Volume 96, Number 3, 2023

Pages 861-875

Daniela Černotová, Karolína Hrůzová, David Levčík, Jan Svoboda, Aleš Stuchlík
Linking Social Cognition, Parvalbumin Interneurons, and Oxytocin in Alzheimer’s Disease: An Update
Abstract: Finding a cure for Alzheimer's disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.

Pages 877-912
Shalini Mani*, Rajni Dubey*, I-Chun Lai*, M. Arockia Babu, Sakshi Tyagi, Geeta Swargiary, Deepansh Mody, Manisha Singh, Shriya Agarwal, Danish Iqbal, Sanjay Kumar, Munerah Hamed, Punya Sachdeva, Abdulmajeed G. Almutary, Hind Muteb Albadrani, Shreesh Ojha, Sandeep Kumar Singh, Niraj Kumar Jha *These authors contributed equally to this work.
Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Pages 913-925

Sharon L. Naismith, Johannes C. Michaelian, Cherry Santos, Inga Mehrani, Joanne Robertson, Kasey Wallis, Xiaoping Lin, Stephanie A. Ward, Ralph Martins, Colin L. Masters, Michael Breakspear, Susannah Ahern, Jurgen Fripp, Peter R. Schofield, Perminder S. Sachdev, Christopher C. Rowe
Tackling Dementia Together via The Australian Dementia Network (ADNeT): A Summary of Initiatives, Progress, and Plans
Abstract: In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia’s leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national Registry for Mild Cognitive Impairment and dementia with 74 participating clinical sites, an extensive map of memory clinic services, national Memory and Cognition Clinic Guidelines and specialized screening for trials sites in five states. This paper provides an overview of ADNeT’s achievements to date and future directions. With the increase in dementia cases expected over coming decades, and with recent advances in plasma biomarkers and disease-modifying therapies, the nationally coordinated initiatives and partnerships ADNeT has established are critical for increased national prevention efforts, co-ordinated implementation of emerging treatments for Alzheimer’s disease, innovation of early and accurate diagnosis, driving continuous improvements in clinical care and patient outcome and access to post-diagnostic support and clinical trials. For a heterogenous disorder such as dementia, which is now the second leading cause of death in Australia following cardiovascular disease, the case for adequate investment into research and development has grown even more compelling.

Pages 927-945

Jiahui Yang, Xiaohua Shi, Yingying Wang, Ming Ma, Hongyu Liu, Jiaoqi Wang, Zhongxin Xu
Multi-Target Neuroprotection of Thiazolidinediones on Alzheimer’s Disease via Neuroinflammation and Ferroptosis
Abstract: Alzheimer's disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients.

Pages 947-966
Systematic Review

Kristian Steen Frederiksen, Krista L. Lanctôt, Wendy Weidner, Julie Hviid Hahn-Pedersen, Soeren Mattke (Handling Associate Editor: Elżbieta Kuźma)
A Literature Review on the Burden of Alzheimer’s Disease on Care Partners
Abstract: Background: Many individuals with Alzheimer’s disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments. Objective: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD. Methods: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical health of care partners, and the economic or financial burden of AD. Results: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost. Conclusions: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions.

Pages 967-977
Systematic Review

Elizabeth Healy
Impact of the MIND Diet on Cognition in Individuals with Dementia
Abstract: Background: Alzheimer’s disease (AD) plagues 6.5 million Americans 65+, yet treatments are lacking. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been developed to address the expansive impact of dementias on the general public. This systematic review evaluated the impact of the MIND diet on cognition in those with pathologies across the dementia spectrum. Objective: To evaluate the application of the MIND diet for prevention and/or treatment of dementia. Methods: PubMed was used to conduct a search using the MIND diet and terms related to cognition. Articles were excluded if they were published prior to 2018, studied a population without dementia or significant risk factors, or did not include those 65+. The overall quality of each source was analyzed based on the cognitive test(s) used, the selection of subjects, and the sample size. Results: The search generated 33 papers, which yielded 11 articles after screening. Of these studies, one was conducted on those with mild cognitive impairment, one with AD, two with general dementia, and seven with at-risk individuals. All the studies found a positive correlation between adherence and some form of cognitive functioning, but results were mixed for specific cognitive domains. Conclusions: These findings suggest that the MIND diet may be a useful long-term treatment option for those with various dementia pathologies. However, more research is needed on subjects with onset dementias. Additionally, there is a need for more research into the mechanisms behind the common comorbidities.

Pages 979-1010
Systematic Review

Leila Salhi, Yaman Al Taep, Eric Salmon, Dorien Van hede, France Lambert
How Periodontitis or Periodontal Bacteria Can Influence Alzheimer’s Disease Features? A Systematic Review of Pre-Clinical Studies
Abstract: Background: The negative effects of periodontitis on systemic diseases, including diabetes, cardiovascular diseases, and Alzheimer’s disease (AD), have been widely described. Objective: This systematic review aimed to gather the current understanding of the pathophysiological mechanisms linking periodontitis to AD. Methods: An electronic systematic search of the PubMed/MEDLINE, Scopus, and Embase databases was performed using the following PECO question: How can periodontitis or periodontal bacteria influence Alzheimer’s disease features?”. Only preclinical studies exploring the biological links between periodontitis and AD pathology were included. This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO), and the Syrcle and Camarades protocols were used to assess the risk of bias. Results: After a systematic screening of titles and abstracts (n=3,307), thirty-six titles were selected for abstract reading, of which 13 were excluded (k=1), resulting in the inclusion of 23 articles. Oral or systemic exposure to periodontopathogens or their byproducts is responsible for both in situ brain manifestations and systemic effects. Significant elevated rates of cytokines and amyloid peptides (Aβ) and derivate products were found in both serum and brain. Additionally, in infected animals, hyperphosphorylation of tau protein, hippocampal microgliosis, and neuronal death were observed. Exposure to periodontal infection negatively impairs cognitive behavior, leading to memory decline. Conclusions: Systemic inflammation and brain metastatic infections induced by periodontal pathogens contribute to neuroinflammation, amyloidosis, and tau phosphorylation, leading to brain damage and subsequent cognitive impairment.

