bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal effects of gantenerumab treatment on amyloid‐PET‐derived perfusion estimates in an early AD population
Authors: Silvestri Erica , Tonietto Matteo , Gobbi Susanna , Scelsi Marzia Antonella , Klein Gregory
Published: January 2025

Background

Amyloid PET imaging enables the simultaneous assessment of both perfusion and amyloid deposition in people with Alzheimer’s Disease (AD) in a single procedure. Perfusion can be derived from kinetic modeling of the full dynamic PET acquisition (i.e., relative blood flow ‐ R1), or more simply as ‘early‐frame’ Standardized Uptake Value Ratio (eSUVR). However, simplified measures could be biased by the amyloid tracer binding to amyloid. Here, we 1) assessed the effect of gantenerumab, an investigational anti‐amyloid monoclonal antibody, on perfusion metrics; 2) tested if the presence of amyloid affects perfusion estimation.

Method

Fifty‐nine participants underwent dynamic [18F]‐florbetaben PET imaging at baseline and week 116 in the GRADUATE I and II phase III trials of gantenerumab in early AD (NCT03444870, NCT03443973) (Tab. 1). A dual‐time‐window acquisition was employed (0‐30 and 90‐110 mins windows). Perfusion and amyloid load were estimated in: frontal, parietal, temporal, and occipital cortices, and composite neocortex region of interest (ROI), using the cerebellar gray matter as reference region. Perfusion was assessed as R1 using the simplified reference tissue model; and as eSUVR calculating the average activity during the initial 3, 5, or 10 minutes. Amyloid load was computed from the late time‐window as SUVR. Differences in mean perfusion change from baseline between placebo and gantenerumab were tested using a mixed model for repeated measures adjusted for treatment and APOE‐ε4 status. Pearson correlation measured the relationship between amyloid load and perfusion at baseline. All analyses were exploratory in nature and no adjustment for multiplicity was applied.

Result

No treatment effect was observed on R1 in any of the ROIs considered. However, gantenerumab arm resulted in a greater perfusion decrease when using eSUVR, with greater effects observed with longer eSUVR windows. Yet, all perfusion estimates correlated positively with amyloid load, with the correlation strength increasing with longer eSUVR time windows (Fig. 1, Tab. 2).

Conclusion

Perfusion significantly decreased in both arms, with R1 showing no difference between the two. PET‐derived perfusion metrics correlate positively with amyloid load, indicating amyloid‐dependence. Although kinetic modeling mitigates this bias, it does not fully eliminate it, warranting careful interpretation of these metrics in anti‐amyloid treatment assessments.
Traditional Chinese Medicine for Alzheimer’s Disease: A Systematic Review and Meta‐Analysis
Authors: Chen Yuqing , Zhang Danning , Chen Teng , Wen Lei , Hou Ruihua
Published: January 2025

Background

The treatment of Alzheimer’s Disease (AD) remains a challenge for modern medicine due to its complex pathogenesis. Traditional Chinese Medicine (TCM) has accumulated significant value and success in prevention and treatment of diseases, and are regarded as new and promising candidates of AD pharmacological treatments. The current study aimed to systematically evaluate the current evidence base for TCM as a treatment for AD.

Method

A systematic search of the literature was performed on electronic databases including PubMed, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and Web of Science. Thirteen studies were included in this review, subject to inclusion and exclusion criteria. Screening, data extraction, and quality assessment were undertaken following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. A total of 710 references were identified through searching the databases using the previously described search strategy. After excluding duplicates, titles and abstracts of 596 references were screened; of these, 13 were included in our systematic review and meta‐analysis, and a total of 1,183 participants were randomised. The primary outcome measures for efficacy were cognitive function, measured using the Standardized Mini‐Mental State Examination (MMSE) or ADAS‐cog. Secondary outcome measures included behavioural disturbances measured using the NPI, and activities of daily living assessed using the Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL).

Result

Our results show a significant improvement of TCM compared to control for cognitive functioning, when measured on both the MMSE and ADAS‐CoG scales. This significant difference did not translate to scores of neuropsychiatric symptoms or ability of daily living activities. We show that TCM has potential to help to slow cognitive decline and improving cognitive function as compared to conventional drug treatment and placebo, but is limited in its effects on psychiatric symptoms and practical activities.

Conclusion

These findings highlight TCM as potential adjuvant therapies, with conventional medicine, to improve effectiveness and reduce limitations of conventional AD drug regimes. Studies with larger sample size, rigorous study designs, accurate long‐term reporting, and correlation to neuropathological markers are needed in the future to enhance the evidence base for the use of TCM in AD patients, and to further confirm its efficacy.
VEGFR1‐mediated neuronal cell death following Aß1‐42 oligomers treatment‐ Implications in AD pathogenesis
Authors: Das Pritam
Published: January 2025

Background

Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor‐1 (VEGFR‐1/FLT1) and decreased expression of VEGFR‐2/KDR in AD brain. Increased expression of VEGFR‐1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between aberrant VEGFR‐1 expression in AD pathogenesis. In this study, we explored the potential role of aberrant VEGFR‐1 expression in neurons on AD pathology.

Method

To confirm VEGFR‐1 expression in AD brains, we performed immunostaining in AD brain sections (AD n = 5 (Braak stage V‐VI, and normal controls n = 5 Braak 0‐II) in AD brains. To determine a potential detrimental role of neuronal VEGFR‐1 expression on AD associated pathologies, we exposed SH‐SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5uM Aß 1‐42 oligomers for 72hrs.

