Volume 97, Number 1, IN PRESS

Scoping Review
Klaus Hauer, Ilona Dutzi, Christian Werner, Jürgen Bauer, Phoebe Ullrich
Delirium Prevention in Early Rehabilitation During Acute Hospitalization and Implementation of Programs Specifically Tailored to Older Patients with Cognitive Impairment: A Scoping Review with Meta-Analysis
Abstract: Background: No systematic review on delirium prevention within early, hospital-based rehabilitation on implementation of approaches specifically tailored for patients with cognitive impairment (PwCI), such as Alzheimer’s disease or vascular dementia, has been published despite the high relevance of specific medical care in this vulnerable population. Objective: To document design and effectiveness of delirium prevention programs by early rehabilitation during acute, hospital-based medical care and implementation of programs specifically tailored to PwCI. Methods: In a three-step approach, we first identified published systematic reviews of hospital-based, early rehabilitation interventions for older persons (>65 years) in relevant databases. In a second step, we screened each single trial of included reviews according to predefined inclusion criteria. In a third step, we analyzed studies with focus on delirium prevention. Results: Among n=25 studies identified, almost all intervention programs did not specifically target cognitive impairment (CI). Interventions were heterogeneous (modules: n=2-19); almost all study samples were mixed/unspecified for cognitive status with more affected patients excluded. Only one study exclusively included delirium patients, and only one included CI patients. Results of random effect meta-analysis showed significant effects of generic programs to reduce delirium incidence during hospitalization by 41% (p>0.001, odds ratio, 95% confidence interval: 0.59 [0.49, 0.71] with modest heterogeneity (I2: 30%). Conclusions: Study results document a lack of implementation for delirium prevention programs specifically tailored to PwCI by early, hospital-based rehabilitation. Specifying existing rehab concepts or augmenting them by CI-specific modules may help to develop, optimize, and implement innovative delirium prevention in PwCI in acute medical care.

Carrie E. Johnson, Marilyn J. Duncan, M. Paul Murphy
Sex and Sleep Disruption as Contributing Factors in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.

Yunfeng Li*, Xiongjin Chen*, Mulan Zhou, Sifan Feng, Xiaoping Peng, Yan Wang *Yunfeng Li and Xiongjin Chen contributed equally to this paper.
Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer’s Disease
Abstract: Alzheimer's disease is a pervasive neurodegenerative disease that is estimated to represent approximately 70% of dementia cases worldwide, and the molecular complexity that has been highlighted remains poorly understood. The accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles formed by tau hyperphosphorylation, and neuroinflammation are the major pathological features of Alzheimer’s disease (AD). Over the years, there has been no apparent breakthrough in drug discovery based on the Aβ and tau hypotheses. Neuroinflammation has gradually become a hot spot in AD treatment research. As the primary cells of innate immunity in the central nervous system, microglia play a key role in neuroinflammation. Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes are vital molecules in neuroinflammation. In the pathological context of AD, the complex interplay between TLR4 and the NLRP3 inflammasomes in microglia influences AD pathology via neuroinflammation. In this review, the effect of the activation and inhibition of TLR4 and NLRP3 in microglia on AD pathology, as well as the cross-talk between TLR4 and the NLRP3 inflammasome, and the influence of essential molecules in the relevant signaling pathway on AD pathology, were expounded. In addition, the feasibility of these factors in representing a potential treatment option for AD has been clarified.

Chenyin Chu, Yi Ling Clare Low, Liwei Ma, Yihan Wang, Timothy Cox, Vincent Doré, Colin L. Masters, Benjamin Goudey, Liang Jin, Yijun Pan
How Can We Use Mathematical Modeling of Amyloid-β in Alzheimer’s Disease Research and Clinical Practices?
Abstract: The accumulation of amyloid-β (Aβ) plaques in the brain is considered a hallmark of Alzheimer’s disease (AD). Mathematical modeling, capable of predicting the motion and accumulation of Aβ, has obtained increasing interest as a potential alternative to aid the diagnosis of AD and predict disease prognosis. These mathematical models have provided insights into the pathogenesis and progression of AD that are difficult to obtain through experimental studies alone. Mathematical modeling can also simulate the effects of therapeutics on brain Aβ levels, thereby holding potential for drug efficacy simulation and the optimization of personalized treatment approaches. In this review, we provide an overview of the mathematical models that have been used to simulate brain levels of Aβ (oligomers, protofibrils, and plaques). We classified the models into five categories: the general ordinary differential equation models, the general partial differential equation models, the network models, the linear optimal ordinary differential equation models, and the modified partial differential equation models (i.e., Smoluchowski equation models). The assumptions, advantages and limitations of these models are discussed. Given the popularity of using the Smoluchowski equation models to simulate brain levels of Aβ, our review summarizes the history and major advancements in these models (e.g., their application to predict the onset of AD and their combined use with network models). This review is intended to bring mathematical modeling to the attention of more scientists and clinical researchers working on AD to promote cross-disciplinary research.

Systematic Review
Jissa Martin, Natasha Reid, David D. Ward, Shannon King, Ruth E. Hubbard, Emily H. Gordon
Investigating Sex Differences in Risk and Protective Factors in the Progression of Mild Cognitive Impairment to Dementia: A Systematic Review
Abstract: Background: Developing effective strategies for reducing dementia risk requires a detailed understanding of the risk and protective factors associated with the progression of mild cognitive impairment (MCI) to dementia. Objective: We aimed to systematically review the evidence for sex differences in these factors. Methods: Five online databases (PubMed/CINAHL/EMBASE/PsycINFO/Cochrane) were searched from inception until 17 October 2022 for cohort studies that focused on sex differences in risk and protective factors in the progression of MCI to dementia. Results: A total of 2,972 studies were identified, of which 12 studies from five countries were included in the systematic review. There was substantial variability in study designs, study populations and outcome measures. Sex differences were present in the associations of sociodemographic, health, psychological factors, genetic and other biomarkers with the progression of MCI to dementia. APOE ε4 status and depression appeared to increase the risk of progression for females, whereas history of stroke, MRI markers and cerebrospinal fluid biomarkers appeared to increase the risk of progression for males. APOE ε2 status and marital status (unmarried) were observed to reduce risk of progression in males and females, respectively. Conclusions: The ability of studies to accurately detail risk factors for dementia are likely limited when solely controlling for the effects of sex. Although the heterogeneity and underpowered nature of the studies made it difficult to synthesize the findings for each risk factor, this study highlights the apparent need for further research examining risk factors for dementia in males and females with MCI separately.