Pages 1011-1017
Short Communication

Hijiri Shinagawa, Kazuki Ohuchi, Yuya Goto, Kohei Hashimoto, Hideki Kijima, Shogo Maekawa, Hisaka Kurita, Masatoshi Inden (Handling Associate Editor: Shun Shimohama)
Vacuolar Protein-Sorting Proteins Are Reduced Even Before Cognitive Decline in a Mouse Model of Alzheimer’s Disease
Abstract: Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer’s disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson’s disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these proteins.

Pages 1019-1024
Short Communication

Borroni Barbara, Urso Daniele, Zecca Chiara, Binetti Giuliano, Fostinelli Silvia, Benussi Luisa, Ghidoni Roberta, Tarantino Barbara, Rivolta Jasmine, Dell’Abate Maria Teresa, Alberici Antonella, Logroscino Giancarlo (Handling Associate Editor: Paulo Caramelli)
Survival in Incident Cases with Frontotemporal Lobar Degeneration: A Registry-Based Study
Abstract: Population-based registries represent a unique sample to estimate survival. The aim of the present study was to assess survival rates and predictors of outcome in incidental frontotemporal lobar degeneration (FTLD). Incident cases with FTLD, included between January 1, 2017 to December 31, 2017, have been followed for five years. Median survival was 8.16 years from disease onset and 5.38 years from diagnosis. Survival rates did not differ between phenotypes. Shorter disease duration from onset to diagnosis was associated with poorer outcome (p=0.01). FTLD is a relatively homogeneous disease in terms of survival. Future multinational population-based studies are needed to confirm these findings.

Pages 1025-1040
Vrinda Kalia, Erin R. Kulick, Badri Vardarajan, Yian Gu, Jennifer J. Manly, Mitchell S.V. Elkind, Joel D. Kaufman, Dean P. Jones, Andrea A. Baccarelli, Richard Mayeux, Marianthi-Anna Kioumourtzoglou, Gary W. Miller
Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia
Abstract: Background: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations. Objective: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5 µm in aerodynamic diameter (PM2.5), PM less than 10 µm in aerodynamic diameter (PM10), and nitrogen dioxide (NO2) in an ethnically diverse, older population. Methods: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project in New York City, collected from 1995–2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis. Results: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2. PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer’s disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. Conclusions: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population.

Pages 1041-1049
Sebastian Köhler, Lion M. Soons, Huibert Tange, Kay Deckers, Martin P.J. van Boxtel
Sleep Quality and Cognitive Decline Across the Adult Age Range: Findings from the Maastricht Aging Study (MAAS)
Abstract: Background: Sleep disturbances have been linked with cognitive decline and a higher risk of dementia. However, there is a lack of studies with sufficient follow-up duration, a detailed neuropsychological assessment and adequate control of main confounders. Objective: To investigate the relation between self-reported sleep quality and cognitive decline over 12 years in cognitively healthy individuals from the general population. Methods: We used data from the Maastricht Aging Study (MAAS), a Dutch population-based prospective cohort study of 1,823 community-dwelling adults aged 24 to 82 years at baseline. Cognitive performance was measured at baseline, 6 and 12 years on verbal memory, executive functions, and information processing speed. Sleep quality was assessed at baseline using the sleep subscale score of the 90-item Symptom Checklist (SCL-90). Additional modifiable dementia risk factors were summarized in the LIfestyle for BRAin health (LIBRA) risk score. Weighted linear mixed models tested the association between continuous scores and tertiles of subjective sleep quality and change in cognitive performances over time. Models were adjusted for age, gender, educational level, LIBRA, and use of hypnotic (sleep) medication. Results: Worse sleep quality was associated with faster decline in processing speed. At older age (≥65 years), it was also associated with faster decline in verbal memory. Association were independent of other modifiable dementia risk factors and use of hypnotic medication. Directionally similar but non-significant associations were found between worse sleep quality and executive functions. Conclusions: In this population-based study across the adult age range, poor self-reported sleep was associated with accelerated cognitive decline.

Pages 1051-1058
Won Jong Chwa, Cyrus A. Raji, Kat Toups, Ann Hathaway, Deborah Gordon, Henrianna Chung, Alan Boyd, Benjamin D. Hill, Sharon Hausman-Cohen, Mouna Attarha, Michael Jarrett, Dale E. Bredesen
Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. Objective: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). Methods: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. Results: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons. Conclusions: A precision-medicine guided approach to intervention may carry potential in curtailing both WM and GM atrophy, as rates of morphological change aligned more closely with normal aging than AD across all studied regions. Improvements in cognitive scores were statistically significant but may not necessarily represent clinical significance. Further studies should be pursued to further delineate cognitive trends as well as the mechanisms behind subtle regional differences in response to precision medicine-guided intervention.

