) for NT (p = 4.31×10−4).

Conclusions

Aβ accumulation rate was higher in the DS cohort compared to NT. This is consistent with the additional APP gene copy in DS, and we observed an accumulation rate 65% faster in this cohort. There was a higher variability in the DS population requiring further investigation towards understanding the influence of genetic and lifestyle factors on Aβ deposition.
Association between military service identified through public data tracing and Alzheimer’s disease neuropathology at autopsy
Authors: Vilen Leigha H , Zuelsdorff Megan , Salamat Shahriar , Pfaff Alexandra , Rissman Robert A , Bendlin Barbara B , Kind Amy J. , Powell W. Ryan
Published: December 2023

Background

Military veterans face increased risk of Alzheimer’s disease and related dementias (ADRD) compared to the general population, but the association between the military exposome and ADRD pathology is poorly understood. Existing biobanks rarely collect military service information, complicating efforts to characterize military risk factors. Public data tracing methods linking the military exposome to existing neuropathological data have the potential to catalyze research on the mechanisms driving brain health disparities.

Method

Subjects were decedents from two Alzheimer’s Disease Research Center brain banks who died between 1986‐2018 and were characterized on neurofibrillary tangle burden (NFT‐B score, n = 1154). Military service was characterized through public data tracing (Figure 1): systematic extractions from public records including obituaries, newspapers, and enlistment records (Figure 2). NFT‐B score, per National Institute of Aging and Alzheimer’s Association guidelines for neuropathologic change, was extracted from the standardized Neuropathology Dataset form or from original autopsy reports. Generalized ordered logistic regression with site‐level clustered standards errors was used to model NFT‐B score, adjusting for age, sex, and year of death.

Result

Public data tracing identified 373 decedents (32% of the sample) with a history of military service. After adjusting for age, sex, and year of death, decedents with a history of military service had a 12% greater odds (OR = 1.12, 95% CI: 1.11–1.13) of a more severe NFT burden compared to those without a history of military service, which was proportional when comparing the odds at each increasing B score level (B score = (1,2, or 3), vs (0), B score = (2,3) vs (0,1) and B score = (3) vs (0,1,2)) (Table 1).

Conclusion

Public data tracing offers a promising way to retrospectively add the military exposome into brain tissue biomarkers research. Military service was associated with more severe neurofibrillary tangle pathology, one of the primary neuropathological features of Alzheimer’s disease. Future research should explore the feasibility and validity of public data tracing for more detailed characterization of military service, such as length and branch of service, involvement in specific conflicts, or exposure to environmental toxins, which may elucidate mechanisms underlying its association with ADRD pathology.
Safety and pharmacokinetics of single ascending doses of TAK‐594/DNL593, a brain‐penetrant progranulin replacement therapy, in healthy volunteers: Interim results from Part A of a Phase 1/2 clinical trial
Authors: Berger Amy Chang , Cohen Isaac , Jafarnejad Mohammad , Chiu Chi‐Lu , Bhalla Akhil , Damo Lorna , Shanbhag Niraj M , Simen Arthur , Lu Hong , Zicha Stephen , Bednar Martin , Troyer Matthew D. , Ho Carole , Tsai Richard
Published: December 2023

Background

Loss of function mutations in the granulin (GRN) gene, which encodes the lysosomal protein progranulin (PGRN), account for 5‐10% of frontotemporal dementia (FTD‐GRN). Deficiency of PGRN in neurons and microglia results in lysosomal dysfunction, which in turn leads to neuroinflammation and neurodegeneration. TAK‐594/DNL593 is a novel PGRN replacement therapy that has been engineered to deliver PGRN across the blood brain barrier (BBB) and into lysosomes. In PGRN‐deficient mice, TAK‐594/DNL593 corrected age‐dependent elevations of disease biomarkers that are also observed in patients with FTD‐GRN (Logan et al. 2021).

Methods

Study DNLI‐H‐0001 (NCT05262023) is a Phase 1/2 randomized, placebo‐controlled study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TAK‐594/DNL593 in 3‐parts. Part A evaluated single ascending doses of TAK‐594/DNL593 in healthy participants (randomized 6:2 drug to placebo). Part B, currently enrolling, will evaluate multiple doses of TAK‐594/DNL593 for 6 months in participants with FTD‐GRN (randomized 2:1 drug to placebo) and will be followed by Part C, an 18‐month open‐label extension.