Systematic Review
Matteo Carpi, Mariana Fernandes, Nicola Biagio Mercuri, Claudio Liguori
Sleep Biomarkers for Predicting Cognitive Decline and Alzheimer’s Disease: A Systematic Review of Longitudinal Studies
Abstract: Background: Sleep disturbances are considered a hallmark of dementia, and strong evidence supports the association between alterations in sleep parameters and cognitive decline in patients with mild cognitive impairment and Alzheimer's disease (AD). Objective: This systematic review aims to summarize the existing evidence on the longitudinal association between sleep parameters and cognitive decline, with the goal of identifying potential sleep biomarkers of AD-related neurodegeneration. Methods: Literature search was conducted in PubMed, Web of Science, and Scopus databases from inception to 28 March 2023. Longitudinal studies investigating the association between baseline objectively-measured sleep parameters and cognitive decline were assessed for eligibility. Results: Sixteen studies were included in the qualitative synthesis. Sleep fragmentation, reduced sleep efficiency, reduced REM sleep, increased light sleep, and sleep-disordered breathing were identified as predictors of cognitive decline. Sleep duration exhibited a U-shaped relation with subsequent neurodegeneration. Additionally, several sleep microstructural parameters were associated with cognitive decline, although inconsistencies were observed across studies. Conclusions: These findings suggest that sleep alterations hold promise as early biomarker of cognitive decline, but the current evidence is limited due to substantial methodological heterogeneity among studies. Further research is necessary to identify the most reliable sleep parameters for predicting cognitive impairment and AD, and to investigate interventions targeting sleep that can assist clinicians in the early recognition and treatment of cognitive decline. Standardized procedures for longitudinal studies evaluating sleep and cognition should be developed and the use of continuous sleep monitoring techniques, such as actigraphy or EEG headband, might be encouraged.

Systematic Review
Anne Anschuetz, Karima Schwab, Charles R. Harrington, Claude M. Wischik, Gernot Riedel
A Meta-Analysis on Presynaptic Changes in Alzheimer’s Disease
Abstract: Background: A key aspect of synaptic dysfunction in Alzheimer’s disease (AD) is loss of synaptic proteins. Previous publications showed that presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity. Objective: The objective of this meta-analysis was to provide an update on the available literature and to further characterize patterns of presynaptic protein loss in AD. Methods: Systematic literature search was conducted for studies published between 2015-2022 which quantified presynaptic proteins in postmortem tissue from AD patients and healthy controls. Three-level random effects meta-analyses of twenty-two identified studies was performed to characterize overall presynaptic protein loss and changes in specific regions, proteins, protein families, and functional categories. Results: Meta-analysis confirmed overall loss of presynaptic proteins in AD patients. Subgroup analysis revealed region specificity of protein loss, with largest effects in temporal and frontal cortex. Results concerning different groups of proteins were also highly variable. Strongest and most consistently affected was the family of synaptosome associated proteins, especially SNAP25. Among the most severely affected were proteins regulating dense core vesicle exocytosis and the synaptic vesicle cycle. Conclusions: Results confirm previous literature related to presynaptic protein loss in AD patients and provide further in-depth characterization of most affected proteins and presynaptic functions.

Short Communication
Svetlana Ukraintseva, Hongzhe Duan, Rachel Holmes, Olivia Bagley, Deqing Wu, Arseniy Yashkin, Alexander Kulminski, Igor Akushevich, Heather Whitson, Eric Stallard, Anatoliy Yashin, Konstantin Arbeev
Patterns of Aging Changes in Bodyweight May Predict Alzheimer’s Disease
Abstract: Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ~10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.

Short Communication
Lina Lapeyre, Jocelyne Piret, Chantal Rhéaume, Vincent Pons, Olus Uyar, Paul Préfontaine, Serge Rivest, Guy Boivin
Herpes Simplex Virus 1 Infection Does Not Increase Amyloid-β Pathology in APP/PS1 Mice
Abstract: Using APP/PS1 mice that overproduce amyloid-β (Aβ) peptides, we investigated whether intranasal infection with a neurovirulent clinical strain of herpes simplex virus 1 (HSV-1) before Aβ deposition could accelerate or increase Alzheimer’s disease-like pathology. After HSV-1 infection, APP/PS1 mice presented a similar disease as wild type animals based on body weight changes, clinical symptoms, and survival rates. The number and volume of Aβ plaques, the number of microglia, and the percentages of circulating monocyte subsets were similar in APP/PS1 mice infected or not with HSV-1. Thus, intranasal infection with HSV-1 does not alter Aβ pathology in this mouse model.

Nina Possemis, Daphne ter Huurne, Leonie Banning, Angelique Gruters, Stephanie Van Asbroeck, Alexandra König, Nicklas Linz, Johannes Tröger, Kai Langel, Arjan Blokland, Jos Prickaerts, Marjolein de Vugt, Frans Verhey, Inez Ramakers (Handling Associate Editor: David Loewenstein)
The Reliability and Clinical Validation of Automatically-Derived Verbal Memory Features of the Verbal Learning Test in Early Diagnostics of Cognitive Impairment
Abstract: Background: Previous research has shown that verbal memory accurately measures cognitive decline in the early phases of neurocognitive impairment. Automatic speech recognition from the verbal learning task (VLT) can potentially be used to differentiate between people with and without cognitive impairment. Objective: Investigate whether automatic speech recognition (ASR) of the VLT is reliable and able to differentiate between subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Methods: The VLT was recorded and processed via a mobile application. Following, verbal memory features were automatically extracted. The diagnostic performance of the automatically derived features was investigated by training machine learning classifiers to distinguish between participants with SCD versus MCI/dementia. Results: The ICC for inter-rater reliability between the clinical and automatically derived features was 0.87 for the total immediate recall and 0.94 for the delayed recall. The full model including the total immediate recall, delayed recall, recognition count, and the novel verbal memory features had an AUC of 0.79 for distinguishing between participants with SCD versus MCI/dementia. The ten best differentiating VLT features correlated low to moderate with other cognitive tests such as logical memory tasks, semantic verbal fluency, and executive functioning. Conclusions: The VLT with automatically derived verbal memory features showed in general high agreement with the clinical scoring and distinguished well between SCD and MCI/dementia participants. This might be of added value in screening for cognitive impairment.