Pages 1059-1070
Jiajie Lu, Rihong Huang, Yuecheng Peng, Jinming Zhang, Kairong Liang, Yezhong Wang, Yi Feng, Zhaotao Wang
Mendelian Randomization Analyses Accounting for Causal Effect of COVID-19 on Brain Imaging-Derived Phenotypes
Abstract: Background: The coronavirus disease 2019 (COVID-19) has been a major challenge to global health and a financial burden. Little is known regarding the possible causal effects of COVID-19 on the macro- and micro-structures of the human brain. Objective: To determine the causal links between susceptibility, hospitalization, and the severity of COVID-19 and brain imaging-derived phenotypes (IDPs). Methods: Mendelian randomization (MR) analyses were performed to investigate the causal effect of three COVID‐19 exposures (SARS‐CoV‐2 infection, hospitalized COVID‐19, and critical COVID‐19) on brain structure employing summary datasets of genome‐wide association studies. Results: In terms of cortical phenotypes, hospitalization due to COVID-19 was associated with a global decrease in the surface area (SA) of the cortex structure (β = -624.77, 95% CI: -1227.88 to -21.66, p = 0.042). At the regional level, SARS-CoV-2 infection was found to have a nominally causal effect on the thickness (TH) of the postcentral region (β = -0.004, 95% CI: -0.007 to -0.001, p = 0.01), as well as eight other IDPs. Hospitalized COVID-19 has a nominally causal relationship with TH of postcentral (β = -0.004, 95% CI: -0.007 to -0.001, p = 0.01) and other 6 IDPs. The nominally causal effects of critical COVID-19 on TH of medial orbitofrontal (β = 0.004, 95% CI: 0.001to 0.007, p = 0.004) and other 7 IDPs were revealed. Conclusions: Our study provides compelling genetic evidence supporting causal relationships between three COVID-19 traits and brain IDPs. This discovery holds promise for enhancing predictions and interventions in brain imaging.

Pages 1071-1081
Jie Zhou*, Zhi-Bo Wang*, Yan Sun, Yan Fu, Da Li, Lan Tan, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Cerebrospinal Fluid Complement 4 Levels Were Associated with Alzheimer’s Disease Pathology and Cognition in Non-Demented Elderly
Abstract: Background: Numerous studies have shown that the complement system plays an important role in Alzheimer's disease (AD). However, whether complement 4 (C4) protein in cerebrospinal fluid (CSF) was associated with AD pathology, especially in the early stage of AD, is still unclear. Objective: We aimed to explore the association of CSF C4 with AD pathology and cognition in the preclinical AD. Methods: The study included a total of 287 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Based on the A/T scheme, they were divided into four groups to access the changes of CSF C4 in the preclinical AD. Linear regression models were used to test the associations between CSF C4 and AD core biomarkers, namely Aβ42, P-tau, and T-tau. Results: The level of CSF C4 decreased in the A+T- group compared with the A-T- group (p = 0.04) and it increased in the A-T+ group compared to the A+T- group (p = 0.01). In pooled samples, C4 was significantly associated with AD core biomarkers (all p < 0.05), but only in the A+ group after stratification according to the A/T scheme. Furthermore, CSF C4 levels at baseline were associated with longitudinal cognitive changes. Conclusions: Our results showed that CSF C4 levels changed dynamically in the preclinical AD, and that the responses of CSF C4 to brain Aβ pathology, tau pathology and neurodegeneration were found only in the presence of amyloid plaques, both of which indicates the complex link between C4 and AD.

Pages 1083-1096
Aline Mendes, Sverre Bergh, Bruno Mario Cesana, Ron Handels, Alfonso Ciccone, Emmanuel Cognat, Andrea Fabbo, Sara Fascendini, Giovanni B. Frisoni, Lutz Froelich, Maria Cristina Jori, Patrizia Mecocci, Paola Merlo, Oliver Peters, Magdalini Tsolaki, Carlo Alberto Defanti
Respectful Caring for the Agitated Elderly (ReCAGE): A Multicentre, Prospective, Observational Study to Evaluate the Effectiveness of Special Care Units for People with Dementia
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) bring complexity in the clinical management of people with dementia; therefore, it is important to evaluate different models of care, such as Special Care Units (SCU-B). Objective: To evaluate the SCU-B effectiveness toward alleviating BPSD and improving the quality of life (QoL) of patients and their caregivers. Methods: ReCAGE was a multicenter, controlled, longitudinal study where 508 patients with BPSD were enrolled in two cohorts: 262 patients from centers endowed with a SCU-B, and 246 from centers without SCU-B. Statistical analyses included factorial ANCOVA for comparison among centers. The primary endpoint was effectiveness of the SCU-B, measured through the Neuropsychiatric Inventory (NPI) changes. Secondary endpoints were change in QoL of patients and caregivers, and the tertiary endpoint was time to nursing home admission. Results: The NPI scores decreased in both arms, with a statistically significant difference from baseline to 36 months (p<0.0001) in both cohorts. Over time, NPI decreased more steeply during the first year in the SCU-B arm, but in the following two years the slope was clearly in favor of the control arm. This different pattern of the two cohorts reached statistical significance at the interaction “cohort by time” (p<0.0001). Conflicting results were found regarding the outcomes of quality of life, while there were no differences in time to institutionalization in both cohorts. Conclusions: The RECage study did not confirm the long-term superiority of the pathway comprising a SCU-B. A post-hoc analysis revealed data supporting their acute effectiveness during behavioral crises.

Pages 1097-1113
Niek Brosens, Dimitrios Samouil, Sabine Stolker, Efthymia Vasilina Katsika, Sascha Weggen, Paul J. Lucassen, Harm J. Krugers
Early Life Stress Enhances Cognitive Decline and Alters Synapse Function in Young Male APP/PS1 Mice
Abstract: Background: Exposure to stress early in life increases the susceptibility to Alzheimer’s disease (AD) pathology in aged AD mouse models. So far, the underlying mechanisms have remained elusive. Objective: To investigate 1) effects of early life stress (ELS) on early functional signs of AD pathology that precede the advanced neuropathological changes, and 2) correlate synaptosomal protein content with cognition to identify neural correlates of AD. Methods: APPswe/PS1dE9 mice and littermates were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days 2-9. At 3 months of age, an age where no cognitive loss or amyloid-β (Aβ) pathology is typically reported in this model, we assessed hippocampal Aβ pathology, synaptic strength and composition and interneuron populations. Moreover, cognitive flexibility was assessed and correlated with synaptosomal protein content. Results: While ELS did not affect Aβ pathology, it increased synaptic strength and decreased the number of calretinin+ interneurons in the hippocampal dentate gyrus. Both genotype and condition further affected the level of postsynaptic glutamatergic protein content. Finally, APP/PS1 mice were significantly impaired in cognitive flexibility at 3 months of age, and ELS exacerbated this impairment, but only at relatively high learning criteria. Conclusions: ELS reduced cognitive flexibility in young APP/PS1 mice and altered markers for synapse and network function. These findings at an early disease stage provide novel insights in AD etiology and in how ELS could increase AD susceptibility.