Results

Part A enrolled 35 healthy participants. Single doses of intravenously administered TAK‐594/DNL593 were generally safe and well tolerated. There were no discontinuations related to drug. The majority of treatment emergent adverse events (TEAEs) were mild to moderate, and no infusion related reactions were observed. TAK‐594/DNL593 serum exposures increased in a greater than dose‐proportional manner with low to moderate variability in PK parameters. Cerebrospinal fluid (CSF) total PGRN concentration, sampled 24 hours post‐infusion, also increased dose dependently above baseline levels.

Conclusion

Single dose safety and PK of TAK‐594/DNL593 in healthy participants support initiation of the multiple dose study in participants with FTD‐GRN. The dose‐dependent increase in CSF PGRN is consistent with delivery of TAK‐594/DNL593 across the BBB and supports the potential of TAK‐594/DNL593 to treat FTD‐GRN.

References

Logan, Todd, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, et al. 2021. “Rescue of a Lysosomal Storage Disorder Caused by Grn Loss of Function with a Brain Penetrant Progranulin Biologic.” Cell 184 (18): 4651‐4668.e25. https://doi.org/10.1016/j.cell.2021.08.002.
Practice effects on cognitive testing and amyloid status
Authors: Duff Kevin , Dixon Ava , Embree Lindsay , Hoffman John M.
Published: December 2023

Background

Practice effects are improvements in cognitive test scores due to repeated exposure to the same or similar test materials. Reduced practice effects have been reported in older adults with impaired cognition (e.g., Mild Cognitive Impairment, Alzheimer’s disease). However, to our knowledge, practice effects have not been examined in those who are classified as being amyloid positive or negative. Such information could be useful for screening individuals for clinical trials in these conditions.

Method

One hundred fifty‐five older adults with either intact (n = 63) or impaired (n = 92) cognition completed a brief battery of neuropsychological tests twice across one week and an amyloid positron emission tomography (PET) scan. Based on FDA approved prescribing and visual interpretation information, the amyloid PET scan was classified as positive (n = 95) or negative (n = 60). Practice effects across one week were quantified using regression‐based change scores from an independent sample.

Result

On a composite of seven neuropsychological test scores, those who were classified as amyloid positive showed significantly smaller practice effects than those classified as amyloid negative. Similar results were seen on practice effects for 6 of the 7 individuals tests, with smaller practice effects being seen in the amyloid positive participants.

Conclusion

Practice effects across one week were related to amyloid status in this sample of older adults. As such, these short‐term changes in scores on cognitive tests may be useful for enriching samples for future clinical trials in Alzheimer’s disease.
Brain Health PRO: An Interactive, Online, Educational Program for Dementia
Authors: Belleville Sylvie , Chertkow Howard , Feldman Howard H. , Nygaard Haakon B. , Montero‐Odasso Manuel , Anderson Nicole D. , Bherer Louis , Ferland Guylaine , Camicioli Richard , Chan Senny , Cuesta Marc , Dwosh Emily , Fiocco Alexandra J , Gilbert Brigitte , Itzhak Inbal , Jarrett Pamela , Laurin Danielle , Liu‐Ambrose Teresa , Lupo Jody‐Lynn , McGibbon Chris A , Middleton Laura E , Murphy Kelly J , Phillips Natalie , Pichora‐Fuller M. Kathleen , Revta Carolyn , Savundranayagam Marie Y. , Sexton Andrew , Smith Eric E. , Speechley Mark R. , Trigui Amal , Wittich Walter ,   CCNA‐CAN‐THUMBS UP Study Group
Published: December 2023

Background

The Intervention mapping framework was used to plan and develop Brain Health PRO (BHPro), a 45‐week, theory‐ and evidence‐based online educational program co‐created with users in English and French. The goal of the program is to improve dementia literacy, self‐efficacy, and attitude toward dementia and ultimately have a positive impact on the dementia risk profile. A pilot study evaluated usability and acceptability using a shorter version of the online program, which informed changes for a full efficacy trial.

Method

A group of over 100 researchers contributed expert content targeting seven modifiable risk factors (physical activity, nutrition, cognitive engagement, sleep, social and psychological health, vascular health, vision and audition). 181, ten minute chapters were created in total. All chapters were reviewed and edited by the Citizen’s Advisory group, consisting of older adults in the community. Information and recommendations for lifestyle improvement are delivered incrementally through weekly email interactions, and the platform is designed based on e‐learning principles. Participants complete online questionnaires to assess usability (eg: ease of use, ease of navigation, access, complexity), acceptability (eg: whether the program is interesting, whether they would use it again or recommend it) and level of risk at baseline for each of the seven modifiable risk factors.

