Volume 84, Number 1, IN PRESS

Tom Werber, Zsofia Bata, Eniko Szabo Vaszine, Dalida Borbala Berente, Anita Kamondi, Andras Attila Horvath
The Association of Periodontitis and Alzheimer’s Disease: How to Hit Two Birds with One Stone
Abstract: Alzheimer’s disease (AD) is the leading cause of cognitive impairment in the elderly. Recent evidence suggests that preventive interventional trials could significantly reduce the risk for development of dementia. Periodontitis is the most common dental disease characterized by chronic inflammation and loss of alveolar bone and perialveolar attachment of teeth. Growing number of studies propose a potential link between periodontitis and neurodegeneration. In the first part of the paper, we overview case-control studies analyzing the prevalence of periodontitis among AD patients and healthy controls. Second, we survey observational libraries and cross-sectional studies investigating the risk of cognitive decline in patients with periodontitis. Next, we describe the current view on the mechanism of periodontitis linked neural damage, highlighting bacterial invasion of neural tissue from dental plaques, and periodontitis induced systemic inflammation resulting in a neuroinflammatory process. Later, we summarize reports connecting the four most common periodontal pathogens to AD pathology. Finally, we provide a practical guide for further prevalence and interventional studies on the management of cognitively high-risk patients with and without periodontitis. In this section, we highlight strategies for risk control, patient information, dental evaluation, reporting protocol and dental procedures in the clinical management of patients with a risk for periodontitis and with diagnosed periodontitis. In conclusion, our review summarizes the current view on the association between AD and periodontitis and provides a research and intervention strategy for harmonized interventional trials and for further case-control or cross-sectional studies.

Sirawit Sriwichaiin, Nipon Chattipakorn, Siriporn C. Chattipakorn
Metabolomic Alterations in the Blood and Brain in Association with Alzheimer’s Disease: Evidence from in vivo to Clinical Studies
Abstract: Alzheimer’s disease (AD) has become a major health problem among the elderly population. Some evidence suggests that metabolic disturbance possibly plays a role in the pathophysiology of AD. Currently, the study of metabolomics has been used to explore changes in multiple metabolites in several diseases, including AD. Thus, the metabolomics research in AD might provide some information regarding metabolic dysregulations, and their possible associated pathophysiology. This review summarizes the information discovered regarding the metabolites in the brain and the blood from the metabolomics research of AD from both animal and clinical studies. Additionally, the correlation between the changes in metabolites and outcomes, such as pathological findings in the brain and cognitive impairment are discussed. We also deliberate on the findings of cohort studies, demonstrating the alterations in metabolites before changes of cognitive function. All of these findings can be used to inform the potential identity of specific metabolites as possible biomarkers for AD.

Wenlei Yu*, Linjie Lu*, Xintong Ji, Qiwei Qian, Xiaohan Lin, Huanhuan Wang *These authors contributed equally to this work.
Recent Advances on Possible Association Between the Periodontal Infection of Porphyromonas gingivalis and Central Nervous System Injury
Abstract: Chronic periodontitis caused by Porphyromonas gingivalis (P. gingivalis) infection generally lasts for a lifetime. The long-term existence and development of P. gingivalis infection gradually aggravate the accumulation of inflammatory signals and toxic substances in the body. Recent evidence has revealed that P. gingivalis infection may be relevant to some central nervous system (CNS) diseases. The current work collects information and tries to explore the possible relationship between P. gingivalis infection and CNS diseases, including the interaction or pathways between peripheral infection and CNS injury, and the underlying neurotoxic mechanisms.