Pages 1115-1127
Chisato Fujisawa, Hiroyuki Umegaki, Taiki Sugimoto, Hirotaka Nakashima, Masaaki Nagae, Hitoshi Komiya, Kazuhisa Watanabe, Yosuke Yamada, Takashi Sakurai
Relationship Between Non-Cognitive Intrinsic Capacity and Activities of Daily Living According to Alzheimer’s Disease Stage
Abstract: Background: Few studies have examined the relationship between non-cognitive factors and activities of daily living (ADL) according to Alzheimer’s disease (AD) stage. Objective: We aimed to identify the differences in non-cognitive factors according to AD stages and their involvement in basic and instrumental ADL performance by using intrinsic capacity (IC) in groups with cognition ranging from normal to moderate or severe AD. Methods: We enrolled 6397 patients aged ≥65 years who visited our memory clinic. Non-cognitive IC was assessed using the locomotion, sensory, vitality, and psychological domains. Multiple logistic regression was performed to identify how non-cognitive IC declines over the AD course and examine the correlation between non-cognitive IC and basic and instrumental ADL performance. Results: Non-cognitive IC declined from the initial AD stage and was significantly correlated with both basic and instrumental ADL performance from the aMCI stage through all AD stages. In particular, the relationship between IC and basic ADL was stronger in mild and moderate to severe AD than in the aMCI stage. On the other hand, the relationship between IC and instrumental ADL was stronger in aMCI than in later AD stages. Conclusions: The results show non-cognitive factors, which decline from the aMCI stage, are correlated with ADL performance from the aMCI stage to almost all AD stages. Considering that the relationship strength varied by ADL type and AD stage, an approach tailored to ADL type and AD stage targeting multiple risk factors is likely needed for effectively preventing ADL performance declines.

Pages 1129-1138
Xiaoran Liu, Carrie J. Finno, Todd Beck, Klodian Dhana, Christy Tangney, Pankaja Desai, Kristin Krueger, Denis A. Evans, Kumar B. Rajan
Association of Vitamin E and Cognitive Decline in Older Adults with and without the APOE ɛ4 Allele: A Biracial Population-Based Community Study
Abstract: Background: The association of different types of tocopherols (vitamin E) with cognition might vary by the APOE ɛ4 allele status. Objective: We examined the association of dietary tocopherols with cognitive decline among participants with and without the APOE ɛ4 allele over a median of 12 years. Methods: 2,193 participants from the Chicago Health and Aging Project were included in the analyses. Global cognition was assessed in three-year cycles. We used a 144-item FFQ to assess dietary intakes of tocopherols and hME Sequenom mass-array platform to assess APOE genotype. We used linear mixed effects models to examine the relationship between tocopherol from food sources and global cognitive decline. Results: The mean baseline age was 74.1 (SD=5.9) years. Among APOE ɛ4 carriers, participants in the highest quintile of intakes of dietary vitamin E had a slower cognitive decline of 0.022 SDU (95% CI: 0.000, 0.043) compared to those in the lowest quintile. A higher intake of dietary α-tocopherol from food sources only was associated with slower cognitive decline in APOE ɛ4 carriers (p for trend 0.002) but not among the non-carriers (p for trend 0.937). Among APOE ɛ4 carriers, those in the highest quintile of intake of α-tocopherol had a 16.4% slower rate of decline of global cognition compared to those in the lowest quintile (β = 0.034, 95% CI: 0.013, 0.054). Conclusions: Individuals consuming high α-tocopherol from food sources had slower cognitive decline among APOE ɛ4 carriers. In older adults, different forms of vitamin E might moderate the relationship of APOE ɛ4 with global cognition.

Pages 1139-1149
Vaisakh Puthusseryppady, Allan Bregola, Julieta Camino, Tamara Backhouse, Eneida Mioshi
Is Carer Management Style Associated with Longitudinal Functional Decline in Dementia?
Abstract: Background: Various intrinsic (related to dementia) and extrinsic (not related to dementia) factors have been suggested to contribute separately to disability in people living with dementia (PLwD). Objective: To investigate if the combination of specific intrinsic and extrinsic factors at baseline is associated with longitudinal declines in activities of daily living (ADL) performance of PLwD at 12-month follow-up. Methods: 141 community-dwelling PLwD-carer dyads were assessed on their global cognition (ACE-III), apathy (CBI-R), carer management styles (DMSS), medical comorbidities (CCI), and ADL performance (DAD) at baseline, and for a subset of participants (n = 53), at 12-month follow-up. Multiple linear regression models were run to assess: 1) the relationships between PLwD’s DAD scores and the remaining variables at baseline and 2) whether these variables’ scores at baseline were associated with longitudinal change in the PLwD’s DAD scores. Results: At baseline, having lower ACE-III (β=0.354, p<0.001), higher CBI-R (β=−0.284, p<0.001), higher DMSS criticism (β=−0.367, p=0.013), lower DMSS encouragement (β=0.370, p= 0.014), and higher CCI scores (β=−2.475, p=0.023) were significantly associated with having lower DAD scores. The PLwD’s DAD scores significantly declined from baseline to follow-up (p<0.001, d=1.15), however this decline was not associated with the baseline scores of any of the independent variables. Instead, it was associated with declines in the PLwD’s ACE-III scores from baseline to follow-up (β=1.021, p=0.001). Conclusions: In our limited sample, cognitive changes seem to be the main factor underlying longitudinal decline in ADL performance for PLwD. Carer management styles appear associated with current ADL performance but not with longitudinal ADL decline.