Result

A pilot study of Brain Health PRO was conducted, including 20 older adults, 13 women and 7 men. They had 16.75 years of education on average and their mean score on Logical Memory Scale II was 10.90. Two focus groups were conducted with a randomly selected group of participants to inform about the usability and acceptability of the program. The focus groups along with user experience questionnaires indicated excellent usability, with all dimensions rated in the positive range. Feedback from the end users were incorporated into the program prior to the main efficacy study.

Conclusion

BHPro was designed out of necessity to pivot in the changing environment brought by COVID‐19. Early data indicate that the BHPro program meets the needs and abilities of older adults in a virtual setting. The platform is easy for older adults to learn and use and is considered relevant.
Synucleinopathy in Alzheimer’s disease: role of the alpha‐synuclein seed amplification assays
Authors: Bellomo Giovanni , Toja Andrea , Ma Yihua , Farris Carly , Chipi Elena , Wojdala Anna , Paoletti Federico Paolini , Gaetani Lorenzo , Chiasserini Davide , Parnetti Lucilla , Concha Luis
Published: December 2023

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most frequent proteinopathies of the central nervous system. Alpha‐synuclein seed amplification assays (αS‐SAA) are the most promising techniques for the in vivo detection of synucleinopathies, ie, PD and DLB. In neuropathological studies, Lewy Bodies (LBs) have been found in 50‐60% of AD patients. In AD, concomitant LB pathology could lead to parkinsonism and to a more aggressive course of the disease. Whether concomitant LBs could be related to some clinical aspects of AD, i.e., clinical variants or clinical progression, remains to be assessed. In our work, we applied αS‐SAA to determine whether the rate of assay positivity differs in AD vs controls (CTRL), and among AD clinical variants.

Method

We used αS‐SAA to test 457 CSF samples from a cohort of AD, CTRL, and patients with PD and DLB. Classical AD CSF biomarkers were used to select CTRL and AD patients according to the A/T/(N) system. All CTRL showed a CSF A‐/T‐/N‐ profile while all AD patients were A+T+. Details of the subjects included are reported in Table 1. Fisher’s Exact test for count data and logistic regression (by assuming age and gender as covariates) were used to evaluate the significance of the different prevalences observed.

Result

We observed significantly higher αS‐SAA positivity in PD/DLB (86%) and AD patients (30%) with respect to CTRL subjects (13%, 7% in CTRL CN and 16% in CTRL MCI subjects) (Fig‐1A). Among the AD clinical variants, patients with posterior variant exhibited significantly higher αS‐SAA positivity (Fig‐1C). Interestingly, αS‐SAA positivity increased in the diagnostic groups as they progressed to later stages of AD, with the highest percentage in the AD at dementia phase (AD‐dem) group (36%) (Fig‐1B).

Conclusion

Our results show that a large portion of AD cases have concomitant synucleinopathy and αS‐SAA could allow stratification of AD cases, as assay positivity was associated with AD subtypes and progression. Further evaluation of cross‐sectional and longitudinal clinical data is needed to determine potential prognostic value of αS‐SAA in AD. Early detection of synucleinopathy in AD patients will be increasingly important for design of personalized disease‐modifying therapies.
Validation of the Taiwan Version of REM Behavior Disorder Screening Questionnaire
Authors: Huang Mei‐Feng , Yeh Yi‐Chun , Chen Cheng‐Sheng
Published: December 2023

Background

The current diagnostic criteria for rapid eye movement sleep behavior disorder (RBD) requires the rapid eye movement sleep without atonia in polysomnography (PSG). Although PSG provide a high specific method to detect RBD, its limitations are impractical and low sensitivities. Several sleep questionnaires have been developed to screen RBD. REM behavior disorder screening questionnaire (RBDSQ) is commonly used at present, and which has not been validated in Taiwan, so we aimed to test the validity of RBDSQ.

Method

One‐hundred and six elders who received PSG in Sleep Center were recruited, including 52 RBD and 54 RBD‐negative. All patients had completed the Taiwan version of RBDSQ. The internal consistency (estimated by Cronbach’s alpha coefficient) and test‐retest reliability (estimated by intra‐class correlation coefficient; ICC) were used to assess the reliability of the RBDSQ. And we calculated the areas under the curves (AUC) and the best cut‐off point of the RBDSQ.