Seunghee Na, Chonghwee Lee, SeongHee Ho, Yun Jeong Hong, Jee Hyang Jeong, Kee Hyung Park, SangYun Kim, Min Jeong Wang, Seong Hye Choi, SeungHyun Han, Seung Wan Kang, Sungmin Kang, Dong Won Yang
A Longitudinal Study on Memory Enhancement in Subjective Cognitive Decline Patients: Clinical and Neuroimaging Perspectives
Abstract: Background: Subjective cognitive decline (SCD) refers to the self-reported persistent cognitive decline despite normal objective testing, increasing the risk of dementia compared to cognitively normal individuals. Objective: This study aims to investigate the attributes of SCD patients who demonstrated memory function improvement. Methods: In this prospective study of SCD, a total of 120 subjects were enrolled as part of a multicenter cohort study aimed at identifying predictors for the clinical progression to mild cognitive impairment or dementia (CoSCo study). All subjects underwent 18F-florbetaben PET and brain MRI scans at baseline and annual neuropsychological tests. At the 24-month follow-up, we classified SCD patients based on changes in memory function, the z-score of the Seoul verbal learning test delayed recall. Results: Of the 120 enrolled patients, 107 successfully completed the 24-month follow-up assessment. Among these, 80 patients (74.8%) with SCD exhibited memory function improvements. SCD patients with improved memory function had a lower prevalence of coronary artery disease at baseline and performed better in the trail-making test part B compared to those without improvement. Anatomical and biomarker analysis showed a lower frequency of amyloid PET positivity and larger volumes in the left and right superior parietal lobes in subjects with improved memory function. Conclusions: Our prospective study indicates that SCD patients experiencing memory improvement over a 24-month period had a lower amyloid burden, fewer cardiovascular risk factors, and superior executive cognitive function. Identifying these key factors associated with cognitive improvement may assist clinicians in predicting future memory function improvements in SCD patients.

Titikorn Chunchai, Nattayaporn Apaijai, Sornram Janjek, Busarin Arunsak, Nipon Chattipakorn, Siriporn C. Chattipakorn
Mitochondrial Fusion Promoter Given During Ischemia Has Greater Neuroprotective Efficacy Than When Given at Onset of Reperfusion in Rats with Cardiac Ischemia/Reperfusion Injury
Abstract: Background: Cardiac ischemia/reperfusion (I/R) injury has been shown to impose deleterious effects not only on the heart but also on the brain. Our previous study demonstrated that pretreatment with a mitochondrial fusion promoter (M1) provided central neuroprotective effects following cardiac I/R injury. Objective: To investigate the effects of M1 given during the ischemic phase and M1 given at the beginning of reperfusion on brain pathologies following cardiac I/R. Methods: Male Wistar rats were randomly divided into either a sham operation (n=6) or cardiac I/R injury (n=18) group. Rats with cardiac I/R injury were then randomly divided into 3 subgroups: 1) Control, 2) M1 treatment during cardiac ischemia (2 mg/kg, intravenous (i.v.)), and 3) M1 treatment at the beginning of reperfusion (2 mg/kg, i.v.). After euthanasia, the brain of each rat was removed for further analysis. Results: Cardiac I/R injury caused brain mitochondrial dynamic imbalance, brain mitochondrial dysfunction, brain apoptosis, microglial dysmorphology, brain inflammation, tau hyperphosphorylation, and synaptic dysplasticity. M1 treatment at both time points effectively improved these parameters. M1 given during the ischemic phase had greater efficacy with regard to preventing brain mitochondrial dysfunction and suppressing brain inflammation, when compared to M1 given at the beginning of reperfusion. Conclusions: Our findings suggest that treatment with this mitochondrial fusion promoter prevents mitochondrial dynamic imbalance in the brain of rats with cardiac I/R injury, thereby attenuating brain pathologies. Interestingly, giving the mitochondrial fusion promoter during the ischemic phase exerted greater neuroprotection than if given at the beginning of reperfusion.

Alin Alshaheri Durazo, Alexandra J. Weigand, Katherine J. Bangen, Rachel Membreno, Sunder Mudaliar, Kelsey R. Thomas for the Department of Defense Alzheimer’s Disease Neuroimaging Initiative
Type 2 Diabetes Moderates the Association Between Amyloid and 1-Year Change in Everyday Functioning in Older Veterans
Abstract: Background: Type 2 diabetes mellitus (T2DM) affects ~25% of Veterans, a prevalence rate double that of the general population. T2DM is associated with greater dementia risk and has been shown to exacerbate the impact of Alzheimer’s disease (AD) risk factors on declines in daily functioning; however, there are few studies that investigate these patterns in older Veterans. Objective: This study sought to determine whether T2DM moderates the association between amyloid-β (Aβ) positron emission tomography (PET) and 1-year change in everyday functioning in older Veterans. Methods: One-hundred-ninety-eight predominately male Vietnam-Era Veterans without dementia from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) with (n=74) and without (n=124) T2DM completed Aβ PET imaging and everyday functioning measures, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB) and Everyday Cognition (Ecog). Linear mixed effects models tested the moderating role of T2DM on the association between Aβ PET and 1-year change in everyday functioning. Results: The 3-way T2DM x Aβ PET x time interaction was significant for CDR-SB (p<0.001) as well as the Memory (p=0.007) and Language (p=0.011) subscales from the Ecog. Greater amyloid burden was associated with greater increases in functional difficulties, but only in Veterans with T2DM. Conclusions: Higher Aβ was only associated with declines in everyday functioning over 1 year in Veterans with T2DM. Given that people with T2DM are more likely to have co-occurring cerebrovascular disease, the combination of multiple neuropathologies may result in faster declines. Future studies should examine how diabetes duration, severity, and medications impact these associations.

Youjie Zeng, Si Cao, Ke Pang, Juan Tang, Guoxin Lin
Causal Association Between Sepsis and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization Study
Abstract: Background: Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear. Objective: Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis. Methods: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane's Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability. Results: The results of IVW indicated that sepsis significantly increased the risk of Alzheimer’s disease (OR = 1.11, 95% CI: 1.01-1.21, p = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy. Conclusions: The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis.

Larry Schmued, Bryan Maloney, Calvert Schmued, Debomoy K. Lahiri
Treatment with 1, 10 Phenanthroline-5-Amine Reduced Amyloid Burden in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. Objective: For the novel assessment of the effect of oral administration of 1,10-phenanthroline-5-amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid-β protein precursor (AβPP) and tau. Methods: AβPP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. Results: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. Conclusions: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the “metal-seeding” of Aβ.