Pages 1151-1162
Hamed Azami, Elham Daftarifard, Anne Humeau-Heurtier, Alberto Fernandez, Daniel Abasolo, Tarek K. Rajji
Assessment and Comparison of Nonlinear Measures in Resting-State Magnetoencephalograms in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: Nonlinear dynamical measures, such as fractal dimension (FD), entropy, and Lempel-Ziv complexity (LZC), have been extensively investigated individually for detecting information content in magnetoencephalograms (MEGs) from patients with Alzheimer’s disease (AD). Objective: To compare systematically the performance of twenty conventional and recently introduced nonlinear dynamical measures in studying AD versus mild cognitive impairment (MCI) and healthy control (HC) subjects using MEG. Methods: We compared twenty nonlinear measures to distinguish MEG recordings from 36 AD (mean age=74.06±6.95 years), 18 MCI (mean age=74.89±5.57 years), and 26 HC subjects (mean age=71.77±6.38 years) in different brain regions and also evaluated the effect of the length of MEG epochs on their performance. We also studied the correlation between these measures and cognitive performance based on the Mini-Mental State Examination (MMSE). Results: The results obtained by LZC, zero-crossing rate (ZCR), FD, and dispersion entropy (DispEn) measures showed significant differences among the three groups. There was no significant difference between HC and MCI. The highest Hedge’s g effect sizes for HC versus AD and MCI versus AD were respectively obtained by Higuchi’s FD (HFD) and fuzzy DispEn (FuzDispEn) in the whole brain and was most prominent in left lateral. The results obtained by HFD and FuzDispEn had a significant correlation with the MMSE scores. DispEn-based techniques, LZC, and ZCR, compared with HFD, were less sensitive to epoch length in distinguishing HC form AD. Conclusions: FuzDispEn was the most consistent technique to distinguish MEG dynamical patterns in AD compared with HC and MCI.

Pages 1163-1172
Linda K. McEvoy, Jaclyn Bergstrom, Donald J. Hagler Jr, David Wing, Emilie T. Reas
Elevated Pure Tone Thresholds Are Associated with Altered Microstructure in Cortical Areas Related to Auditory Processing and Attentional Allocation
Abstract: Background: Hearing loss is associated with cognitive decline and increased risk for Alzheimer’s disease, but the basis of this association is not understood. Objective: To determine whether hearing impairment is associated with advanced brain aging or altered microstructure in areas involved with auditory and cognitive processing. Methods: 130 participants, (mean 76.4±7.3 years; 65% women) of the Rancho Bernardo Study of Healthy Aging had a screening audiogram in 2003-2005 and brain magnetic resonance imaging in 2014-2016. Hearing ability was defined as the average pure tone threshold (PTA) at 500, 1000, 2000, and 4000 Hz in the better-hearing ear. Brain-predicted age difference (Brain-pad) was calculated as the difference between brain-predicted age based on a validated structural imaging biomarker of brain age, and chronological age. Regional diffusion metrics in temporal and frontal cortex regions were obtained from diffusion-weighted MRIs. Linear regression analyses adjusted for age, gender, education, and health-related measures. Results: PTAs were not associated with brain-PAD (β=0.09; 95% CI: -0.084 to 0.243; p=0.34). PTAs were associated with reduced restricted diffusion and increased free water diffusion primarily in right hemisphere temporal and frontal areas (restricted diffusion: βs= -0.21 to -0.30; 95% CIs from -0.48 to -0.02; ps< 0.03; free water: βs= 0.18 to 0.26; 95% CIs 0.01 to 0.438; ps< 0.04). Conclusions: Hearing impairment is not associated with advanced brain aging but is associated with differences in brain regions involved with auditory processing and attentional control. It is thus possible that increased dementia risk associated with hearing impairment arises, in part, from compensatory brain changes that may decrease resilience.

Pages 1173-1182
Catarina Bernardes, Marisa Lima, Diana Duro, Anuschka Silva-Spínola, João Durães, Miguel Tábuas-Pereira, Inês Baldeiras, Sandra Freitas, Isabel Santana
Montreal Cognitive Assessment in Mild Cognitive Impairment: Relationship with Cerebrospinal Fluid Biomarkers and Conversion to Dementia
Abstract: Background: Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer’s disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer’s disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking. Objective: This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia. Methods: Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models. Results: MoCA z-scores were correlated with Aβ42 (p=0.026), t-tau (p=0.033), and p-tau (p=0.01). Impaired MMSE (p<0.001) and MoCA z-scores (p=0.019), decreased Aβ42 (p<0.001) and increased t-tau (p<0.001) and p-tau (p<0.001) were associated with shorter estimated time of conversion. Aβ42 (p<0.001) and MMSE z-scores (p=0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p=0.004) (but not MMSE) was an independent predictor of conversion as well as CSF Aβ42. Conclusions: This study confirms the role of CSF-AD-b, namely Aβ42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients.

Pages 1183-1193
Yingying Zhu, Natalia Olchanski, Joshua T. Cohen, Karen M. Freund, Jessica D. Faul, Howard M. Fillit, Peter J. Neumann, Pei-Jung Lin (Handling Associate Editor: Jenny van der Steen)
Life-Sustaining Treatments Among Medicare Beneficiaries with and without Dementia at the End of Life
Abstract: Background: Older adults with dementia including Alzheimer’s disease have difficulty communicating their treatment preferences and thus may receive intensive end-of-life (EOL) care that confers limited benefits. Objective: This study compared the use of life-sustaining interventions during the last 90 days of life among Medicare beneficiaries with and without dementia. Methods: This cohort study utilized population-based national survey data from the 2000-2016 Health and Retirement Study linked with Medicare and Medicaid claims. Our sample included Medicare fee-for-service beneficiaries aged 65 years or older deceased between 2000 and 2016. The main outcome was receipt of any life-sustaining interventions during the last 90 days of life, including mechanical ventilation, tracheostomy, tube feeding, and cardiopulmonary resuscitation. We used logistic regression, stratified by nursing home use, to examine dementia status (no dementia, non-advanced dementia, advanced dementia) and patient characteristics associated with receiving those interventions. Results: Community dwellers with dementia were more likely than those without dementia to receive life-sustaining treatments in their last 90 days of life (advanced dementia: OR=1.83 [1.42-2.35]; non-advanced dementia: OR=1.16 [1.01-1.32]). Advance care planning was associated with lower odds of receiving life-sustaining treatments in the community (OR=0.84 [0.74-0.96]) and in nursing homes (OR=0.68 [0.53-0.86]). More beneficiaries with advanced dementia received interventions discordant with their EOL treatment preferences. Conclusions: Community dwellers with advanced dementia were more likely to receive life-sustaining treatments at the end of life and such treatments may be discordant with their EOL wishes. Enhancing advance care planning and patient-physician communication may improve EOL care quality for patients with dementia.