Result

We found increased VEGFR‐1 immunoreactivity in dystrophic neurites in the vicinity of Thio‐S positive “cored” amyloid plaques, whereas VEGFR‐2 antibody staining showed minimal neuronal staining in AD samples. And treatment with hypoxia or Aß oligomers both in SH‐SY5Y cells and mouse primary neurons showed increased VEGFR‐1 expression and cleaved caspase 3 activation, leading to neuronal cell death. Significantly, siRNA mediated knockout of VEGFR‐1 in the neurons prevented both hypoxia and Aß oligomer induced cell death. We also show that treatment with either hypoxia or Aß oligomers reduced mRNA expression of cell survival genes including Hippo pathway YAP1 and VEGFR‐2, and siRNA mediated VEGFR‐1 knockdown normalized both YAP1 and VEGFR‐2 levels. Significantly, over‐expression of the VEGFR‐1 by itself reduced mRNA expression of YAP1 and VEGFR‐2 and readily induced neuronal cell death, implicating the VEGFR‐1/VEGFR‐2/YAP1 signaling axis in hypoxia and Aß oligomer induced neuronal cell death, which is a novel finding.

Conclusion

These results demonstrate that VEGFR‐1 may play an important transcriptional regulatory role in neuronal cell survival responses and suggest that modulating VEGFR‐1 expression and signaling could have beneficial effects in AD pathogenesis.
The role of TLR4/MyD88 signaling in systemic inflammation in an Alzheimer mouse model
Authors: Yang Junling , Fukuchi Ken‐ichiro
Published: January 2025

Background

Many lines of evidence support that systemic inflammation promotes Alzheimer’s disease (AD) progression. Amyloid plaques are closely accompanied with neuroinflammation characterized by activated microglia and reactive astrocytes. Aging is the largest known risk factor for AD and is characterized by chronic, systemic, low‐grade inflammation (inflamm‐aging). However, the precise molecular mechanisms by which chronic, systemic inflammation contributes to development of AD remain to be elucidated. In order to investigate the role of TLR/MyD88 signaling in chronic, systemic, low‐grade inflammation associated with development of AD, an AD mouse model (TgAPP/PS1) with MyD88+/+ (wild‐type) or MyD88± (MyD88 heterozygous: one allele is deleted) was treated with low dose lipopolysaccharide (LPS) for 3 months.

Method

We treated 6‐month‐old female MyD88+/+ TgAPP/PS1 and MyD88± TgAPP/PS1 mice with LPS (0.5 mg/Kg/weekly intraperitoneal injection) or PBS for 3 months and, then, performed a battery of behavioral tests including open‐field, T‐maze, elevated plus‐maze, and Morris water maze (n = 6‐7/group).

Result

In the open‐field, LPS‐treated MyD88± TgAPP/PS1 mice spent more time in the periphery (P<0.05) and tended to spend less time in the center of the open‐field, suggesting increased anxiety. In the acquisition phase of Morris water maze, there were significant day effects for path lengths (F (4, 84) = 24.66, P< 0.001) and escape latencies (F (4, 84) = 23.39, P < 0.001) caused by a reduction in both values over days in all 4 groups. There were no intergroup differences in the path lengths and the latencies. In the probe trial, the percentages of time spent in the correct quadrant for LPS‐treated MyD88+/+ TgAPP/PS1 mice were significantly greater than any other groups (F (3, 21) = 5.46, P<0.01). There were no intergroup differences in the visible platform subtask.

Conclusion

Surprisingly, chronic and systemic LPS treatment improved memory only in MyD88+/+ TgAPP/PS1 mice but not in MyD88± TgAPP/PS1 mice. We are currently investigating pathological and biochemical changes in these experimental animals.
Fiber tract profiles of community dwelling older adults with LATE‐NC and associations with postmortem TDP‐43
Authors: Heywood Ashley , Schneider Julie A. , Bennett David A. , Arfanakis Konstantinos , Wang Lei
Published: January 2025

Background

TAR DNA‐binding protein 43 (TDP‐43), has been shown to be involved in various neurodegenerative disorders involving axonal damage including ALS, FTLD, and LATE. Studying the relationships between postmortem TDP‐43 and antemortem white matter (WM) structural integrity can allow for a better understanding of underlying neural mechanisms of the disease. Measures of white matter integrity assume fiber bundles to maintain similar characteristics along the length of the tract, however, advanced computational research has identified that white matter integrity varies in stereotyped patterns along the tract.

Methods

In‐vivo diffusion‐weighted images were gathered on a 1.5T scanner from subjects from the Religious Orders Study and the Rush Memory and Aging Project. Tractography was conducted for each subject using Mrtrix3 and Automated Fiber Quantification (AFQ) was used to calculate fractional anisotropy (FA) along fiber tracts for 20 major fiber bundles. A semi‐quantitative rating of TDP‐43 severity was assessed in 5 brain regions. We utilized regression models to relate postmortem disease and antemortem FA at 100 nodes along each fiber tract while controlling for coexisting Alzheimer’s disease pathology and demographics.

Results

The 63 subjects were 91.2 (SD = 6.2) [range: 71.7‐103.6] years old at death. Thirty‐eight percent had TDP‐43 pathology and 36% had cognitive changes before death. Overall, fiber tract profiles revealed variation of FA along each fiber bundle. Results measuring the relationship to disease revealed a significant negative relationship (FWE corrected‐p<0.05) between postmortem TDP‐43 and FA at unique portions of the left hippocampal cingulum.