Lujing Jiang*, Xiangming Hu*, Junguo Jin, Weimian Wang, Bingyan Yu, Guo Chen, Haojian Dong, Yingling Zhou *These authors contributed equally to this work.
Inflammatory Risk Status Shapes the Association Between Uric Acid and Cognitive Function in Non-Hyperuricemia Middle Aged and Elderly
Abstract: Background: The association between uric acid (UA) and cognitive function still remains controversial. Moreover, the role of inflammation in the above association is also unclear. Objective: We aimed to determine the association between UA and cognitive function among non-hyperuricemia adults, and in particular, whether the association was shaped by different inflammation levels. Methods: From the China Health and Retirement Longitudinal Study (CHARLS), 7,272 participants aged 45 and above were enrolled in 2011. Cognitive function measurement included orientation and attention, episodic memory, and visuospatial ability. Fasting blood samples were collected to measure levels of UA and high-sensitivity C-reactive protein (hs-CRP). Generalized estimating equation models were used to evaluate the effect of UA on cognitive function in all participants and those at different levels of hs-CRP (hs-CRP <3 mg/L or ≥3 mg/L). Results: Among non-hyperuricemia adults (mean age: 58.08, 49.59% males) for a median of 7 years follow-up, participants with higher levels of UA had better cognitive function score compared to those with lower UA levels (β: 0.09, 95% confidence interval [CI]: 0.01-0.17, p = 0.023). And this association was significant under low-grade inflammation levels condition (β:0.10, 95% CI: 0.10-0.19, p = 0.024), but not in high-grade inflammation levels condition. Further, the cognitive function benefit of elevated UA existed only in people with persistent low-grade inflammation levels at a longitudinal perspective (β: 0.14, 95% CI: 0.01-0.27, p = 0.039). Conclusions: Elevated UA levels were associated with better cognitive function in non-hyperuricemia population, especially for those at low inflammation levels.

Regina E.Y. Kim, Minho Lee, Dong Woo Kang, Sheng-Min Wang, Donghyeon Kim, Hyun Kook Lim
Increased Likelihood of Dementia with Coexisting Atrophy of Multiple Regions of Interest
Abstract: Background: Brain volume is associated with cognitive decline in later life, and cortical brain atrophy exceeding the normal range is related to inferior cognitive and behavioral outcomes in later life. Objective: To investigate the likelihood of cognitive decline, mild cognitive impairment (MCI), or dementia, when regional atrophy is present in participants’ magnetic resonance imaging (MRI). Methods: Multi-center MRI data of 2,545 adults were utilized to measure regional volumes using NEUROPHET AQUA. Four lobes (frontal, parietal, temporal, and occipital), four Alzheimer’s disease-related regions (entorhinal, fusiform, inferior temporal, and middle temporal area), and the hippocampus in the left and right hemispheres were measured and analyzed. The presence of regional atrophy from brain MRI was defined as ≤ 1.5 standard deviation (SD) compared to the age- and sex-matched cognitively normal population. The risk ratio for cognitive decline was investigated for participants with regional atrophy in contrast to those without regional atrophy. Results: The risk ratio for cognitive decline was significantly higher when hippocampal atrophy was present (MCI, 1.84, p<0.001; dementia, 4.17, p<0.001). Additionally, participants with joint atrophy in multiple regions showed a higher risk ratio for dementia, e.g., 9.6 risk ratio (95% confidence interval, 8.0‒11.5), with atrophy identified in the frontal, temporal, and hippocampal gray matter, than those without atrophy. Conclusions: Our study showed that individuals with multiple regional atrophy (either lobar or AD-specific regions) have a higher likelihood of developing dementia compared to the age- and sex-matched population without atrophy. Thus, further consideration is needed when assessing MRI findings.

Yu shin Park, Hye Jin Joo, Yun Seo Jang, Hajae Jeon, Eun-Cheol Park, Jaeyong Shin
Socioeconomic Status and Dementia Risk Among Intensive Care Unit Survivors: Using National Health Insurance Cohort in Korea
Abstract: Background: In aging populations, more elderly patients are going to the intensive care unit (ICU) and surviving. However, the specific factors influencing the occurrence of post-intensive care syndrome in the elderly remain uncertain. Objective: To investigate the association between socioeconomic status (SES) and risk of developing dementia within two years following critical care. Methods: This study included participants from the Korean National Health Insurance Service Cohort Database who had not been diagnosed with dementia and had been hospitalized in the ICU from 2003 to 2019. Dementia was determined using specific diagnostic codes (G30, G31) and prescription of certain medications (rivastigmine, galantamine, memantine, or donepezil). SES was categorized into low (medical aid beneficiaries) and non-low (National Health Insurance) groups. Through a 1:3 propensity score matching based on sex, age, Charlson comorbidity index, and primary diagnosis, the study included 16,780 patients. We used Cox proportional hazard models to estimate adjusted hazard ratios (HR) of dementia. Results: Patients with low SES were higher risk of developing dementia within 2 years after receiving critical care than those who were in non-low SES (HR: 1.23, 95% CI: 1.04-1.46). Specifically, patients with low SES and those in the high-income group exhibited the highest incidence rates of developing dementia within two years after receiving critical care, with rates of 3.61 (95% CI: 3.13-4.17) for low SES and 2.58 (95% CI: 2.20-3.03) for high income, respectively. Conclusions: After discharge from critical care, compared to the non-low SES group, the low SES group was associated with an increased risk of developing dementia.

Jill K. Morris, Paul J. Kueck, Riley E. Kemna, Zachary D. Green, Casey S. John, Michelle Winter, Sandra A. Billinger, Eric D. Vidoni
Biomarker Responses to Acute Exercise and Relationship with Brain Blood Flow
Abstract: Background: There is evidence that aerobic exercise is beneficial for brain health, but these effects are variable between individuals and the underlying mechanisms that modulate these benefits remain unclear. Objective: We sought to characterize the acute physiological response of bioenergetic and neurotrophic blood biomarkers to exercise in cognitively healthy older adults, as well as relationships with brain blood flow. Methods: We measured exercise-induced changes in lactate, which has been linked to brain blood flow, as well brain-derived neurotrophic factor (BDNF), a neurotrophin related to brain health. We further quantified changes in brain blood flow using arterial spin labeling. Results: As expected, lactate and BDNF both changed with time post exercise. Intriguingly, there was a negative relationship between lactate response (area under the curve) and brain blood flow measured acutely following exercise. Finally, the BDNF response tracked strongly with change in platelet activation, providing evidence that platelet activation is an important mechanism for trophic-related exercise responses. Conclusions: Lactate and BDNF respond acutely to exercise, and the lactate response tracks with changes in brain blood flow. Further investigation into how these factors relate to brain health-related outcomes in exercise trials is warranted.