Result

We found that Cronbach’s alpha was 0.737 and the ICC was 0.738. Validity of RBDSQ at optimal cut‐off point 4/5 were estimated with sensitivity 0.659, specificity 0.656 and an estimate of AUC was 0.714 (0.613‐0.816). In elderly subgroup (Age≧60), an estimate of AUC was 0.804 (0.697‐0.913),with sensitivity 0.633 and specificity 0.774.

Conclusion

Taiwan version of RBDSQ has good sensitivity, specificity and reliability, and is able to be used as a screening tool of RBD, especially in elderly group.
Fragments of Amyloid Precursor Protein in Urine Are Novel and Practical Biomarkers for Early Screening of Dementia
Authors: Gu Ben J , Fowler Christopher J , Zhu Jingyu , Chen Xiaotong , Lam Linh Q , Jiao Bin , Thai Christine , Masters Colin L , Xiao Jun , Zhao Qianhua , Lin Yong , Shen Lu
Published: December 2023

Background

It has been shown that Aß is a normal component in urine (Ghiso et al, FEBS Lett, 1997) and may change with disease status (Takata et al, Neurosci Lett, 2008), however, research on amyloid in urine has been neglected for long time.

Method

We examined β amyloid proteins in urine from cognitive normal and dementia patients including Alzheimer’s disease (AD) and frontotemporal dementia (FTD) using Western blotting.

Result

Several protein fragments were identified including the 12KD and 14KD bands recognized by the anti‐APP C‐termini antibody (Ab369), 14KD and 28KD bands by W0‐2 (Figure 1), and 28KD, 56KD and 68KD bands by Aducanumab (Figure 2) and anti‐APP N‐termini antibody (22C11). Further analysis with immunoprecipitation and mass spectrometry confirmed the presence of various APP fragments and Aß in urine. One type of peptide was found to have high affinity to Aß and APP fragments using microscale thermophoresis and circular dichroism spectroscopy. With the assistance from AIBL, we further invented a lateral flow immunoassay device with colloidal gold nanoparticles coated with anti‐APP/Aß antibodies. In the early clinical trials with aged people and children, 95% of dementia patients, 90% of MCI, 85% of SMC showed positivity while 90% of healthy children were negative. The second quality examination was performed in Oriental (Dongfeng) Hospital (Pudong, Shanghai) in Mar‐June 2022. The examination of detection limit, critical threshold, repeatability, tolerance to interferences (creatinine, protein, glucose, nitrites, pH) was performed and all passed. Furthermore, 43 of 49 cases showed positive (87.7%) while only 1 out of 30 controls was positive (3.3%). Since then, the device has been tested in a dozen of large hospitals and pathology laboratories in China, all provided positive feedback. The preliminary results from 175 AIBL participants showed overall 83.8% positivity to clinically diagnosed MCI (n = 37), while for those Aβ PET scan negative MCI (n = 17), positivity was 94.1% (Figure 3).

Conclusion

Our results indicates the high accuracy of this device, which has high potential to be used as an early screening tool for MCI and dementia. The longitudinal studies are currently undergoing in China (Xiangya Hospital) and in Australia (AIBL).
Feasibility of 18F‐florzolotau Quantification in Patients with Alzheimer’s Disease Based on an MRI‐free Tau PET Template
Authors: Lu Jiaying , Ju Zizhao , Wang Min , Sun Xun , Jia Chenhao , Li Ling , Bao Weiqi , Zhang Huiwei , Jiao Fangyang , Lin Huamei , Yen Tzu‐Chen , Cui Ruixue , Lan Xiaoli , Zhao Qianhua , Guan Yihui , Zuo Chuantao ,   the Shanghai Memory Study (SMS)
Published: December 2023

Background

Quantification of tau accumulation using positron emission tomography (PET) is critical for the diagnosis of Alzheimer’s disease (AD). This study aimed to evaluate the feasibility of 18F‐florzolotau quantification in patients with AD using a magnetic resonance imaging (MRI)‐free tau PET template, since individual high‐resolution MRI is costly and not always available in practice.