Conclusion

Findings support current literature indicating white matter integrity does not follow a uniform pattern along fiber tracts in older adults. Pathology relationships reveal unique portions of tracts which have unique relationships to TDP‐43. Understanding the relationship between disease and these vulnerable regions will be critical in elucidating the effect of TDP‐43 on white matter integrity leading to cognitive decline.
Deciphering the pathological significance of self‐propagating Aβ strains in different animal models
Authors: Morales Rodrigo
Published: January 2025

Background

Alzheimer’s disease (AD) is an heterogenous disorder characterized by the accumulation of amyloid‐beta (Aβ) and tau. One possible explanation for the clinical and pathological variation in AD lies in the presence of distinct conformational strains of Aβ. Numerous studies provide compelling evidence for the existence of such strains as well as their ability to template their conformations in a prion‐like manner. However, the interaction of such Aβ strains with different hosts has yet to be thoroughly examined. Here, we examined the host‐seed interaction of different human brain‐derived and synthetic misfolded Aβ strains in two different mouse models of amyloid pathology. We specifically explored the potential differences in amyloid propagation and pathological manifestations considering Aβ strains and animal models as variables.

Method

50‐day‐old Tg2576 mice were intra‐cerebrally challenged with mouse or human brain‐derived Aβ seeds, or synthetic Aβ strains. Age‐matched APP/PS1 mice were intra‐cerebrally challenged with the biological Aβ seeds as well. Cerebral pathology was assessed in 300‐day‐old Tg2576 mice, and in 180‐day‐old APP/PS1 mice.

Result

Two structurally defined synthetic misfolded Aβ strains induced remarkably different pathological features in Tg2576, including different rates of aggregation, tropism to specific brain regions, and differential recruitment of Aβ40/Aβ42 peptides. Moreover, the administration of human brain homogenates derived from AD patients, displaying unique patterns of amyloidosis, seeded distinct phenotypes in challenged APP/PS1 mice, as evaluated by their seeding activity, vascular pathology, and reactivity to thioflavin‐S. Finally, we observed that the same human brain homogenate induced a different cerebral Aβ pathology when inoculated into Tg2576 and APP/PS1 mice.

Conclusion

Our findings support the concept of Aβ strains and demonstrate that they may drive different clinical and pathological outcomes in humans. Our work highlights the contribution of the host in pathological characteristics. Future research could lead to successful personalized diagnostic approaches and treatments.
Disease trajectories before dementia: Evidence from a large‐scale community‐based prospective study
Authors: Li Jialin , Xia Ding , Cui Mei , Wang Yingzhe , Li Jincheng , Jin Li , Chen Xingdong , Suo Chen , Jiang Yanfeng
Published: January 2025

Background

Dementia patients often have several co‐existing diseases, whereas the specific temporality and development patterns between them remain uncertain.

Method

Based on the multicenter, community‐based prospective UK Biobank, enriched disease diagnoses were extracted from hospital admission linkage, along with basic demographic information and individual genome data from the baseline visit. We constructed disease trajectory before dementia utilizing the phenome‐wide association analysis to firstly filter potential precursors, the directional test to select temporal disease pairs, and conditional logistic regression to finally quantify association strength. Disease trajectory was also constructed across diverse subpopulations stratified by dementia subtypes (Alzheimer’s disease and vascular dementia), sex, median diagnosis age, and Apolipoprotein E (ApoE) ε4 status (carrier or not), respectively. Mendelian randomization (MR) was further adopted to suggest causality for longitudinal associations.

Result

Our study comprised 434,266 participants without baseline dementia and 4,638 individuals with all‐cause dementia, with a median follow‐up of 10.9 years. Initially, 1,253 diseases were extracted as potential nodes of disease trajectory preceding dementia. We ultimately defined three clusters of disease trajectory preceding all‐cause dementia, initiated by circulatory, metabolic, and respiratory system diseases (Figure 1). The initial diseases in the trajectory were diagnosed approximately 5‐15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischemic heart disease was the specific trajectory before vascular dementia. Angina, progressing to atrial fibrillation and then dementia, is a key trajectory in males, senior dementia patients, and ApoE ε4 non‐carriers. Dementia patients without ApoE ε4 typically developed urinary system disorders after musculoskeletal and connective tissue diseases. Lipid metabolism disorders remained in trajectories across all subgroups. However, MR based on inverse variance weighting indicated a modest causal relationship between lipid disorder and Alzheimer’s disease (Odds ratio = 1.05, P value = 0.234).

Conclusion

This study offers a comprehensive view of longitudinal disease trajectories before dementia among diverse subpopulations, indicating critical precursor diseases and specific development patterns. The findings emphasize the importance of clinical attention to patients with cardiometabolic dysfunction in midlife for screening and prevention of dementia. Further population studies and mechanism explorations are needed to validate and generalize the trajectories.
The Canadian Multi‐Ethnic Research on Aging (CAMERA) Study: Objectives and Design
Authors: Marawi Tulip , Rai Harleen , Nyman Alexander J , Gopinath Georgia , Alexander Madeline Wood , Yep Rachel , Boshmaf Silina Z , Munoz Douglas P , Swardfager Walter , Black Sandra E , Goubran Maged , Rabin Jennifer S
Published: January 2025

Background

Despite being among the fastest‐growing ethnoracial groups in Canada and the United States, individuals of Asian descent are significantly underrepresented in research on Alzheimer’s disease and related dementias (ADRD). Limited evidence suggests a lower incidence of dementia among Asian Americans compared to their White counterparts; however, there is variability in risk factors among Asian American subgroups. Understanding this heterogeneity is crucial for tailoring dementia prevention and intervention strategies in Asian populations. To address this gap, we launched the CAnadian Multi‐Ethnic Research on Aging (CAMERA) study in Toronto, Canada.