Ning Hao, Xue Bai, An Hu, Gaofeng Zhao, Yansheng Chen, Jianhe Zhao, Qiong Ling, Xiangyu Li, Chuipu Cai, Qi Wang, Zhaojun Wang, Jiansong Fang
Assessing the Global, Regional, and National Impact of High Body Mass Index on Alzheimer’s Disease and Other Dementias Between 1990 and 2019
Abstract: Background: Obesity significantly increases Alzheimer’s disease (AD) and dementia risk. Understanding the link between a high body mass index (BMI) and these conditions is crucial for effective management and prevention. Objective: We aimed to estimate the burden of AD and other dementias attributed to high BMI from 1990 to 2019 based on sex, age, and socio-demographic indicators (SDI) at global, regional, and national levels. Methods: We collected data on deaths, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR) from the 2019 Global Burden of Disease study for AD and dementia attributed to high BMI. We explored the correlation between SDI levels and ASDR. Results: In 2019, there were 198,476.2 deaths (95% UI: 32,695.4–593,366.4) and 3,159,912.4 DALYs (848,330.5–8,042,531) attributed to high BMI. Numbers of deaths, DALYs, ASMR, and ASDR increased since 1990. Females had higher deaths, ASMR, and ASDR than males. Mortality and DALYs rates increased with age. ASMR and ASDR increased across five SDI levels, with the highest rise in Low-middle SDI. High-income North America had the most deaths [30,993.9 (5,101.7–89,912.9)], while North Africa and the Middle East had the highest ASMR [4.61 (0.79–13.64)] and ASDR [72.56 (20.98–181.16)] in 2019. Conclusions: The burden of AD and other dementias attributed to high BMI increased since 1990 globally and is still heaviest in developed regions. Females accounted predominantly for the burden than males. Timely measures are needed to against high BMI.

Ioanna Antigoni Angelidou, Hannah Stocker, Konrad Beyreuther, Birgit Teichmann
Validation of the “Perceptions regarding pRE-symptomatic Alzheimer’s Disease Screening” (PRE-ADS) Questionnaire in the German Population: Attitudes, Motivations, and Barriers to Pre-Symptomatic Dementia Screening
Abstract: Background: Attitudes, motivations, and barriers to pre-symptomatic screening for Alzheimer’s disease (AD) in the general population are unclear and validated measurement tools are lacking. Objective: Translation and validation of the German version of the “Perceptions regarding pRE-symptomatic Alzheimer’s Disease Screening” (PRE-ADS) questionnaire. Methods: A convenience sample (N = 256) was recruited via an online platform. Validation of the PRE-ADS-D consisted of assessments of: reliability, structural validity using Principal Component Analysis (PCA) and Exploratory Factor Analysis (EFA) and construct validity using known-group-tests. A subscale “Acceptability of Screening”, with 5 PRE-ADS-D items, was extracted to measure acceptance of screening in clinical practice. The STROBE checklist was used for reporting. Results: EFA revealed a three-factor model for the PRE-ADS-D. Acceptable to good internal consistency was found for the 25-item scale (α = 0.78), as well as for the three factors “Concerns about Screening” (α = 0.85), “Intention to be Screened” (α = 0.87), and “Preventive Health Behaviors” (α = 0.81). Construct validity was confirmed for both the 25-item PRE-ADS-D and the “Acceptability of Screening” scale (α = 0.91). Overall, 51.2% of the participants showed a preference for screening. Non-parametric tests were conducted to further explore group differences of the sample. Conclusions: The PRE-ADS-D is a reliable and valid tool to measure attitudes, motives, and barriers regarding pre-symptomatic dementia screening in the German-speaking general population. Additionally, the subscale “Acceptability of Screening” demonstrated good construct validity and reliability, suggesting its promising potential as a practical tool in clinical practice.

Pankaj Gurjar, Azmat Ali Khan, Amer M. Alanazi, Vasil'ev Vasilii Gennad'evich, George Zouganelis, Athanasios Alexiou (Handling Associate Editor: Rekha Khandia)
Molecular Dissection of Herpes Simplex Virus Type 1 to Elucidate Molecular Mechanisms Behind Latency and Comparison of Its Codon Usage Patterns with Genes Modulated During Alzheimer’s Disease as a Part of Host-Pathogen Interaction
Abstract: Background: Herpes simplex virus type 1 (HSV-1) is associated with Alzheimer's disease, which goes into a cycle of latency and reactivation. The present study was envisaged to understand the reasons for latency and specific molecular patterns present in the HSV-1. Objective: The objective is the molecular dissection of Herpes simplex virus type 1 to elucidate molecular mechanisms behind latency and compare its codon usage patterns with genes modulated during Alzheimer’s disease as a part of host-pathogen interaction. Methods: In the present study, we tried to investigate the potential reasons for the latency of HSV-1 virus bioinformatically by determining the CpG patterns. Also, we investigated the codon usage pattern, the presence of rare codons, codon context, and protein properties. Results: The top 222 codon pairs graded based on their frequency in the HSV-1 genome revealed that with only one exception (CUG-UUU), all other codon pairs have codons ending with G/C. Considering it an extension of host-pathogen interaction, we compared HSV-1 codon usage with that of codon usage of genes modulated during Alzheimer's disease, and we found that CGT and TTT are only two codons that exhibited similar codon usage patterns and other codons showed statistically highly significant different codon preferences. Dinucleotide CpG tends to mutate to TpG, suggesting the presence of mutational forces and the imperative role of CpG methylation in HSV-1 latency. Conclusions: Upon comparison of codon usage between HSV-1 and Alzheimer's disease genes, no similarities in codon usage were found as a part of host-pathogen interaction. CpG methylation plays an imperative role in latency HSV-1.