Pages 1195-1206
Malika G. Fernando, Renuka Silva, W.M.A.D. Binosha Fernando, H. Asita de Silva, A. Rajitha Wickremasinghe, Asoka S. Dissanayake, Hamid R. Sohrabi, Ralph N. Martins, Shehan S. Williams
Effect of Virgin Coconut Oil Supplementation on Cognition of Individuals with Mild-to-Moderate Alzheimer’s Disease in Sri Lanka (VCO-AD Study): A Randomized Placebo-Controlled Trial
Abstract: Background: Virgin coconut oil (VCO) is a potential therapeutic approach to improve cognition in Alzheimer’s disease (AD) due to its properties as a ketogenic agent and antioxidative characteristics. Objective: This study aimed to investigate the effect of VCO on cognition in people with AD and to determine the impact of apolipoprotein E (APOE) ε4 genotype on cognitive outcomes. Methods: Participants of this double-blind placebo-controlled trial (SLCTR/2015/018, 15.09.2015) were 120 Sri Lankan individuals with mild-to-moderate AD (MMSE=15-25), aged >65 years, and they were randomly allocated to treatment or control groups. The treatment group was given 30 mL/day of VCO orally and the control group, received similar amount of canola oil, for 24 weeks. The Mini-Mental Sate Examination (MMSE) and Clock drawing test were performed to assess cognition at baseline and at the end of the intervention. Blood samples were collected and analyzed for lipid profile and glycated hemoglobin (HbA1C) levels. Results: There were no significant difference in cognitive scores, lipid profile, and HbA1C levels between VCO and control groups post-intervention. The MMSE scores, however, improved among APOE ε4 carriers who had VCO, compared to non-carriers (2.37, p=0.021). APOE ε4 status did not influence the cognitive scores in the control group. The attrition rate was 30%. Conclusions: Overall, VCO did not improve cognition in individuals with mild-to-moderate AD following a 24-week intervention, compared to canola oil. However, it improved the MMSE scores in APOE ε4 carriers. Besides, VCO did not compromise lipid profile and HbA1C levels and is thus safe to consume.

Pages 1207-1219
Philippos Koulousakis, Emily Willems, Melissa Schepers, Ben Rombaut, Jos Prickaerts, Tim Vanmierlo*, Daniel van den Hove* *These authors contributed equally to this work.
Exogenous Oxytocin Administration Restores Memory in Female APP/PS1 Mice
Abstract: Background: Current treatment options for Alzheimer’s disease (AD) are limited, inefficient, and often have serious side effects. Oxytocin is a neuropeptide implicated in a variety of central processes, such as social and reproductive behaviors. Among others, it has garnered attention in various domains of psychiatric research, while its role in the development and course of neurodegenerative disorders like AD is rather unknown. Objective: This study aimed to investigate the role of exogenous oxytocin administration on memory, specifically in view of AD, as a potential novel treatment option. Methods: We describe a novel treatment approach by using a relatively low dose of long-term intranasal oxytocin treatment, to restore memory deficits in female APPswePS1dE9 mice. Results: Female APPswePS1dE9 mice treated with oxytocin showed increased spatial memory performance in the object location task and improved working memory in the Y-Maze, while indicating decreased sociability. Conclusions: These results indicate that oxytocin is able to reverse acquired cognitive deficits in female APPswePS1dE9 mice.

Pages 1221-1230
Utako Adachi, Sono Toi, Megumi Hosoya, Takao Hoshino, Misa Seki, Hiroshi Yoshizawa, Yukiko Tsutsumi, Kenji Maruyama, Kazuo Kitagawa
Association of Age-Related Spontaneous Internal Jugular Vein Reflux with Cognitive Impairment and Incident Dementia
Abstract: Background: It remains unclear whether changes in the venous circulation contribute to cognitive decline. Objective: This study aimed to clarify whether the spontaneous jugular vein reflux (JVR) is associated with cognitive impairment and incident dementia. Methods: Patients with any evidence of cerebral vessel disease on magnetic resonance imaging (MRI) were consecutively enrolled between October 2015 to July 2019. We employed carotid duplex sonography to measure the internal jugular vein (IJV). The subjects were classified into two groups based on the degree of JVR on either side: none, mild (JVR(-) group) and moderate, severe (JVR (+) group) JVR. They underwent both the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese (MoCA-J) global tests. Their cognitive status was prospectively assessed until March 2023. Results: 302 patients with an MMSE score ≥24 underwent duplex sonography of the IJV. Among them, 91 had spontaneous JVR on either side. Both MMSE and MoCA-J were significantly lower in patients with JVR (+) group than in the JVR (-) group. After the adjustment for risk factors and MRI findings, intergroup differences in MoCA-J remained significant. Among the cognitive subdomains, median executive function and memory scores were significantly lower in the JVR (+) group than in the JVR (-) group. During the median 5.2-year follow-up, 11 patients with incident dementia were diagnosed. Patients with severe JVR were significantly more likely to be diagnosed with dementia (log-rank test, p=0.031). Conclusions: Spontaneous IJV reflux especially severe JVR, was associated with global cognitive function, and potentially with incident dementia.