Method

CAMERA is a 5‐year longitudinal observational study based at Sunnybrook Health Sciences Centre in Toronto, Canada. CAMERA aims to enroll 300 cognitively unimpaired adults aged 55‐85 who self‐identify as South Asian, Chinese, or non‐Hispanic White (n = 100/group). Participants are recruited from the greater Toronto area using culturally appropriate, community‐based participatory approaches. We formed a community advisory board (CAB) comprising community members who share the same identity, language, culture, and values as CAMERA participants. The CAB actively engages in the research process, participant recruitment, research questions, and knowledge translation. In terms of the study protocol, at baseline (Year 1), Year 3, and Year 5, participants complete clinical, cognitive, brain MRI, blood (for genetic and biomarker analysis), and language‐ and culturally neutral eye‐tracking assessments. Every year, participants complete a series of questionnaires via REDCap covering demographic, community, cultural and social, mental and physical health, and sex‐specific health factors.

Result

As of April 2024, we have enrolled 131 participants. Of those, 92 participants completed baseline Year 1 testing. Of the 92 participants, 31 (33.7%) self‐identified as South Asian, 36 (39.1%) as Chinese, and 25 (27.2%) as non‐Hispanic White. Participants have a mean age of 68.1 years (SD = 6.2), and are mostly female (62 (67.4%)).

Conclusion

To our knowledge, this will be the first longitudinal cohort study that brings together sensitive brain imaging tools, novel blood‐based markers, and comprehensive cognitive data to investigate ADRD risk in understudied Asian subgroups. This research will yield currently unavailable data to inform the development of precision strategies to prevent and delay ADRD in Asian and other populations.
Sex differences in the association between depression and dementia
Authors: Jahng Anna , Kang Jaemyeong
Published: January 2025

Background

Sex differences in the association between depression and dementia have been reported with inconsistent results. This study aims to explore sex differences in the relationship between dementia and depression, using the history of major depressive disorder (MDD) and Centre for Epidemiological Studies Depression Scale (CES‐D‐10) as measures.

Method

Utilizing data from the 8th wave of the Korean Longitudinal Study of Aging (KLoSA) conducted in 2020 with 5717 participants, we investigated the sex effect on the association between various measures of depression and history of dementia using binary logistic regression. Two depression history variables (‘Felt MDD’ and ‘Treated for MDD’ in the last two years) and one depressive symptom variable (CES‐D‐10) were used as independent variables. Subgroup analyses in each sex group were explored. All analyses were adjusted for age, education, current smoking and alcohol consumption, regular exercise, and history of cerebrovascular disease and psychiatric disorder. Additionally, Area Under the Receiver Operating Characteristic (AUROC) analyses were performed to investigate the predictive power of CES‐D‐10 for dementia.

Result

No significant differences were observed between males and females for the prevalence of ‘Felt MDD,’ ‘Treated for MDD,’ CES‐D‐10 score, and history of dementia. While significant sex (female) interaction was detected in the association between ‘Felt MDD’ and dementia (Odds Ratio [OR] 2.103, 95% Confidence Interval [CI] 1.430 – 3.094) and between CES‐D‐10 and dementia (OR 1.039, CI 1.017 – 1.061), no significant sex interaction was found in the association between ‘Treated for MDD’ and dementia (OR 1.713, CI 0.937 – 3.310). Subgroup analyses revealed a significant association between ‘Treated for MDD’ and dementia (OR 10.142, CI 2.753 – 37.358) in males. In females, ‘Felt MDD’ (OR 3.142, CI 1.296 – 7.614) and CES‐D‐10 (OR 1.092, CI 1.032 – 1.157) showed significant association with dementia. Also, CES‐D‐10 demonstrated higher AUC predicting dementia in females (0.705) compared to males (0.666) or both sexes combined (0.692).

Conclusion

A greater association was found between depression and dementia in the female group compared to the male group. This might imply that sex plays a role in the association between depression and dementia.
A cognitive resilience gene expression signature in excitatory intratelencephalic cortical neurons
Authors: Fish Lauren A , Telpoukhovskaia Maria , Algoo Jonathan , Hadad Niran , Gurdon Brianna , Dai Miko , Ouellette Andrew R , Neuner Sarah M , Dunn Amy R , Willcox Jon A. L. , Wu Yiyang , Dumitrescu Logan C. , Bellur Orhan , Zhang Jigang , O'Connell Kristen MS , Dammer Eric B. , Seyfried Nicholas T , Muzumdar Sukalp , Gillis Jesse , Robson Paul , Arnold Matthias , Hohman Timothy J , Philip Vivek M. , Menon Vilas , Kaczorowski Catherine C.
Published: January 2025

Background

Alzheimer’s disease (AD) is a devastating form of dementia, and its prevalence is rising as human lifespan increases. Our lab created the AD‐BXD mouse model, which expresses AD mutations across a genetically diverse reference panel (BXD), to identify factors that confer resilience to cognitive decline in AD. This model mimics key characteristics of human AD including variation in age of onset and severity of cognitive decline.

Method

To facilitate discovery of conserved mechanisms of resilience to AD, we generated a cross‐species single‐nuclei transcriptomic dataset from normal and AD human (ROSMAP) and AD‐BXD mouse frontal cortex tissue. We interrogated resilience‐associated gene expression signatures, validated resilience candidate genes with human reference data, and used a druggability ranking and drug repositioning pipeline to nominate drugs to promote resilience to AD. To learn more about the context of resilience gene expression, we used a hierarchical mapping algorithm to predict anatomical locations of cells expressing resilience gene signatures.