Herbert B. Allen
A Novel Approach to the Treatment and Prevention of Alzheimer’s Disease Based on the Pathology and Microbiology
Abstract: Utilizing the pathology and microbiology found in tissue from patients with documented Alzheimer’s disease (AD), the pathogenesis of this fateful disorder has been made clear. Borrelia burgdorferi and Treponema denticola spirochetes enter the brain, mostly via neuronal pathways and the entorhinal circulation. These organisms easily pass through the blood-brain barrier and have an affinity for neural tissue. Once in the brain, the spirochetes make intra- and extracellular biofilms, and it is the biofilms that create the pathology. Specifically, it is the intracellular biofilms that are ultimately responsible for neurofibrillary tangles and dendritic disintegration. The extracellular biofilms are responsible for the inflammation that initially is generated by the first responder, Toll-like receptor 2. The hypothesis that arises from this work is two-pronged: one is related to prevention; the other to treatment. Regarding prevention, it is very likely possible that AD could be prevented by periodic administration of penicillin (PCN), which would kill the spirochetes before they made biofilms; this would prevent the disease and would not allow any of the above deleterious changes generated by the biofilms to occur. As regards treatment, it may be possible to slow or prevent further decline in early AD by administration of PCN together with a biofilm disperser. The disperser would disrupt the biofilm coating and enable the PCN to kill the spirochetes. This protocol could be administered in a trial with the control arm utilizing the current treatment. The progress of the treatment could be evaluated by one of the current blood tests that is semi-quantitative. The specific protocols are listed.

Paolo Farace, Stefano Tamburin
Combining Low-Dose Radiation Therapy and Magnetic Resonance Guided Focused Ultrasound to Reduce Amyloid-β Deposition in Alzheimer’s Disease
Abstract: Amyloid-β deposition is one of the neuropathological hallmarks of Alzheimer’s disease (AD), but pharmacological strategies toward its reduction are poorly effective. Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-β. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-β and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced cognitive decline. However, selective irradiation of cortical amyloid-β plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-β deposition in AD since its preclinical stages.

Short Communication
Guillermo González-Ortega, Sara Llamas-Velasco, Ana Arteche-López, Juan Francisco Quesada-Espinosa, Verónica Puertas-Martín, Adolfo Gómez-Grande, Jorge López-Álvarez, Rosa Ana Saiz Díaz, José Miguel Lezana-Rosales, Alberto Villarejo-Galende, Jesús González de la Aleja
Early-Onset Dementia Associated with a Heterozygous, Nonsense, and de novo Variant in the MBD5 Gene
Abstract: The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients with atypical early-onset dementia.

Helen Macpherson, Sarah A. McNaughton, Karen E. Lamb, Catherine M. Milte (Handling Associate Editor: Lynne Shinto)
Associations of Diet Quality with Midlife Brain Volume: Findings from the UK Biobank Cohort Study
Abstract: Background: Higher quality diets may be related to lower dementia rates. Midlife is emerging as a critical life stage for a number of dementia risk factors. Objective: This study examines whether diet quality is related to brain structure during midlife, and if this differs by sex. Methods: This study used data from 19184 UK Biobank participants aged 40-65 years. Diet quality was assessed using three dietary indices including the Mediterranean Diet Score (MDS), Healthy Diet Score (HDS), and Recommended Food Score (RFS). MRI brain measures included total, grey, white, and hippocampal volume. Linear regression examined associations between diet quality and brain volume, controlling for potential confounders. Results: Better quality diet across all indices was significantly related to larger grey matter volume: MDS β=429.7 (95% CI: 65.2, 794.2); HDS β=700.1 (348.0, 1052.1); RFS β=317.1 (106.8, 527.3). Higher diet scores were associated with greater total volume: HDS β= 879.32 (286.13, 1472.50); RFS β=563.37 (209.10, 917.65) and white matter volume: RFS β=246.31 (20.56, 472.05), with the exception of Mediterranean diet adherence. Healthy eating guidelines and dietary variety associations with total and grey matter volume were more prominent in men. Conclusion: Findings suggest that diet quality is associated with brain structure during midlife, potentially decades prior to the onset of dementia.

Fennie Choy Chin Wong, Seyed Ehsan Saffari, Chathuri Yatawara, Kok Pin Ng, Nagaendran Kandiah for the Alzheimer’s Disease Neuroimaging Initiative
Influence of White Matter Hyperintensities on Baseline and Longitudinal Amyloid-β in Cognitively Normal Individuals
Abstract: Background: The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42) pathology have not been well-elucidated. Objective: Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. Methods: This study included 72 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between BL WMH/ICV and Aβ1-42 on memory and executive function. Results: Mean age of the subjects (Nmales = 36) = 73.80 years, SD = 6.73; mean education years = 17.1, SD = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p = 0.008) and two-year change in Aβ1-42 (p = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p = 0.003). Conclusion: BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer’s disease.