Method

18F‐florzolotau PET and MRI scans were obtained in a discovery cohort including 1) patients within the AD continuum (n = 87), 2) cognitively impaired patients with non‐AD (n = 32), and 3) cognitively unimpaired subjects (n = 24). The validation cohort comprised 24 patients with AD. Following MRI‐dependent spatial normalization (standard approach) in randomly selected subjects (n = 40) to cover the entire spectrum of cognitive function, selected PET images were averaged to create the 18F‐florzolotau‐specific template. Standardized uptake value ratios (SUVRs) were calculated in five predefined regions of interest (ROIs) including entorhinal cortex, inferior temporal cortex, temporal meta‐ROI, temporoparietal cortex, and neocortical areas. MRI‐free and MRI‐dependent methods were compared in terms of continuous and dichotomous agreement, diagnostic performances, and associations with specific cognitive domains.

Result

MRI‐free SUVRs had high continuous and dichotomous agreement with MRI‐dependent measures for all ROIs (intraclass correlation coefficient ≥ 0.980; agreement ≥ 94.5%). Similar findings were observed for AD‐related effect sizes, diagnostic performances with respect to categorization across the cognitive spectrum, and associations with cognitive domains. The robustness of the MRI‐free approach was confirmed in the validation cohort.

Conclusion

The use of an 18F‐florzolotau‐specific template is a valid alternative to MRI‐dependent spatial normalization, improving the clinical generalizability of this second‐generation tau tracer.
Effects of γ‐secretase modulator BPN‐15606 in amyloidogenic responses to air pollution in mouse cortex
Authors: Godoy‐Lugo Jose A , Thorwald Max A , Diaz Arnold , Levi Jon , Peng Lei , Zhang Hongqiao , Sioutas Constantinos , Mack William J , Bonaguidi Michael Anthony , Finch Caleb E
Published: December 2023

Background

Epidemiological studies show chronic exposure to air pollution accelerates cognitive decline and increase AD risk. In mouse models, brain accumulation of amyloid beta (Aβ) is enhanced by air pollution. Pharmacological approaches show benefit of γ‐secretase modulation (GSM; BPN‐15606), decreasing Aβ42 and amyloid plaques in mouse brain. We hypothesize that GSM will limit Aβ42 production during air pollution exposure in the diesel exhaust particle (DEP) model.

Method

C57BL/6 mice were exposed to DEP for 8 weeks. DEP from National Institute of Science and Technology (NIST 2975) was suspended in water and re‐aerosolized for 5 hr/day at concentration of 100 µg/m3. GSM was mixed into chow (10mg/day dose). Experimental groups were filtered air (FA), DEP, FA+GSM, and DEP+GSM; proteins from soluble fraction of cerebral cortex were analyzed by immunoblots.

Result

GSM alone increased amyloid precursor protein (APP) and the Aβ38 peptide. Air pollution (DEP) increased APP, with no further change in DEP+GSM. PSEN1, key enzyme for γ‐secretase function, decreased with DEP+GSM, along with the Aβ42 peptide and the Aβ42/40 ratio.

Conclusion

During exposure to DEP, GSM decreased Aβ42 and the ratio of Aβ42/40. These results suggest that γ‐secretase modulation is beneficial during air pollution, preventing Aβ42 increases.
Effect of white matter tract microstructural integrity on gamma entrainment using flickering light stimulation
Authors: Park Yeseung , Yoon Euisuk , Park Jieun , Kim Jun Sung , Han Ji Won , Kim Ki Woong
Published: December 2023

Background

Although gamma entrainment using flickering light stimulation (FLS), which was found to reduce Alzheimer’s disease pathologies in mice model, it failed to reduce cerebral amyloid burden in patients with AD or mild cognitive impairment. We investigated the optimal parameters of the FLS for entraining gamma waves in older adults in their brain may be influenced by white‐matter tract microstructural integrity (WMMSI) in humans.

Method

We enrolled 31 cognitively normal volunteers aged ≥ 65 years and measured resting‐state electroencephalography and the steady‐state visually evoked potential (SSVEP) of gamma rhythms induced by optimal FLS. We analyzed the spectral power change of the electroencephalogram induced by FLS using event‐related synchronization (ERS) and the propagation of gamma rhythms from the visual cortex to other brain regions using spectral Granger causality (sGC). Diffusion tensor images were acquired, and the microstructural integrity of white‐matter tracts of interest was measured. We investigated the relationship between white matter integrity and entrainment and propagation using fractional anisotropy (FA).

Result

After excluding five participants with SSVEP deficit, 26 participants were included in the final analysis. The lowest quartile group of the FA of the left posterior thalamic radiation exhibited a significantly lower ERS of gamma rhythms in the visual cortex than the second‐to‐highest quartile group (p = 0.045). In the multiple linear regression analyses, the effects of the FA of the middle longitudinal fasciculus and superior longitudinal fasciculus 3 on the sGC of the gamma rhythm connectivity from the occipital to the temporal, central, and frontal regions were statistically significant in both hemispheres (p < 0.05).