Result

We found the strongest gene expression signature associated with cognitive resilience to AD arises from excitatory layer 4/5 (eL4/5) cortical intratelencephalic neurons. This resilience signature includes genes involved in synaptic plasticity, vesicle transport, and axonal and dendritic development. We found that 27 of the 61 genes in the resilience signature are druggable and identified several candidate drugs for further investigation (Telpoukhovskaia et al., 2022). We also identified genes expressed across a continuum of cognitive performance. Our hierarchical mapping approach showed that the eL4/5 neurons expressing resilience signature genes are distributed throughout the frontal cortex, mainly in the somatomotor area.

Conclusion

We identified 61 candidate resilience genes to target with new or existing drugs. We also determined that expression of resilience candidate genes occurs in eL4/5 neurons in the somatomotor region of the cortex. Ongoing projects in the lab aim to evaluate efficacy of nominated drugs and profile learning‐specific proteomes of eL4/5 neurons in resilient and susceptible AD‐BXD strains. When integrated with existing genetic, behavioral, and pathological data, our work will elucidate the cellular, molecular, and genetic mechanisms that contribute to cognitive resilience in face of neurodegenerative disease pathology.
A Literature Review of Randomized Controlled Trials for Hospice‐eligible Patients Living with Dementia and Agitation
Authors: Wang YuHsuan (Olivia) , Fritts Arianne , Molina‐Henry Doris P. , Grill Joshua D , Mintzer Jacobo , Raman Rema
Published: January 2025

Background

Most hospice‐eligible patients with dementia report agitation with antipsychotics and antidepressants with major side effects predominantly used in this population to control symptoms. Little is known about current evidence on randomized controlled trials (RCTs) on reducing agitation in this population.

Objectives

We aimed to summarize and evaluate the existing literature on RCTs aimed at reducing agitation among hospice‐eligible patients with dementia.

Methods

We conducted a literature review using the following keywords (end‐of‐life, late‐stage dementia, agitation, terminal restless, terminal delirium, randomized controlled trials) on MEDLINE, Pubmed, PyscINFO, Proquest, CINAHL, EBSCO, EMBASE, Cochrane Library, and references of previous publications. This review considered English language RCTs and review articles on RCTs that focus on interventions for reducing agitation among patients who were terminally ill, reported symptoms of agitation, and were diagnosed with dementia.

Results

The search included published articles from January 1990 to February 2024. Forty‐four articles were identified. Of these articles, sixteen RCTs did not include terminally ill patients with dementia and agitation; seventeen did not focus on reducing agitation; four were not completed trials, two were written in German, and one could not be retrieved. Of the four relevant articles included in this review, three tested a nonpharmacological intervention and one tested a pharmacological intervention. The sample sizes in all four studies were small: ranging from 30 to 90 participants. Of the three studies that reported race, more than 75% of participants were White. None of the studies reported Latino ethnicity. Only one study could apply to the last five‐year period, but the use of agitation reduction was the secondary outcome of the study. No interventional trials with a pharmacological approach have been reported in the previous twenty years.

Conclusion

Our literature review identified only four RCTs conducted in hospice‐eligible patients with agitation in the last four decades with no medication being evaluated in over a decade. Research is urgently needed to identify, develop, and test treatments for end‐of‐life agitation in patients with dementia.
Infections and cognitive function, depression, and frailty: a cross‐sectional study in the Longitudinal Aging Study in India (LASI)
Authors: Gore‐Langton Georgia R , Mansfield Kathryn E , Ravi Prithvee , Doubatty Arrisonia , Alladi Suvarna , Kinra Sanjay , Warren‐Gash Charlotte
Published: January 2025

Background

Some infections may be associated with poor brain health, but evidence from low and middle‐income countries (LMICs) is limited. Therefore, we aimed to investigate associations between nine infections and cognitive function, depression, and frailty in India.

Methods

We conducted a cross‐sectional study using data from Wave 1 (2017‐2019) of the Longitudinal Aging Study in India (LASI) survey of adults (≥45years) from 35 of India’s 36 states and union territories. Survey data were collected via face‐to‐face interviews and direct health measurements. We investigated the association between nine infections either self‐reported ever (periodontal disease) or in the two years before interview (jaundice/hepatitis, malaria, tuberculosis, typhoid, chikungunya, diarrhoea/gastroenteritis, dengue, urinary tract infection [UTI]), and global cognitive function, depression and frailty. We used survey‐weighted logistic regression to estimate odds ratios comparing impaired cognition, depression, or frailty in people with at least one infection (and each individual infection) to those without infection.

Results

We included 64,682 respondents; median age 59 years (IQR:50‐67), 53.5% female. Accounting for survey weighting, thirty‐five percent (n = 23,783) of respondents reported at least one infection. After adjusting for demographic, social/environmental, lifestyle, and chronic health conditions, we saw evidence of association between having at least one infection and both depression (OR: 1.30 [95%CI: 1.23‐1.36]) and frailty (OR: 1.78 [95%CI: 1.69‐1.87]) (Figure 1). We saw strong associations between jaundice/hepatitis and frailty (OR: 2.20 [95%CI: 1.90‐2.54]), and UTIs and both frailty (OR: 3.08 [95%CI: 2.65‐3.59]) and depression (OR: 1.38 [95%CI:1.19, 1.61]). In contrast, having at least one infection was associated with reduced odds of impaired cognition (OR: 0.81 [95%CI: 0.76‐0.87]).

Conclusions

Our results suggest that infections are associated with increased depression and frailty in adults ≥45 years in India. However, reported infections were associated with better cognition, which may be explained by preferential recall of infections in those with better cognition. Longitudinal studies are needed to investigate a causal link between infections and adverse brain health, and to guide interventions to reduce the burden of impaired cognition, depression, and frailty in India and LMICs more widely.
COVID‐19 Mortality Rates and Changes in Antidementia and Psychotropic Medication Use Among Nursing Home Residents
Authors: Rataj Alison C , Alcusky Matthew , Ott Brian R. , Baek Jonggyu , Liang Shiwei , Lapane Kate L
Published: January 2025

Background

We examined the relationship between nursing home (NH) COVID‐19 mortality rates and changes in antidementia and psychotropic medication initiation before and during the pandemic and explored the influence of staffing and resident factors.