Elisa Colato, Konstantinos Chiotis, Daniel Ferreira, Mariam S. Mazrina, Laetitia Lemoine, Rosaleena Mohanty, Eric Westman, Agneta Nordberg, Elena Rodriguez-Vieitez, for the Alzheimer’s Disease Neuroimaging Initiative
Assessment of Tau Pathology as Measured by 18F-THK5317 and 18F-Flortaucipir PET and Their Relation to Brain Atrophy and Cognition in Alzheimer’s Disease
Abstract: Background: In Alzheimer's disease (AD), the abnormal aggregation of hyperphosphorylated tau leads to synaptic dysfunction and neurodegeneration. Recently developed tau PET imaging tracers are candidate biomarkers for diagnosis and staging of AD. Objective: We aimed to investigate the discriminative ability of 18F-THK5317 and 18F-flortaucipir tracers and brain atrophy at different stages of AD, and their respective associations with cognition. Methods: Two cohorts, each including 29 participants (healthy controls [HC], prodromal AD, and AD dementia patients), underwent 18F-THK5317 or 18F-flortaucipir PET, T1-weighted MRI, and neuropsychological assessment. For each subject, we quantified regional 18F-THK5317 and 18F-flortaucipir uptake within six bilateral and two composite regions of interest. We assessed global brain atrophy for each individual by quantifying the brain volume index, a measure of brain volume-to-cerebrospinal fluid ratio. We then quantified the discriminative ability of regional 18F-THK5317, 18F-flortaucipir, and brain volume index between diagnostic groups, and their associations with cognition in patients. Results: Both 18F-THK5317 and 18F-flortaucipir outperformed global brain atrophy in discriminating between HC and both prodromal AD and AD dementia groups. 18F-THK5317 provided the highest discriminative ability between HC and prodromal AD groups. 18F-flortaucipir performed best at discriminating between prodromal and dementia stages of AD. Across all patients, both tau tracers were predictive of RAVL learning, but only 18F-flortaucipir predicted MMSE. Conclusion: Our results warrant further in vivo head-to-head and antemortem-postmortem evaluations. These validation studies are needed to select tracers with high clinical validity as biomarkers for early diagnosis, prognosis, and disease staging, which will facilitate their incorporation in clinical practice and therapeutic trials.

Anna Brugulat-Serrat, Alba Cañas, Lidia Canals, Paula Marne, Nina Gramunt, Marta Milà-Alomà, Marc Suárez-Calvet, Eider M. Arenaza-Urquijo, Oriol Grau-Rivera, José María González-de-Echávarri, Carolina Minguillon, Karine Fauria, Gwendlyn Kollmorgen, Ivonne Suridjan, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, José Luis Molinuevo, Gonzalo Sánchez-Benavides, for the ALFA study
Enhancing the Sensitivity of Memory Tests: Reference Data for the Free and Cued Selective Reminding Test and the Logical Memory Task from Cognitively Healthy Subjects with Normal Alzheimer’s Disease Cerebrospinal Fluid Biomarker Levels
Abstract: Background: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer’s disease (AD) pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment. Objective: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid (A) and tau (T) cerebrospinal fluid (CSF) biomarkers. Methods: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable. Results: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected. Conclusion: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.

Xiao-Qin Zhang*, Le Xu*, Si-Yu Yang, Lin-Bo Hu, Fei-Yuan Dong, Bing-Gui Sun, Hao-Wei Shen *These authors contributed equally to this work.
Reduced Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Neurons in the Medial Prefrontal Cortex in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.