Conclusion

These findings suggest intact WMMSI may be required for proper gamma entrainment using FLS. Therefore, future clinical trials on gamma entrainment using FLS needs to consider WMMSI for participant selection.
Patient advisory board for dementia research (Part‐Beirat): survey on knowledge on participatory research
Authors: Daum Marcel , Kilimann Ingo , Drewelow Eva , Gerullis Kai , Ferra Fenia Gkolfo , Tomlin Jack , Walde Peggy , Völlm Birgit , Teipel Stefan , Klein Olga A.
Published: December 2023

Background

Participatory research refer to the process of actively involving people with lived experience of a condition into the research process to improve its relevance, quality, and impact. Evidence indicates that engaging patients in research increases recruitment rates and supports researchers in obtaining funding, developing study protocols, and selecting appropriate outcome measures. The challenge is to establish a sustainable structure to include patient groups which are underrepresented yet, such as patients with neurodegenerative diseases.

Objective

To develop, implement, and evaluate a patient advisory board (the “PART‐Beirat”) facilitating involvement in research at the Rostock University Medical Center. As part of the project, we examine the prior knowledge and attitudes toward participatory research.

Method

The project consists of three phases over three years and is supported by the Robert Bosch Stiftung. The first phase involves establishing the PART‐project’s organizational structure, developing key documents and procedures, collecting knowledge (e. g. systematic reviews, survey) and raising awareness. In the second phase, we will connect people with lived experience with researchers to establish topic‐specific (neurodegenerative diseases) PART‐advisory boards. In the third phase, we will increase the number of projects within the PART‐Beirat, monitor their progress and share best practices across the research landscape. In phase one, we conduct a standardized survey on the current knowledge on participatory research among older adults. The questionnaire is based on a previous study conducted at the University of Zurich in 2020.

Result

The survey covers participants’ prior knowledge and attitude towards participatory research, willingness to engage as well as time they would want to invest into participatory research. Data collection of the survey will begin in January 2023. Descriptive results of the survey will be presented.

Conclusion

At present, we are underway to develop the organizational structure of the patient advisory board to involve hard‐to‐reach patients and caregivers (PART project). The results of the survey will help us to identify the current level of knowledge on participatory research as well as attitudes towards and willingness to contribute to participatory research. This will provide us with a baseline which we hope to improve in the next three years with the establishment of the PART‐Beirat.
Development of a remotely applied app‐based cognitive training for early Alzheimer’s disease
Authors: Brem Anna‐Katharine , Krebs Christine R. , Brill Esther , Falkner Michael , Klöppel Stefan
Published: December 2023

Background

Cognitive training (CT) has been proposed to attenuate cognitive decline in early Alzheimer’s disease and can be administered remotely. Here, we describe the design and development of an adaptive app‐based CT to remotely train cognitive functions that are affected early in the course of Alzheimer’s disease. We furthermore present interim results of CT acceptance and adherence in a group of participants with subjective cognitive decline (SCD).

Method

We used the Unity Game Engine software and the programming language C# to design a CT app with 16 games that target AD‐typical impairments in episodic and semantic memory and spatial processing, including working memory tasks to facilitate transfer processes (Figure 1). During each training session three games (each 10 min) are played. The training is adaptive to ensure a constant level of challenge, i.e., players progress to higher levels when they win rounds and decrease to lower levels when they lose rounds. The broad range of tasks ensures continued motivation and adherence of the participants over a prolonged training period. We aimed to design the game interfaces and navigation as user‐friendly as possible to maximize usability. Via an integrated help button participants can furthermore ask for help during home training. CT adherence can be assessed remotely.

Result

Preliminary results on adherence and game experience show that participants with SCD (n = 62) like the games (5.49±0.13) and are motivated to perform well (6.3±0.08), despite being challenged (5.84±0.09) (7‐point Likert scale). After a 10‐week CT intervention, cognitive improvement is rated at 4.94±0.24 and participants would recommend the CT to a friend at 7.01±0.37 (9‐point Likert scale). Moreover, they would recommend that the games should be played for 32±2.64 min per day. The drop‐out rate is very low (4.6%). At the time of AAIC we will present additional data on acceptance/adherence and feasibility.