Method

Changes in medication initiation were collected through a nationally representative cross‐sectional Dementia Treatment Survey (2022) of NH Directors of Nursing. Outcome measures were created by collapsing a 5‐point Likert scale contrasting less/about the same vs. more initiation and less versus more/about the same initiation. NH’s peak monthly COVID‐19 death rate per 1,000 residents (05/2020‐12/2022) was calculated from the CMS COVID‐19 Nursing Home data file. Covariates were drawn from NH Compare, Provider of Service, Master Beneficiary Summary, Minimum Data Set 3.0, and Medicare administrative claims files. Adjusted odds ratios (aORs) were estimated from multivariable logistic models.

Result

NHs with higher COVID‐19 death rates at the peak of the pandemic were more likely to report a decrease (aORdecrease: 2.65, 95% CI: 1.07‐6.53) and less likely to report an increase (aORincrease: 0.28, 95% CI = 0.09‐0.87) for antidementia medication initiation. No association with psychotropic medication initiation was observed. NH’s reported increased resident behavior problems during the pandemic had higher odds of psychotropic initiation (aOR = 11.25, CI = 3.86‐32.83).

Conclusion

Increased COVID‐19 mortality rates were associated with decreased initiation of antidementia medication use during, compared to before the pandemic. Higher mortality reported with antipsychotic use in this population did not appear to be a factor in NHs during the pandemic. Increased behavior changes may be due to consequences of COVID‐19 (i.e., social isolation); our findings indicate that increased behavior changes were associated with more psychotropic drug use.
Automating Microinfarct Screening in Hematoxylin and Eosin‐stained Human Brain Tissues: A Machine Learning Approach
Authors: Oliveira Luca Cerny , Chauhan Joohi , Lai Zhengfeng , Cheung Samson , Villablanca Amparo , Jin Lee‐Way , DeCarli Charles S. , Chuah Chen‐Nee , Dugger Brittany N
Published: January 2025

Background

Microinfarcts, characteristic lesions of vascular dementia (VaD), are heterogenous and vary in appearance, which pose a considerable challenge for VaD grading as there is great interrater variability in microinfarct assessment. We propose a novel application of machine learning (ML) in the automated screening of microinfarcts, addressing a gap in the post‐mortem analysis of VaD in whole slide images (WSIs) from human brain.

Method

Our study adapts a patch‐based pipeline with convolutional neural networks (CNNs) to automate microinfarct screening in WSIs. We compare performance and computational cost of different fields‐of‐view (FOV) for the patch‐based method. Additionally, we propose a postprocessing step and leverage multiple FOVs to mitigate false positives. This study is validated against 66 annotated WSIs (N = 40 infarcted, N = 26 un‐infarcted) from Frontal, Parietal, and Occipital white matter regions across 22 cases. Annotations are from a single trained expert, who delineated microinfarct regions and graded white matter rarefaction.

Result

We report screening performance, i.e, the ability to distinguish infarct‐positive from infarct‐negative WSIs, and detection performance, i.e, the ability to localize the microinfarct regions within a WSI. Despite the inherent challenges of the inexact boundaries of microinfarcts, our models demonstrate notable efficacy in screening WSIs for infarcts, with ResNet‐18 achieving 100% accuracy at WSI level. However, the sensitivity in detecting infarct regions is below 50%, based on Intersection over Union thresholds above 20% overlap (a performance metric used to evaluate the accuracy of object detection models). Leveraging multiple FOV improves both detection and screening performances, reducing false positives.

Conclusion

This work presents a proof‐of‐concept pipeline driven by machine learning to automate microinfarct screening & detection in WSIs. This workflow provides new avenues in the automated analysis of neuropathological images of microinfarcts, bringing potential advancement in ML‐based dementia and neuropathology research.
Dysregulated Angiopoietin‐Tie signalling contributes to neurovascular dysfunction in Alzheimer’s disease
Authors: Ince Selvi , Love Seth , Miners James Scott
Published: January 2025

Background

Cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness within the precuneus is common in early‐stage Alzheimer’s disease (AD). Pericyte‐derived angiopoietin‐1 (ANGPT‐1) activates endothelial TIE‐2 receptors promoting vascular stability whereas endothelial cell‐derived ANGPT‐2, a weak agonist or antagonist of TIE‐2, promotes BBB leakiness. Endothelial TIE‐1 also regulates TIE‐2 signalling. We recently showed elevated ANGPT2 level in mild‐cognitive impairment related to albumin, a marker of BBB leakiness, in CSF. In this study, we examined ANGPT/TIE signalling in brain tissue and microvessel‐enriched fractions (MVFs) in relation to AD progression and cerebrovascular injury.

Method

We studied parietal cortex (Brodmann area 7) from Braak tangle stage (BS) 0‐II (n = 17), III‐IV (n = 23) and V‐VI (n = 22) from cases obtained from the South‐West Dementia Brain Bank, University of Bristol. ANGPT‐1, ANGPT‐2, TIE‐1, and TIE‐2 levels in brain tissue and MVFs were measured by ELISA. CD31 level was used to adjust for endothelial content. MAG and PLP1 levels, to assess brain oxygenation and fibrinogen, to assess BBB integrity, were measured by ELISA. One‐way ANOVA with Tukey’s post hoc testing was used to compare groups and Pearson’s correlation coefficient was used to assess relationships between ANGPT/TIE, MAG:PLP and fibrinogen.