Ioanna Katzourou, Ganna Leonenko, Dobril Ivanov, Alun Meggy, Rachel Marshall, Rebecca Sims, Julie Williams, Peter Holmans, Valentina Escott-Price and the Alzheimer's Disease Neuroimaging Initiative
Cognitive Decline in Alzheimer’s Disease Is Not Associated with APOE
Abstract: Background: The rate of cognitive decline in Alzheimer’s disease (AD) has been found to vary widely between individuals, with numerous factors driving this heterogeneity. Objective: This study aimed to compute a measure of cognitive decline in patients with AD based on clinical information and to utilize this measure to explore the genetic architecture of cognitive decline in AD. Methods: An in-house cohort of 616 individuals, hereby termed the Cardiff Genetic Resource for AD, as well as a subset of 577 individuals from the publicly available ADNI dataset, that have been assessed at multiple timepoints, were used in this study. Measures of cognitive decline were computed using various mixed effect linear models of Mini-Mental State Examination (MMSE). After an optimal model was selected, a metric of cognitive decline for each individual was estimated as the random slope derived from this model. This metric was subsequently used for testing the association of cognitive decline with apolipoprotein E (APOE) genotype. Results: No association was found between the number of APOE ε2 or ε4 alleles and the rate of cognitive decline in either of the datasets examined. Conclusion: Further exploration is required to uncover possible genetic variants that affect the rate of decline in patients with AD.

Vanesa Pytel, María Nieves Cabrera-Martín, Alfonso Delgado-Álvarez, José Luis Ayala, Paloma Balugo, Cristina Delgado-Alonso, Miguel Yus, María Teresa Carreras, José Luis Carreras, Jorge Matías-Guiu, Jordi A Matías-Guiu
Personalized Repetitive Transcranial Magnetic Stimulation for Primary Progressive Aphasia
Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available. Objective: We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting. Methods: We conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. Target for active TMS varied among the cases and was determined during a pre-treatment phase from a list of potential regions. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET. Results: Twenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). For statistical analyses, data for the two variants were combined. Compared to the control group (n=7), the group receiving active-site rTMS (n=20) showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally. Conclusion: We found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment.

Quinton D. Cotton, Amy J.H. Kind, Alice J. Kim, Laura M. Block, Jochen René Thyrian, Jessica Monsees, Manish N. Shah, Andrea Gilmore-Bykovskyi
Dementia Caregivers’ Experiences Engaging Supportive Services While Residing in Under-Resourced Areas
Abstract: Background: Family caregivers of people living with dementia benefit from supportive service use to address care needs associated with caregiving. Yet, research consistently demonstrates low rates of service use. Existing research has focused on barriers and facilitators to service use, with few studies examining the influence of caregivers’ environmental context which often patterns social advantage and health services accessibility. Objective: To describe the perspectives caregivers residing in socially disadvantaged areas have in regards to utilizing supportive services. Methods: Ten informal caregivers residing in socially disadvantaged areas participated in in-depth interviews that were analyzed using thematic analysis. Results: Across all interviews, caregivers spontaneously described common precedents of service use (crisis or accumulation of unmet needs) and a distinct sequence of stages (seeking, initiating, and utilizing) surrounding service engagement. Major themes characterizing caregivers’ experiences throughout service engagement highlight the varied influence of personal, familial, health, and social system-related factors. Findings demonstrate that caregivers may have different service needs as dementia progresses and that gerontological social work practice can facilitate service use. Conclusion: While preliminary, these findings provide important insights into new domains that can be further examined in future research and intervention efforts to improve supportive service use in socially disadvantaged and underserved communities.

Fangmei He*, Yuchen Zhang*, Xiaofeng Wu, Youjun Li, Jie Zhao, Peng Fang, Liming Fan, Chenxi Li, Tian Liu, Jue Wang and Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Early Microstructure Changes of White Matter Fiber Bundles in Patients with Amnestic Mild Cognitive Impairment Predicts Progression of Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Background: Amnestic mild cognitive impairment (aMCI) is the transitional stage between normal aging and Alzheimer’s disease (AD). Some aMCI patients will progress into AD eventually, whereas others will not. If the trajectory of aMCI can be predicted, it would enable early diagnosis and early therapy of AD. Objective: To explore the development trajectory of aMCI patients, we used diffusion tensor imaging to analyze the white matter microstructure changes of patients with different trajectories of aMCI. Methods: We included three groups of subjects:1) aMCI patients who convert to AD (MCI-P); 2) aMCI patients who remain in MCI status (MCI-S); 3) normal controls (NC). We analyzed the fractional anisotropy and mean diffusion rate of brain regions, and we adopted logistic binomial regression model to predicate the development trajectory of aMCI. Results: The fraction anisotropy value is significantly reduced, the mean diffusivity value is significantly increased in the two aMCI patient groups, and the MCI-P patients presented greater changes. Significant changes are mainly located in the cingulum, fornix, hippocampus, and uncinate fasciculus. These changed brain regions significantly correlated with the patient's Mini-Mental State Examination scores. Conclusion: The study predicted the disease trajectory of different types of aMCI patients based on the characteristic values of the above-mentioned brain regions. The prediction accuracy rate can reach 90.2%, and the microstructure characteristics of the right cingulate band and the right hippocampus may have potential clinical application value to predict the disease trajectory.