Jennifer L. Bruno*, Jacob S. Shaw*, Hadi Hosseini *These authors contributed equally to this work.
Toward Personalized Cognitive Training in Older Adults: A Pilot Investigation of the Effects of Baseline Performance and Age on Cognitive Training Outcomes
Abstract: Background: Cognitive training holds potential as a non-pharmacological intervention to decrease cognitive symptoms associated with Alzheimer’s disease (AD), but more research is needed to understand individual differences that may predict maximal training benefits. Objective: We conducted a pilot study using a six-month training regimen in healthy aging adults with no cognitive decline. We investigated the effects of baseline performance and age on training and transfer improvements. Methods: Out of 43 participants aged 65-84 years, 31 successfully completed cognitive training (BrainHQ) in one of three cognitive domains: processing speed (N=13), inhibitory control (N=9), or episodic memory (N=9). We used standardized assessments to measure baseline performance and transfer effects. Results: All 31 participants improved on the cognitive training regimen and age was positively associated with training improvement (p=0.039). The processing speed group improved significantly across many near- and far-transfer tasks. In the inhibitory control group, individuals with lower baseline performance improved more on inhibitory control and cognitive flexibility tasks. In the episodic memory group, older individuals improved most on a memory task while younger individuals improved most on an executive function far-transfer task. Conclusions: Individual differences are predictive of cognitive training gains, and the impact of individual differences on training improvements is specific to the domain of training. We provide initial insight regarding how non-pharmacological interventions can be optimized to combat the onset of cognitive decline in older adults. With future research this work can inform the design of effective cognitive interventions for delaying cognitive decline in preclinical AD.

Christian LoBue, Barbara E. Stopschinski, Nil Saez Calveras, Peter M. Douglas, Ryan Huebinger, C. Munro Cullum, John Hart, Mitzi M. Gonzales
Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort
Abstract: Background: Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer’s disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. Objective: Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. Methods: Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. Results: Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. Conclusions: Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted.

Xiao Da, Evan Hempel, Yangming Ou, Olivia Rowe, Zach Malchano, Mihaly Hajos, Ralph Kern, J. Thomas Megerian, Aylin Cimenser
Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer’s Disease
Abstract: Background: Patients with Alzheimer’s disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. Objective: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD. Methods: In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset of OVERTURE participants who meet the inclusion criteria for detailed white matter (N=38) and myelin content (N=36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed. Results: Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region. Conclusions: The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.

Jessica Grothe*, Adam Kropidlowski*, Melanie Luppa, Melanie Elgner, Katja Funke, Alexander Pabst, Georg Schomerus, Jens Dietzel, Dorothee Saur, Andrew Sommerlad, Steffi G. Riedel-Heller**, Tobias Luck** *,**These authors contributed equally to this work.
Psychometric Evaluation of the A-NKS: A Diagnostic Instrument to Assess Impairment of Activities of Daily Living in Mild and Major Neurocognitive Disorder According to DSM-5
Abstract: Background: Activities of daily living (ADL) functioning are important in the diagnosis of neurocognitive disorders (NCD), yet no standardized and validated instrument exist based on international classification systems. Objective: We aimed to psychometrically evaluate the differentiated assessment of ADL and instrumental ADL (IADL) impairments due to NCD according to DSM-5 criteria (Instrument für die Erfassung von Alltagsbeeinträchtigungen bei Neurokognitiven Störungen; A-NKS). Methods: We conducted a pilot study involving 92 participant-informant dyads of participants with mild or major NCDs, cognitively healthy individuals, and an informant, to test acceptability, internal consistency, and convergent validity with similar measures. Results: Both A-NKS versions demonstrated excellent internal consistency (α = 0.95 – 0.99) and correlate with other instrumental ADL instruments (participant [informant]: Barthel Index: rs = -0.26, p ≤ 0.05 [rs = -0.30, p ≤ 0.01]; Amsterdam IADL: rs = 0.59, p ≤ 0.01 [rs = 0.48, p ≤ 0.01]; SIDAM ADL: rs = 0.46, p ≤ 0.001 [rs = 0.47, p ≤ 0.001]). Additionally, there are correlations with the scale autonomy of the WHOQOL-OLD (rs = -0.50, p ≤ 0.001 [rs = -0.37, p ≤ 0.001]) and physical, as well as cognitive activities (rs = -0.39, p ≤ 0.001 [rs = -0.50, p ≤ 0.001]). They were well-accepted by participants and informants. Conclusions: The A-NKS is an instrument with acceptable psychometric properties to assess ADL due to neurodegenerative decline in healthy individuals, and those with mild or major NCD. Further research is needed to confirm reliability and validity and investigate the factor structure.

Yingying Ge*, Alya S. AlObaidi*, George A. Kuchel, Jenna M. Bartley, Phillip P. Smith, Wanxia He, Xiangyou Hu *These authors contributed equally to this work.
Dysfunctional Bladder Morphology and Functional Impairments Are Identified in the Alzheimer’s Disease APPNL-G-F/NL-G-F Murine Model
Abstract: Background: While symptoms related to lower urinary tract dysfunction (LUTD) are common in individuals with Alzheimer’s disease (AD), pathophysiological links between AD and LUTD remain unclear. Objective: This study aimed to investigate whether AD neuropathology would cause autonomic dysfunction along the spinal cord-bladder axis, which could result in alterations in bladder muscle kinetics. Methods: We utilized APPNL-G-F/NL-G-F knock-in (APP KI) and APPwt/wt (wild-type) mice at two different ages, 4- and 10-month-old, to investigate how AD impacts bladder tissue function by immunohistochemistry, western blotting, and pharmacomyography. Results: We showed that the mucosal layer partially separated from the detrusor in 10-month-old APP KI mouse bladders. Although there was no detectable amyloid deposition in the APP KI bladder, we found amyloid plaques in APP KI lumbar spinal cord. Further immunoblot analysis revealed that tyrosine hydroxylase protein levels were significantly reduced in both 4- and 10-month-old bladder tissues, suggesting reduction of norepinephrine synthesis in APP KI mouse bladders. In contrast, the level of β2 adrenergic receptor was increased in 4-month-old but not 10-month-old APP KI bladders. In bladder strips, the adrenergic agonist isoproterenol induced increased relaxation in 4- but not 10-month-old APP KI bladders. With 10 Hz electrical field stimulation, 10-month-old APP KI bladder strips were more responsive than wild-type controls, with no differences observed in 4-month-old APP KI bladders. Conclusions: APP KI mice exhibit LUTD, which is likely arising from amyloid pathology in the spinal cord, and results in maturational declines in presynaptic activity combined with compensatory postsynaptic upregulation.