Conclusion

Remotely administered app‐based CT is applicable in the home setting and successful in motivating participants with early AD, which is also reflected in high adherence rates and acceptability. Future research should extend app‐based interventions to also target individuals with advanced cognitive impairment and applications for use in care‐home settings.
Legal Aspects of Alzheimer Prediction
Authors: Wittrock Julia , Schmitz‐Luhn Björn , Woopen Christiane ,   the PreTAD Consortium
Published: December 2023

Background

When diagnostic and therapeutic measures are increasingly replaced by predictive methods and preventive treatments, the applicable law is also subject to a variety of effects. In particular, a major question is about the eligibility of predictive measures for reimbursement by the statutory health insurance schemes in different countries. Secondly, in spite of the chances associated with early knowledge about disease risks, there can be negative legal and factual disadvantages, e.g. disclosure obligations for insurance contracts. Thirdly, the existing requirements for medical information and consent must be reassessed: The decision about the determination of future risks is particularly and increasingly complex, while the extent of the legal obligation of the physician to inform about decision‐relevant but not specifically medical remote effects has not yet been conclusively clarified.

Method

We scrutinize existing legislation and jurisprudence from Germany, Switzerland and Spain to identify uncertainties, hindrances or gaps in the existing legal framework, suggest adjustment and recommend legally safe and ethically justified paths for medical care in light of the changes described above.

Result

The existing legal framework bears uncertainties for the application of increasingly available methods to predict the individual risk for Alzheimer’s dementia. Therefore, an ethico‐legal framework for responsible and patient‐oriented dementia prediction is being developed.

Conclusion

The poster highlights the most pertinent legal questions and challenges associated with dementia prediction, and shows the integration of empirical data and ethical assessments into an ethico‐legal framework.
Strengthening home‐based dementia care services in Lithuania – accessibility, assessment, and delivery
Authors: Ciurlionis Marius , Smagariene Solveiga Inokaityte , Sakiene Ilona , Istomina Natalja
Published: December 2023

Background

Increased diagnostic rates of dementia in Lithuania were an essential factor that led to changes in the legislative framework. At the same time, there is still capacity for change in dementia diagnostic tools, as multiple methods and techniques are currently used. Therefore the development of a single diagnostic process is critical. In addition, family physicians are anticipated to play a more significant part in the diagnostic process due to the increasing number of people living with dementia (PLWD), as family physicians are directly linked to homecare teams.

Aims

This study aimed to identify ways homecare teams could deliver customized care and the barriers that impede access to these services. Identifying these subjects could improve understanding of how legislation addresses the accessibility and quality of dementia‐related services for those in need.

Methods

Revision of legal acts and related regulations has taken part, which included analysis of the content of services provided at home, amount and length of services, accessibility, and waiting times. Revision of requirements for professionals working in community settings and their postgraduate education programs were scrutinized at a large scale during this study. A home care assessment tool was also included in the research to determine whether people with unrecognized dementia would be entitled to receive care.

Results

It was revealed that the family physician role is sparse in dementia recognition, and quite frankly, patients with dementia symptoms are sent for psychiatric consultation to confirm the diagnosis. As a result, it leads to a bureaucratic and long‐lasting process, and the start of care is postponed. The study also identified that professionals working at homecare teams do not receive specialized training to address PLWD needs. In addition, nurses are not taught how to recognize primary dementia symptoms and report them. Moreover, legal acts do not oblige healthcare providers to promote and maintain the well‐being of those in need and their caregivers. Emotional well‐being, personal dignity, and control over daily life are also not addressed. Although an assessment tool is structured, people with primary cognitive symptoms would be able to receive home‐based care.
Comparison of sleep and wake EEG biomarkers in mild cognitive impairment and Alzheimer’s disease
Authors: Meghdadi Amir H. , Levendowski Daniel J , Kovacevic Natasha , Hamilton Joanne M , Boeve Brad F. , St Louis Erik , Salat David H , Berka Chris
Published: December 2023

Background

EEG slowing, a biomarker of cognitive decline in Alzheimer’s disease (AD), has been reported in wake or sleep EEG [1,2,3]. However, the relation between wake and sleep EEG and their comparative sensitivity to early stage of cognitive decline is less understood. In this study we compared sleep and wake EEG biomarkers using a common set of endpoints.