Brittany DeFeis*, Gelan Ying*, Andrea M. Kurasz, Liselotte De Wit, Priscilla Amofa, Sr., Melanie Chandler, Dona Locke, Anne Shandera-Ochsner, Vaishali Phatak, Glenn Smith *These authors contributed equally to this work.
Latent Factor Structure of Outcome Measures Used in the HABIT® Mild Cognitive Impairment Intervention Programs
Abstract: Background: In Alzheimer's disease and related disorders (ADRD) research, common outcome measures include cognitive and functional impairment, as well as persons with mild cognitive impairment (pwMCI) and care partner self-reported mood and quality of life. Studies commonly analyze these measures separately, which potentially leads to issues of multiple comparisons and/or multicollinearity among measures while ignoring the latent constructs they may be measuring. Objective: This study sought to examine the latent factor structure of a battery of 12-13 measures of domains mentioned above, used in a multicomponent behavioral intervention (The HABIT® program) for pwMCI and their partners. Methods: Exploratory factor analysis (EFA) involved 214 pwMCI-partner pairs. Subsequent Confirmatory factor analyses (CFA) used 730 pairs in both pre- and post-intervention conditions. Results: EFA generated a three-factor model. Factors could be characterized as partner adjustment (29.9%), pwMCI adjustment (18.1%), and pwMCI impairment (12.8%). The subsequent CFA confirmed our findings, and the goodness-of-fit for this model was adequate in both the pre- (CFI=0.937; RMSEA=0.057, p=0.089) and post-intervention (CFI=0.942; RMSEA=0.051, p=0.430) groups. Conclusion: Results demonstrated a stable factor structure across cohorts and intervention conditions suggesting that three broad factors may provide a straightforward and meaningful model to assess intervention outcome, at least during the MCI phase of ADRD.

Kay L. Cox, Linda Clare, Elizabeth V. Cyarto , Kathryn A. Ellis, Christopher Etherton-Beer, Jenny Southam, David Ames, Leon Flicker, Osvaldo P. Almeida, Dina LoGiudice, Danny Liew, Philip Vlaskovsky, Nicola T. Lautenschlager (Handling Associate Editor: Klaus Hauer)
A Randomized Controlled Trial on the Effects of a 6-Month Home-Based Physical Activity Program with Individual Goal-Setting and Volunteer Mentors on Physical Activity, Adherence, and Physical Fitness in Inactive Older Adults at Risk of Cognitive Decline: The INDIGO Study
Abstract: Background: Increasing physical activity (PA) in those who have memory concerns requires innovative approaches. Objective: To compare in this randomized controlled trial (RCT) the effects on PA, adherence, and fitness of two approaches to deliver a 6-month home-based PA program in older, inactive individuals at risk of cognitive decline. Methods: Individuals (n = 52) aged 60-85 years, inactive with mild cognitive impairment or subjective cognitive decline were recruited from the community and memory clinics. Randomization was to 6 months of 150 min/week moderate intensity PA with either: goal-setting with mentor support; or education and peer contact. A subset of participants (n = 36) continued for a further 6 months. PA, moderate and vigorous PA, and secondary outcomes, fitness, goal performance/satisfaction and self-efficacy were assessed at baseline, 6 and 12 months. Modelling of primary and secondary outcomes was conducted with linear mixed models. Results: Participants were mean age (± sd) 70.1 (6.4) years. Six-month retention was 88.5% (n = 46). No significant between-group differences were observed for PA or fitness. Post-hoc combined group data showed a significant, moderate-large effect size increase in PA with time. PA increased by a mean 1,662 (943, 2383) steps/day (95% CI) and 1,320 (603, 2037) steps/day at 6 and 12 months (p < 0.001). Median (quartiles Q1-Q3) 6 and 6-12 month combined group adherence was 88.9 (74.4 - 95.7)% and 84.6 (73.9 – 95.4)% respectively. Conclusion: In this target group, no differences were detected between groups both intervention strategies were highly effective in increasing PA and fitness.