Pages 1231-1241
Alfonso Delgado-Álvarez, Cristina Delgado-Alonso, María Valles-Salgado, María José Gil-Moreno, Lucía Fernández-Romero, Jorge Matías-Guiu, Jordi A. Matias-Guiu
Normative Data in Cross-Cultural Neuropsychological Instruments in Spaniards and Colombians Living in Spain
Abstract: Background: Cross-Cultural Dementia Screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), and European Cross-cultural Neuropsychological Test Battery (CNTB) are three novel neuropsychological instruments developed from a cross-cultural perspective to reduce the impact of culture in cognitive assessment and improve the assessment in diverse populations. Objective: We aimed to collect and present normative data on these tests in a majority population sample (Spaniards living in Spain) and in a minority population sample (Colombians living in Spain). Methods: CCD, RUDAS, and CNTB were administered to a group of 300 cognitively healthy participants (150 Spaniards and 150 Colombians). Linear regression modeling strategy was used to provide adjusted norms for demographic factors and to explore the influence of these factors on test performance. Results: Most of the CCD and CNTB scores were predicted by age and years of education, with some tests only predicted by age or showing a ceiling effect. The comparison of normative data between the two samples confirmed the favorable cross-cultural properties of these instruments, with only some differences in processing speed and executive functioning scores. Conclusions: Our study finds a comparable influence of demographic factors in both populations on the performance of CCD, RUDAS, and CNTB, confirming their adequate cross-cultural properties. We provide normative data for these tests in Spaniards and Colombians living in Spain.

Pages 1243-1252
Jared J. Tanner, Manish Amin, Catherine Dion, Hari K. Parvataneni, Thomas Mareci, Catherine C. Price (Handling Associate Editor: David Libon)
Perioperative Extracellular Brain Free-Water Changes for Older Adults Electing Total Knee Arthroplasty with General versus Spinal Anesthesia: A Pilot Study
Abstract: Background: Recent research shows that older adults electing to undergo total knee arthroplasty with general anesthesia have a pre- to postoperative acute increase in molecular free-water within their cerebral white matter. It is unknown if this change is similar for individuals who elect spinal anesthesia methods. Objective: To explore white matter microstructural changes in a pilot sample of older adults undergoing total knee arthroplasty and receiving general or spinal anesthesia. Methods: We assessed acute perioperative changes in brain white matter free-water in a limited number of older adults electing total knee arthroplasty under spinal anesthesia (n = 5) and matched groups of older adults who received general anesthesia (n = 5) or had no surgery (n = 5). Patterns of free-water changes were also compared in the larger group of older adults electing total knee arthroplasty under general anesthesia (n = 61) and older adults with chronic knee pain who received no surgical intervention (n = 65). Results: Our pilot results suggest older adults receiving general anesthesia had pre- to post-surgery free-water increases extensively throughout their white matter whereas those receiving spinal anesthesia appeared to have less consistent free-water increases. Conclusions: Our pilot results possibly suggest different patterns of perioperative brain white matter free-water changes based on anesthetic approach. We recommend future, larger studies to further examine the effects of anesthetic approach on perioperative brain free-water. The results of our study have potential implications for acute and chronic cognitive changes, perioperative complications, neurodegenerative processes including Alzheimer’s disease, and understanding neuroinflammation.

Pages 1253-1265
Hideki Matsumoto, Kenji Tagai, Hironobu Endo, Kiwamu Matsuoka, Yuhei Takado, Naomi Kokubo, Hitoshi Shimada, Tetsuya Goto, Tazuko K. Goto, Makoto Higuchi
Association of Tooth Loss with Alzheimer’s Disease Tau Pathologies Assessed by Positron Emission Tomography
Abstract: Background: Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer’s disease (AD) model mouse suggests that tooth loss induces denervation of the mesencephalic trigeminal nucleus and neuroinflammation, possibly leading to accelerated tau dissemination from the nearby locus coeruleus (LC). Objective: To elucidate the relevance of oral conditions and amyloid-β (Aβ) and tau pathologies in human participants. Methods: We examined the number of remaining teeth and the biofilm–gingival interface index in 24 AD-spectrum patients and 19 age-matched healthy controls (HCs). They also underwent positron emission tomography (PET) imaging of Aβ and tau with specific radiotracers, 11C-PiB and 18F-PM-PBB3, respectively. All AD-spectrum patients were Aβ-positive, and all HCs were Aβ-negative. We analyzed the correlation between the oral parameters and radiotracer retention. Results: No differences were found in oral conditions between the AD and HC groups. 11C-PiB retentions did not correlate with the oral indices in either group. In AD-spectrum patients, brain-wide, voxel-based image analysis highlighted several regions, including the LC and associated brainstem substructures, as areas where 18F-PM-PBB3 retentions negatively correlated with the remaining teeth and revealed the correlation of tau deposits in the LC (r = -0.479, p = 0.018) primarily with the hippocampal and neighboring areas. The tau deposition in none of the brain regions was associated with the periodontal status. Conclusions: Our findings with previous preclinical evidence imply that tooth loss may enhance AD tau pathogenesis, promoting tau spreading from LC to the hippocampal formation.