Result

In crude homogenates, ANGPT‐1 level was elevated in BSV‐VI compared to BS0‐II (p = 0.06) and BSIII‐IV (p = 0.0005). TIE‐2 was reduced in BSIII‐IV compared to BS0‐II (p = 0.004) and BSV‐VI (p = 0.001) in crude homogenates and was lower in MVFs in BSV‐VI than BS0‐II (p = 0.02). ANGPT‐2 level was higher in BSV‐VI than BSIII‐IV in brain tissue (p = 0.04). However, both ANGPT‐2 and TIE‐1 levels were unaltered in relation to BS in MVFs. Across the entire cohort, ANGPT‐2 level correlated inversely with MAG:PLP1 ratio in BSIII‐IV (p = 0.052, r = ‐0.42) but positively with MAG:PLP1 (p = 0.04, r = 0.46) and fibrinogen level (p = 0.02, r = 0.49) in BSV‐VI brains.

Conclusion

The expression of the stabilising receptor, TIE‐2, was reduced in early‐stage AD and ANGPT2 expression was differentially related to perfusion and BBB leakiness dependent on disease stage. The study highlights important differences in ANGPT/TIE signalling in relation to disease stage and illustrates a complex relationship between brain, microvascular, and CSF changes that warrants further investigation.
Mechanism of tau‐mediated microglial NF‐κB inhibitor IκBα degradation in Alzheimer’s disease
Authors: Tangavelou Karthikeyan , Jiang Shanya , Mandell Michael , Bhaskar Kiran
Published: January 2025

Background

Microglia are the brain resident immune cells that function as immune surveillance and engulf and clear damage‐associated molecular patterns (DAMPs), such as misfolded and oligomeric tau (TO) relevant Alzheimer’s disease (AD) and prevent nuclear factor‐kB (NF‐kB) mediated immune‐activation. IκBα is an endogenous inhibitor of the NF‐kB subunit p50‐p65/c‐Rel protein complex. IkBα’s association is precisely regulated in microglia to prevent excessive NF‐kB activation and neuroinflammation, which is one of the hallmarks of AD.

Methods

Microglia treated with tau oligomers (TO) purified from autopsy of the human AD brain and analyzed its uptake and clearance via autophagy, proteasome, or calpain using specific inhibitors, bafilomycin‐A (BafA1), MG‐132 and PD150606, respectively. TO’s effect on NF‐kB activity (via assessing IkBα levels) was also tested in the presence or absence of these inhibitors and upon inhibition of protein translation using cycloheximide.

Results

AD‐TO induces endomembrane damage and NF‐kB activity as confirmed by increased galectin 3 puncta and luciferase reporter activity, respectively. AD‐TO impairs autophagy, confirmed by accumulation of p62, and adding BafA1 does not increase either p62 or IkBα levels. Then, to determine the role of proteasome or calpains on IkBα degradation, AD‐TO induced IκBα degradation was attempted to stabilize by either MG‐132 or PD150606. Inhibiting either proteasome or calpains does not prevent the degradation of IkBα. We identified AD‐TO induces elevated calpain activity, which is correlating with autophagy impairment, and inhibiting calpain with PD150606 restored autophagy activity as confirmed by decreased intracellular level of p62 and AD‐TO. Inhibiting the proteostasis activity with either PD150606 + BafA1 or PD150606 + BafA1 + MG‐132 induces secretion of IkBα into the culture medium.

Conclusions

Microglial endocytosed AD‐TO damages endomembrane and activate NF‐kB by constitutively degrading IkBα, which localizes in autophagosomes, and concurrent inhibition of calpains and autophagy leading to secretion of IkBα into the extracellular space.
APOE and gender influence cerebrospinal fluid lipids
Authors: Hanson Angela J , Farris Kristen M , Miglani Jasroop K , Djukovic Danijel , Raftery Daniel
Published: January 2025

Background

High fat diets are a risk factor for Alzheimer Dementia (AD) but little is known about the effect of acute high fat feeding on brain lipid metabolism. Previous studies suggest that diet results may differ by APOE genotype and sex. Here we examined cerebrospinal fluid (CSF) lipidomic profiles after high and low fat feeding in a group of older adults to ascertain how APOE and sex influenced post‐prandial lipids.

Method

As part of the Meal and Memory study (CT# NCT03070535), 78 healthy older adults (50% E4+, each E4 group 56% women) ingested high fat meal (HFM) and low fat meal (LFM) breakfasts 3‐5 weeks apart after overnight fast. Plasma triglycerides (TG) were measured at 7 time points, and lumbar puncture was performed 4 hours post‐meal. Lipidomics were performed on 250 ul of CSF on a Lipidyzer platform consisting of an AB Sciex 5500 MS/MS QTraps system equipped with a SelexION for differential mobility spectrometry (DMS). Multiple reaction monitoring was used to target 1,530 lipid species (across 20 lipid classes/subclasses) in positive and negative ionization modes with and without DMS, respectively. Lipids were analyzed using MetaboAnalyst 6.0 and SAS OnDemand (2021).

Result

HFM expectedly increased plasma triglycerides (TG) (LFM peak TG 134±69 mg/dL, HFM peak TG 149±80, F 8.85, p = 0.004), results unaffected by E4 status or sex. No differences were found between the two meals for the 20 lipid classes or for individual lipid species in CSF. When examined by sex*APOE group, important baseline differences were noted in 10 of the 20 lipid classes. Furthermore, there were meal*group effects for phosphoserines (ANOVA F statistic 3.57, p = 0.024), with all groups except for E4+ men showing decreases in these lipids after HFM compared to LFM.