Mengli Yang*, Jinghuan Gan*, Shuai Liu, Yaqi Yang, Jiuyan Han, Qingbo Meng, Fan Yang, Yong Ji *These authors contributed equally to this work.
Associations Between Plasma Orexin-A Level and Constipation in Cognitive Impairment
Abstract: Background: Constipation is a common symptom in dementia, and the cause is controversial. Rare clinical studies focused on plasma orexin-A levels and constipation in dementia. Objective: To evaluate the associations between orexin-A and constipation in patients with cognitive impairment. Methods: A total of 21 patients with mild cognitive impairment (MCI), 142 with Alzheimer’s disease (AD), and 57 with Lewy body dementia (LBD) were conducted. Besides informant-based history, neurological examinations or neuropsychological assessments, plasma levels of orexin-A, and constipation were assessed. The associations between orexin-A and constipation were evaluated by logistic regression models. Results: There were 47/220 (21.36%) cognitive impairment patients having constipation, and the proportion of constipation in LBD (61.40%) was significantly higher than AD (5.63%) and MCI (19.05%). No significant age or sex differences in the prevalence of constipation were found in the MCI, AD, and LBD groups. We found the cognitive impairment patients with constipation had lower levels of plasma orexin-A [1.00 (0.86, 1.28) versus 1.29 (1.01, 1.50) ng/ml, p < 0.001] than those without. And the plasma levels of orexin-A were significantly associated with the occurrence of constipation after adjusting for all variables in all patients with cognitive impairment (OR = 0.151, 95%CI: 0.042-0.537, p = 0.003). And the same finding was more prominent in the LBD group (p = 0.048). Conclusions: The decrease of plasma level of orexin-A is closely associated with the occurrence of constipation. Orexin-A has an intestinal protective effect and is involved in the gastrointestinal symptoms of patients with cognitive impairment.

Vincent Malotaux, Lise Colmant, Lisa Quenon, Lara Huyghe, Thomas Gérard, Laurence Dricot, Adrian Ivanoiu, Renaud Lhommel, Bernard Hanseeuw
Suspecting Non-Alzheimer’s Pathologies and Mixed Pathologies: A Comparative Study Between Brain Metabolism and Tau Images
Abstract: Background: Alzheimer’s disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist. Objective: We aimed to compare brain hypometabolism and tauopathy to unveil non-AD pathologies. Methods: Sixty-one patients presenting cognitive complaints (age 48-90), including 32 with positive AD biomarkers (52%), performed [18F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) and [18F]-MK-6240-PET (tau). We normalized these images using data from clinically normal individuals (n=30), resulting in comparable FDG and tau z-scores. We computed between-patients correlations to evaluate regional associations. For each patient, a predominant biomarker (i.e., Hypometabolism>Tauopathy or Hypometabolism≤Tauopathy) was determined in the temporal and frontoparietal lobes. We computed within-patient correlations between tau and metabolism and investigated their associations with demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, and white matter hypointensities (WMH). Results: We observed negative associations between tau and FDG in 37 of the 68 cortical regions-of-interest (average Pearson’s r=-0.25), mainly in the temporal lobe. Thirteen patients (21%) had Hypometabolism>Tauopathy whereas twenty-five patients (41%) had Hypometabolism≤Tauopathy. Tau-predominant patients were more frequently females and had greater amyloid burden. Twenty-three patients (38%) had Hypometabolism≤Tauopathy in the temporal lobe, but Hypometabolism>Tauopathy in the frontoparietal lobe. This group was older and had higher CVRF than Tau-predominant patients. Patients with more negative associations between tau and metabolism were younger, had worse cognition, and greater amyloid and WMH burdens. Conclusions: Tau-FDG comparison can help suspect non-AD pathologies in patients presenting cognitive complaints. Stronger Tau-FDG correlations are associated with younger age, worse cognition, and greater amyloid and WMH burdens.

Wenyi Li*, Jiwei Jiang*, Xiangchang Yin, Yuan Zhang, Xinying Zou, Mengfan Sun, Jianjun Jia, Baiping Ma, Jun Xu *These authors have contributed equally to this work.
Mediation of Regional Cerebral Blood Flow in the Relationship between Specific Gut Microbiota and Cognition in Vascular Cognitive Impairment
Abstract: Background: Gut microbiota could affect the onset and development of vascular cognitive impairment (VCI) through modulating metabolic and immune pathways. However, the vascular mechanisms involved remain unclear. Objective: To investigate the gut microbiota associated with VCI and examine the mediating effects of regional cerebral blood flow (CBF) to explore potential therapeutic targets for VCI. Methods: This prospective study enrolled patients with VCI (n=16) and healthy controls (n=18) from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1 and June 30, 2022. The gut microbiota composition and diversity were determined by 16S ribosomal RNA gene sequencing. The association between gut microbiota and Montreal Cognitive Assessment (MoCA) scores was determined using Spearman’s correlation analysis. Regional CBF was calculated using pseudo-continuous arterial spin labeling. The mediating effects of regional CBF on the relationship between specific gut microbiota and cognition in VCI were investigated using mediation analysis. Results: Compared to healthy controls, patients with VCI had significantly greater abundance of Bifidobacterium, Veillonella, Ruminococcus gnavus, Fusobacterium, and Erysipelatoclostridium and smaller abundance of Collinsella. The abundance of Ruminococcus gnavus was negatively associated with MoCA scores in patients with VCI, with the CBF in the left hypothalamus, right hypothalamus, and left amygdala accounting for 63.96%, 48.22%, and 36.51%, respectively, of this association after adjusting for confounders. Conclusions: Ruminococcus gnavus is associated with cognition in VCI, which is strongly mediated by CBF in the bilateral hypothalamus and left amygdala. These findings highlight the potential regulatory roles of nutrition and metabolism-related areas of the brain in VCI.

Jose Antonio Lojo-Ramírez, Miriam Guerra-Gómez, Alba Marta Marín-Cabañas, Paula Fernández-Rodríguez, María Bernal Sánchez-Arjona, Emilio Franco-Macías, David García-Solís
Correlation Between Amyloid PET Imaging and Discordant Cerebrospinal Fluid Biomarkers Results in Patients with Suspected Alzheimer’s Disease
Abstract: Background: Although the concordance between cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers and amyloid-PET findings is well known, there are no data regarding the concordance of amyloid-PET with inconclusive CSF values of amyloid-β (Aβ)1-42 and p-tau for the diagnosis of AD. Objective: To investigate the relationship between the amyloid-PET results with discordant AD biomarkers values in CSF (Aβ1-42+/p-tau- or Aβ1-42-/p-tau+). Methods: An observational retrospective study, including 62 patients with mild cognitive impairment (32/62) or dementia (30/62), suspicious of AD who had undergone a lumbar puncture to determine CSF AD biomarkers, and presented discordant values in CSF between Aβ1-42 and p-tau (Aβ1-42+/p-tau- or Aβ1-42-/p-tau+). All of them, underwent an amyloid-PET with 18F-Florbetaben. An extensive neuropsychological testing as part of their diagnostic process (MMSE and TMA-93), was performed, and it was also obtained the Global Deterioration Scale. Results: Comparing the discordant CSF results of each patient with the cerebral amyloid-PET results, we found that in the group with Aβ1-42+ and p-tau- CSF values, the amyloid-PET was positive in 51.2% and negative in 48.8% of patients, while in the group with Aβ1-42- and p-Tau+ CSF values, the amyloid-PET was positive in 52.6% of patients and negative in 47.4% of them. No significant association was found (p=0.951) between the results of amyloid-PET and the two divergent groups in CSF. Conclusions: No significant relationship was observed between the results of discordant AD biomarkers in CSF and the result of amyloid-PET. No trend in amyloid-PET results was observed in relation to CSF biomarker values.