Mohamed Haddad, Morgane Perrotte, Mohamed Raâfet Ben Khedher, Elise Madec, Aurelie Lepage, Tamás Fülöp, Charles Ramassamy
Levels of Receptor for Advanced Glycation End Products and Glyoxalase-1 in the Total Circulating Extracellular Vesicles from Mild Cognitive Impairment and Different Stages of Alzheimer’s Disease Patients
Abstract: Background: Growing evidence supports that receptor for advanced glycation end products (RAGE) and glyoxalase-1 (GLO-1) are implicated in the pathophysiology of Alzheimer’s disease (AD). Extracellular vesicles (EVs) are nanovesicles secreted by almost all cell types, contribute to cellular communication, and are implicated in AD pathology. Recently, EVs are considered as promising tools to identify reliable biomarkers in AD. Objective: The aim of our study was to determine the levels of RAGE and GLO-1 in circulating EVs from mild cognitive impairment (MCI) and AD patients and to analyze their correlation with the clinical Mini-Mental State Examination and Montreal Cognitive Assessment scores. We have studied the possibility that neuronal cells could release and transfer GLO-1 through EVs. Methods: RAGE and GLO-1 levels were measured in circulating EVs, respectively, by Luminex assay and western blot. Released-EVs from SK-N-SH neuronal cells were isolated and GLO-1 levels were determined by western bot. Results: Our data showed higher levels of RAGE in EVs from late AD patients while GLO-1 levels in EVs from early AD were lower as compared to control and MCI patients. Interestingly, levels of RAGE and GLO-1 in EVs were correlated with the cognitive scores regardless of age. For the first time, we demonstrated that GLO-1 was released from neuronal cells through EVs. Conclusion: Although more samples will be needed, our preliminary results support the use of peripheral EVs cargo as new tools for the discovery of peripheral AD biomarkers.

Lei Xia*, Yayan Pang*, Junjie Li, Bin Wu, Yehong Du, Yuxin Chen, Man Luo, Yan Wang, Zhifang Dong (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy
Abstract: Background: Tauopathies are a group of neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. Objective: In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. Methods: We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. Results: DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. Conclusion: These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.

Yaroslav Kolinko, Lucie Marsalova, Stephanie Proskauer Pena, Milena Kralickova, Peter R. Mouton (Handling Associate Editor: Jack de la Torre)
Stereological Changes in Microvascular Parameters in Hippocampus of a Transgenic Rat Model of Alzheimer’s Disease
Abstract: Background: Microcirculatory factors play an important role in amyloid-β (Aβ)-related neuropathology in Alzheimer’s disease (AD). Transgenic (Tg) rat models of mutant Aβ deposition can enhance our understanding of this microvascular pathology. Objective: Here we report stereology-based quantification and comparisons (between- and within-group) of microvessel length and number and associated parameters in hippocampal subregions in Tg model of AD in Fischer 344 rats and non-Tg littermates. Methods: Systematic-random samples of tissue sections were processed and laminin immunostained to visualize microvessels through the entire hippocampus in Tg and non-Tg rats. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in dentate gyrus (DG) and cornu ammonis (CA) subregions. Results: Thin hair-like capillaries are common near Aβ plaques in hippocampal subregions of Tg rats. There are a 53% significant increase in average length per capillary across entire hippocampus (p ≤ 0.04) in Tg compared to non-Tg rats; 49% reduction in capillary length in DG (p ≤ 0.02); and, higher microvessel density in principal cell layers (p ≤ 0.03). Furthermore, within-group comparisons confirm Tg but not non-Tg rats have significant increase in number density (p ≤ 0.01) and potential diffusion distance (p ≤ 0.04) of microvessels in principal cell layers of hippocampal subregions. Conclusion: We show the Tg deposition of human Aβ mutations in rats disrupts the wild-type microanatomy of hippocampal microvessels. Stereology-based microvascular parameters could promote the development of novel strategies for protection and the therapeutic management of AD.