Conclusion

Meals that produced predictable changes in plasma lipids did not change overall CSF lipids; however, changes were noted when analyzed by APOE*sex and further differed depending on whether the meal was high in fat. These findings suggest that diet or treatments that rely on brain lipid metabolism may need to be further stratified by APOE genotype and sex.
CSF Phosphoproteomics Biomarker Analysis from the Phase 2 Clinical Trial SHINE to Elucidate the Role of CT1812 in Alzheimer’s Disease
Authors: Cho Eunah , Caldwell Jill , Pandey Kiran , Duong Duc M , Seyfried Nicholas T , Caggiano Anthony O , Caro Valentina Di , Hamby Mary E.
Published: January 2025

Background

The sigma‐2 receptor (S2R) modulator CT1812 is a first‐in‐class investigational therapeutic, currently in Phase 2 clinical trials for Alzheimer’s disease (AD). Preclinical and clinical studies have shown that CT1812 displaces Aβ oligomers from synapses and clears them from the brain into the cerebrospinal fluid, restoring cognitive performance in a transgenic mouse model of AD. To investigate the mechanism of action of CT1812 and enable biomarker discovery, a phosphoproteomic analysis of CSF samples from SHINE‐A was performed.

Method

SHINE is a Phase 2 randomized, double‐blind, placebo‐controlled trial to assess the safety and tolerability of two doses of CT1812 for 6‐months in mild to moderate AD patients (NCT03507790), and an interim analysis was performed on the first 24 patients enrolled (SHINE‐A). Tandem‐mass tag mass spectrometry (TMT‐MS) proteomics and phosphoproteomics were performed on baseline and end‐of‐study CSF samples from SHINE‐A (n = 18) and differential abundance (CT1812 vs placebo; p≤0.05) was assessed. STRING pathway analyses (v 12.0) and comparative analyses between differentially abundant proteins and phosphoproteins were conducted (p≤0.05, p≤0.1). Pearson correlation analyses with altered phosphopeptides and CSF Aβ42 and ADAS‐Cog‐11 were performed. An independent cohort from the SPARC trial assessing the effect of CT1812 in AD patients (NCT03493282) was used for clinical validation of findings.

Result

Altered phosphoproteins identified in SHINE‐A CSF samples included AD‐related proteins, APOE (p≤0.05), CHGB, SPARCL1, and SPP1 (p≤0.1). STRING pathway analysis underlined the role of CT1812 in altering key pathways: “vesicle trafficking”, “regulation of neurofibrillary tangle assembly”, “amyloid fibril formation”, and “low‐density lipoprotein particle receptor catabolic process”, these findings replicated in the SPARC independent cohort. Comparative analyses with proteomic data indicated that 2 phosphoproteins were differentially abundant at the protein level: APOE and MEPE (p≤0.1). Correlation analyses between the phosphoproteome and CSF Aβ42 and ADAS‐Cog‐11 identified highly correlated proteins, APOL1, CHGB, SERPINA10, and TALDO1 (p≤0.05).

Conclusion

The altered phosphorylated proteins and pathways affected by CT1812 highlight a potential impact of CT1812 in modulating amyloid, trafficking, and LDL biology, all pathways dysregulated in AD. Overall, findings support proof of mechanisms of action of CT1812 and the continued clinical development of CT1812.
Polygenic score‐wide association study of comorbidities to incident dementia
Authors: Jung Sang‐Hyuk , Woerner Jakob , Lee Dong‐gi , Nam Yonghyun , Shen Li , Won Hong‐Hee , Kim Dokyoon
Published: January 2025

Background

Previous studies have reported various prodromal symptoms and comorbidities that precede the development of dementia. In this study, we comprehensively investigate the impact of genetic predispositions to multiple comorbidities on the risk of incident dementia.

Methods

Our study included 377,653 participants of European descent from the UK Biobank, comprising 370,183 controls and 7,470 cases of incident dementia. We utilized large‐scale genome‐wide association study (GWAS) data from the FinnGen Consortium to generate the polygenic score (PGS) for quantifying genetic predispositions. From 2,405 GWASs, we selected those with a heritability greater than 1% using LD Score regression. We then analyzed pairwise genetic correlations, retaining the more heritable factor in cases where the collinearity (genetic correlation) exceeded 0.9. Consequently, we included 331 eligible PGSs in the Cox proportional hazard model‐based polygenic score‐wide association study (PolyWAS) for incident dementia.

Results

We identified 53 significant comorbidity‐PGSs (Bonferroni corrected p‐value = 0.05/331) through PolyWAS analysis, adjusted for the covariates age, sex, ApoE ε4 status, and dementia PGS. Notably, cardiometabolic‐related diseases categorized under the ICD‐10 code blocks ‘I’ (diseases of the circulatory system) and ‘E’ (endocrine, nutritional and metabolic diseases) showed the most significant associations with the risk of incident dementia. Depression and mood disorders under category ‘F’ (mental, behavioral and neurodevelopmental disorders) were risk factors in Alzheimer’s disease (AD) but not in Vascular dementia (VD). In addition, the genetic predisposition to Medical abortion under the category ‘O’ emerged as a risk factor for all‐cause dementia and its subtypes, including AD and VD. All significant PGSs were positively associated with incident dementia.

Conclusion

Our study implemented a novel association test approach using comorbidity‐PGSs to investigate the genetic predispositions associated with numerous comorbidities and their impact on incident dementia and its subtypes. The proposed PolyWAS approach can better advance our knowledge of disease mechanisms and enhance our understanding of the shared genetics of comorbidities.