Methods

Participants included individuals with mild cognitive impairment (MCI, n = 30, ages 53‐88), Alzheimer’s disease dementia (ADem, n = 15, ages 60‐84), and controls with normal cognition (HC, n = 55, ages 50‐84). Twenty‐channel resting‐state EEG with eyes‐closed was collected during 5‐minutes of wakefulness (STAT X24). Sleep EEG recordings from AF7‐AF8 were collected in‐home and staged using Sleep ProfilerTM. Power spectral densities (PSD) and the derived Theta‐Alpha ratios were computed for wake EEG sites (counterpart bipolar montage), with the wake FP1‐FP2 compared by stage to the sleep EEG at AF7‐AF8. Significant differences in Theta‐Alpha ratios between MCI or ADem vs. HC groups were identified using independent t‐test (p<0.05) with the normalized effect size measured using Hedges‐g (E.S.).

Results

Correlation coefficients between wake Alpha, Theta power and non‐REM sleep were: r = 0.83, 0.75 for stage N1, r = 0.71, 0.66 for stage N2, and r = 0.55, 0.50 for stage N3. Based on the frontal Theta‐Alpha ratios, the ADem group showed significant EEG slowing during both wake (E.S. = 0.73) and sleep (E.S. = 1.65, 1.31, 0.61, 1.71 for N1, N2, N3, and REM) as compared to the HC, while MCI group only exhibited EEG slowing during sleep (E.S. = 0.56, 0.77, 0.51 for N1, N2 and REM). Temporal (T5‐T6) wake EEG manifested significant slowing in both ADem (E.S. = 1.21) and MCI (E.S. = 0.56) groups. Compared to the HC, ADem patients exhibited significantly less sleep time (E.S. = 0.91, p = 0.002) and less stage REM (E.S. = 1.0, p = 0.001).

Conclusions

Cognitive decline in the AD spectrum is associated with common signatures in both sleep and wake EEG. However, the magnitude of these effects and their spatial distribution may be different in sleep versus wakefulness. These findings support a multi modal approach to neurophysiological assessment using both sleep and wakefulness data.
Grassroots Approaches to Community‐Based Representative Recruitment in a Large Multidomain Lifestyle Intervention Trial
Authors: Hill Marcus , Williams Kelvin , Meyer Oanh L. , Robinson Chartay , Omotoye Elizabeth , Alexander Ashley , Tang Tara , Lovato Laura , Wilmoth Sharon , Woolard Nancy , Hill Carl V. , Whitmer Rachel A. , Snyder Heather M , Carrillo Maria C. , Baker Laura D ,   for the U.S. POINTER Study Group
Published: December 2023

Background

U.S. POINTER is a randomized, controlled, multi‐domain 2‐year clinical trial in 2000 older Americans to slow cognitive decline via culturally‐appropriate healthy lifestyle interventions. Participant diversity is essential, with targeted enrollment of 50% women and 23% enrollees from communities of color (reflecting the U.S. population in the 2016 Census). Other recruitment priorities include individuals with lower traditional educational attainment, older age within our eligibility range (75‐79 years old), and rural residence. This diversification aims to (1) better represent our communities particularly affected by ADRD, and (2) help ensure that this intervention can be successful across broad cultural differences for long‐term implementation.

Method

U.S. POINTER developed and deployed a community‐based recruitment strategy via a centrally‐coordinated grassroots outreach team at each site. The strategy includes evidence‐based and innovative community engagement tactics and is a multi‐faceted, agile approach that accounts for variations in: demographics across sites’ respective communities; levels of home institution‐community connectedness/integration; and outreach experience across team members. Tactics include: employing a multi‐tiered outreach framework that leverages existing community networks in order to augment team outreach capacity and ensure continuous community engagement; innovating approval procedures with central IRB to reduce barriers to producing timely outreach materials as needed; and standardizing onboarding for new team members across experience levels.

Result

The POINTER grassroots recruitment strategy has accounted for 22% of the trial’s overall enrollment. As of Jan 18, 2023, POINTER has enrolled 1879 participants, 29% of whom are from communities of color, 30% are men, 30% do not hold college degrees, and 13% are over 75 years old. Lessons learned include navigating local institutional reputations, retaining consistent team personnel for long‐term relationship building, setting trajectories for mutually‐beneficial long‐term community investment, and employing a formidable equity lens at all levels of staffing, outreach, and intervention design to better identify and eliminate barriers to participation, amongst others.

Conclusion

Key recommendations emerging from recruitment success in enrolling a diverse cohort include: approaching recruitment with long‐term vision and commitment toward community investment; leveraging existing community assets and working in partnership with respected community voices; and employing consistent, diverse, multimodal community outreach touchpoints for traction.