Pages 1267-1283
Karl Li, Tanweer Rashid, Jinqi Li, Nicolas Honnorat, Anoop Benet Nirmala, Elyas Fadaee, Di Wang, Sokratis Charisis, Hangfan Liu, Crystal Franklin, Mallory Maybrier, Haritha Katragadda, Leen Abazid, Vinutha Ganapathy, Vijaya Lakshmi Valaparla, Pradeepthi Bagudu, Eliana Vasquez, Leigh Solano, Geoffrey Clarke, Gladys Maestre, Tim Richardson, Jamie Walker, Peter T. Fox, Kevin Bieniek, Sudha Seshadri, Mohamad Habes
Postmortem Brain Imaging in Alzheimer’s Disease and Related Dementias: The South Texas Alzheimer's Disease Research Center Repository
Abstract: Background: Neuroimaging bears the promise of providing new biomarkers that could refine the diagnosis of dementia. Still, obtaining the pathology data required to validate the relationship between neuroimaging markers and neurological changes is challenging. Existing data repositories are focused on a single pathology, are too small, or do not precisely match neuroimaging and pathology findings. Objective: The new data repository introduced in this work, the South Texas Alzheimer's Disease research center repository, was designed to address these limitations. Our repository covers a broad diversity of dementias, spans a wide age range, and was specifically designed to draw exact correspondences between neuroimaging and pathology data. Methods: Using four different MRI sequences, we are reaching a sample size that allows for validating multimodal neuroimaging biomarkers and studying comorbid conditions. Our imaging protocol was designed to capture markers of cerebrovascular disease and related lesions. Quantification of these lesions is currently underway with MRI-guided histopathological examination. Results: A total of 139 postmortem brains (70 females) with mean age of 77.9 years were collected, with 71 brains fully analyzed. Of these, only 3% showed evidence of AD-only pathology and 76% had high prevalence of multiple pathologies contributing to clinical diagnosis. Conclusions: This repository has a significant (and increasing) sample size consisting of a wide range of neurodegenerative disorders and employs advanced imaging protocols and MRI-guided histopathological analysis to help disentangle the effects of comorbid disorders to refine diagnosis, prognosis and better understand neurodegenerative disorders.

Pages 1285-1304
Wenzhe Wu, Audrey Shen, Inhan Lee, Ernesto G. Miranda-Morales, Heidi Spratt, Miguel Pappolla, Xiang Fang, Xiaoyong Bao
Changes of tRNA-Derived Fragments by Alzheimer’s Disease in Cerebrospinal Fluid and Blood Serum
Abstract: Background: Alzheimer's disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. Objective: To investigate whether tRFs in body fluids are impacted by AD. Methods: We first used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. Results: Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. Conclusions: tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression.

Pages 1305-1315
Jarrad Perron, Carly Scramstad, Ji Hyun Ko
Analysis of Costs for Imaging-Assisted Pharmaceutical Intervention in Alzheimer’s Disease with Lecanemab: Snapshot of the First 3 Years
Abstract: Background: The approval of lecanemab for the treatment of Alzheimer’s disease (AD) by the Food and Drug Administration in the United States has sparked controversy over issues of safety, cost, and efficacy. Furthermore, the prognostication of cognitive decline is prohibitively difficult with current methods. The inability to forecast incipient dementia in patients with biological AD suggests a prophylactic scenario wherein all patients with cognitive decline are prescribed anti-AD drugs at the earliest manifestations of dementia; however, most patients with mild cognitive impairment (approximately 77.7%) do not develop dementia over a 3-year period. Prophylactic response therefore constitutes unethical, costly, and unnecessary treatment for these patients. Objective: We present a snapshot of the costs associated with the first 3 years of mass availability of anti-AD drugs in a variety of scenarios. Methods: We consider multiple prognostication scenarios with varying sensitivities and specificities based on neuroimaging studies in patients with mild cognitive impairment to determine approximate costs for the large-scale use of lecanemab. Results: The combination of fluorodeoxyglucose and magnetic resonance was determined to be the most cost-efficient at $177,000 for every positive outcome every 3 years under an assumed adjustment in the price of lecanemab to $9,275 per year. Conclusions: Imaging-assisted identification of cognitive status in patients with prodromal AD is demonstrated to reduce costs and prevent instances of unnecessary treatment in all cases considered. This highlights the potential of this technology for the ethical prescription of anti-AD medications under a paradigm of imaging-assisted early detection for pharmaceutical intervention in the treatment of AD.

Pages 1317-1327
Sofia Michopoulou, Angus Prosser, John Dickson, Matthew Guy, Jessica L. Teeling, Christopher Kipps (Handling Associate Editor: Robert Perneczky)
Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer’s Disease
Abstract: Background: Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. Objective: In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer’s disease (AD). Methods: We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. Results: Regional perfusion reduction in the precuneus and medial temporal regions predicted Aβ42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. Conclusions: Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction.

Pages 1329-1338
Min-Chien Tu, Hsiao-Wen Chung, Yen-Hsuan Hsu, Jir-Jei Yang, Wen-Chau Wu
Neurovascular Correlates of Cobalamin, Folate, and Homocysteine in Dementia
Abstract: Background: Cobalamin (Cbl) and folate are common supplements clinicians prescribe as an adjuvant therapy for dementia patients, on the presumption of their neurotrophic and/or homocysteine (Hcy) lowering effect. However, the treatment efficacy has been found mixed and the effects of Cbl/folate/Hcy on the human brain remain to be elucidated. Objective: To explore the neurovascular correlates of Cbl/folate/Hcy in Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SIVD). Methods: Sixty-seven AD patients and 57 SIVD patients were prospectively and consecutively recruited from an outpatient clinic. Multimodal 3-Tesla magnetic resonance imaging was performed to quantitatively evaluate cerebral blood flow (CBF) and white matter integrity. The relationship between neuroimaging metrics and the serum levels of Cbl/folate/Hcy was examined by using the Kruskal-Wallis test, partial correlation analysis, and moderation analysis, at a significance level of 0.05. Results: As a whole, CBF mainly associated with Cbl/folate while white matter hyperintensities exclusively associated with Hcy. As compared with AD, SIVD exhibited more noticeable CBF correlates (spatially widespread with Cbl and focal with folate). In SIVD, a bilateral Cbl-moderated CBF coupling was found between medial prefrontal cortex and ipsilateral basal ganglia, while in the fronto-subcortical white matter tracts, elevated Hcy was associated with imaging metrics indicative of increased injury in both axon and myelin sheath. Conclusions: We identified the neurovascular correlates of previously reported neurotrophic effect of Cbl/folate and neurotoxic effect of Hcy in dementia. The correlates exhibited distinct patterns in AD and SIVD. The findings may help improving the formulation of supplemental Cbl/folate treatment for dementia.