Rohan Bapat, Da Ma, Tim Q. Duong
Predicting Four-Year’s Alzheimer’s Disease Onset Using Longitudinal Neurocognitive Tests and MRI Data Using Explainable Deep Convolutional Neural Networks
Abstract: Background: Prognosis of future risk of dementia from neuroimaging and cognitive data is important for optimizing clinical management for patients at early stage of Alzheimer’s disease (AD). However, existing studies lack an efficient way to integrate longitudinal information from both modalities to improve prognosis performance. Objective: In this study, we aim to develop and evaluate an explainable deep learning-based framework to predict mild cognitive impairment (MCI) to AD conversion within four years using longitudinal whole-brain 3D MRI and neurocognitive tests. Methods: We proposed a two-stage framework that first uses a 3D convolutional neural network to extract single-timepoint MRI-based AD-related latent features, followed by multi-modal longitudinal feature concatenation and a 1D convolutional neural network to predict the risk of future dementia onset in four years. Results: The proposed deep learning framework showed promising to predict MCI to AD conversion within 4 years using longitudinal whole-brain 3D MRI and cognitive data without extracting regional brain volumes or cortical thickness, reaching a balanced accuracy of 0.834, significantly improved from models trained from single timepoint or single modality. The post hoc model explainability revealed heatmap indicating regions that are important for predicting future risk of AD. Conclusions: The proposed framework sets the stage for future studies for using multi-modal longitudinal data to achieve optimal prediction for prognosis of AD onset, leading to better management of the diseases, thereby improving the quality of life.

Yun Guo*, Yan Sun*, Meng Li, Wan-Yi Qi, Lan Tan, Meng-Shan Tan, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Amyloid Pathology Modulates the Associations of Neuropsychiatric Symptoms with Cognitive Impairments and Neurodegeneration in Non-Demented Elderly
Abstract: Background: The associations between neuropsychiatric symptoms (NPSs) and Alzheimer’s disease (AD) have been well-studied, yet gaps remain. Objective: We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies. Methods: Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration. Results: We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-β (Aβ) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aβ deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aβ, the mediation percentage varied from 6.05% to 17.51% (p < 0.05). Conclusions: NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aβ.

Yu Jung Jang*, Min Gyu Choi*, Byung Jae Yoo, Kyeong Jae Lee, Won Beom Jung, Seong-Gi Kim, Sun Ah Park (Handling Associate Editor: Inhee Mook-Jung) *These authors contributed equally to this work.
Interaction Between a High-Fat Diet and Tau Pathology in Mice: Implications for Alzheimer’s Disease
Abstract: Background: Obesity is a modifiable risk factor for Alzheimer’s disease (AD). However, its relation with tau pathology (i.e., aberrant tau protein behavior in tauopathies such as AD) has been inconclusive. Objective: This study investigated the interaction between a high-fat diet (HFD) and tau pathology in adult male mice. Methods: Transgenic mice overexpressing human P301S Tau (those with the pathology) and wild-type (WT) littermates were subjected to behavioral tests, functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and western blotting analysis to investigate the effects of prolonged HFD versus regular diet during adulthood. Results: HFD increased body weight in both WT and P301S mice but had minimal effect on blood glucose levels. The brain response to HFD was tau genotype-specific. WT mice exhibited decreased recognition memory and enhanced network connectivity in fMRI, while P301S mice exhibited white matter tract disorganization in DTI as the sole significant finding. The reduction of insulin receptor β, insulin downstream signaling, neuronal nuclear protein, CD68-positive phagocytic activity, and myelin basic protein level were confined to the cortex of WT mice. In contrast to P301S mice, WT mice showed significant changes in the tau protein and its phosphorylation levels along with increased soluble neurofilament light levels in the hippocampus. Conclusions: HFD-induced brain dysfunction and pathological changes were blunted in mice with the pathology and more profound in healthy mice. Our findings highlight the need to consider this interaction between obesity and tau pathology when tailoring treatment strategies for AD and other tauopathies.

Maria Stefania De Simone, Gianfranco Spalletta, Daniela Vecchio, Andrea Bassi, Giovanni Augusto Carlesimo, Fabrizio Piras
The Role of the Anterior Thalamic Nuclei in the Genesis of Memory Disorders in Alzheimer’s Disease: An Exploratory Study
Abstract: Background: Increasing evidence is demonstrating that degeneration of specific thalamic nuclei, in addition to the hippocampus, may occur in Alzheimer’s disease (AD) from the prodromal stage (mild cognitive impairment – MCI) and contribute to memory impairment. Objective: Here, we evaluated the presence of macro and micro structural alterations at the level of the anterior thalamic nuclei (ATN) and medio-dorsal thalamic nuclei (MDTN) in AD and amnestic MCI (aMCI) and the possible relationship between such changes and the severity of memory impairment. Methods: For this purpose, a sample of 50 patients with aMCI, 50 with AD, and 50 age- and education-matched healthy controls (HC) were submitted to a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a comprehensive neuropsychological assessment. Results: At macro-structural level, both the ATN and MDTN were found significantly smaller in patients with aMCI and AD when compared to HC subjects. At micro-structural level, instead, diffusion alterations that significantly differentiated aMCI and AD patients from HC subjects were found only in the ATN, but not in the MDTN. Moreover, diffusion values of the ATN were significantly associated with poor episodic memory in the overall patients’ group. Conclusions: These findings represent the first in vivo evidence of a relevant involvement of ATN in the AD-related neurodegeneration and memory profile and strengthen the importance to look beyond the hippocampus when considering neurological conditions characterized by memory decline.