Sanne Kuipers, Geert Jan Biessels, Jacoba P. Greving, Raquel P. Amier, Jeroen de Bresser, Esther E. Bron, Wiesje M. van der Flier, Rob J. van der Geest, Astrid M. Hooghiemstra, Robert J. van Oostenbrugge, Matthias J.P. van Osch, L. Jaap Kappelle, Lieza G. Exalto, Heart-Brain Connection Consortium (Handling Associate Editor: Michelle Mielke)
Sex and Cardiovascular Function in Relation to Vascular Brain Injury in Patients with Cognitive Complaints
Abstract Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms >0.05). Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Tomohiko Sato, Haruo Hanyu, Yumi Koyama, Haruka Horita, Toshinori Aoki, Kentaro Hirao, Hidekazu Kanetaka, Soichiro Shimizu
Discrepancy Between the Degree of Cognitive Impairment and Brain Imaging Abnormalities in Alzheimer’s Disease Patients Is Associated with Cognitive Reserve
Abstract: Background: In Alzheimer’s disease (AD) patients, the severity of cognitive impairment is thought to correlate with the degree of brain imaging abnormalities. However, some patients show only mild cognitive deficit, despite severe brain atrophy on magnetic resonance imaging (MRI) or marked hypoperfusion in the cerebral cortices on single-photon emission computed tomography (SPECT). This suggests that cognitive reserve (CR) can compensate for the clinical manifestations of AD in patients with extensive brain pathology. Objective: We aimed to determine whether this discrepancy between cognitive and imaging findings is associated with CR. Methods: Factors associated with the discrepancy between the degree of cognitive impairment and MRI (medial temporal lobe atrophy) and SPECT (posterior cerebral hypoperfusion) findings were analyzed in 135 patients with probable AD. Factors as proxies for CR included education, occupation, leisure activity, comorbidities, frailty, and other demographics. The discrepancy index (DI) was calculated as the difference between the degree of imaging abnormalities and the degree of cognitive dysfunction. Results: Multiple regression analysis showed that leisure activity and education were significantly associated with the discrepancy between cognitive and imaging findings. When the level of CR was determined based on leisure activity and education, the high-CR group showed a significantly larger DI than the moderate- and low-CR groups. Conclusion: The discrepancy between cognitive and imaging findings in patients with AD is associated with CR, measured using a combination of two indicators, i.e., leisure activity and education. Therefore, lifestyle interventions may delay the appearance of clinical symptoms resulting from underlying AD pathology, by increasing CR.

Aitana Sogorb-Esteve, Romain A. Colas, Jesmond Dalli, Jonathan D. Rohrer
Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation
Abstract: Background: The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective: We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods: 15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results: Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion: This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher).

Teslim S. Abdulkadir, Fatima A. Dawud, Ahmed Sherif Isa, Joseph O. Ayo (Handling Associate Editor: Rongpin Wang)
Taurine and Camel Milk Modulate Neurobehavioral and Biochemical Changes in Aluminum Chloride-Induced Alzheimer’s Disease in Rats
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease associated with deficiency in motor coordination, cognitive impairment, and excessive reactive oxygen species production in the brain. Objective: The study evaluated effects of taurine and camel milk (CM) on neurobehavior, amyloid-beta peptide 1-42 (Aβ) expression, acetylcholinesterase, and superoxide dismutase activities in aluminum chloride (AlCl3) model of Alzheimer’s disease in rats. Methods: Thirty-five female Wistar rats were divided into seven groups (n=5): Normal saline (0.2 mL/kg body weight); AlCl3 (100 mg/kg) (AD); CM (33 mL/kg); Taurine (50 mg/kg); AlCl3 (100 mg/kg) + CM (33 mL/kg); AlCl3 (100 mg/kg) + Taurine (50 mg/kg); and AlCl3 (100 mg/kg) + CM (33 mL/kg) + Taurine (50 mg/kg). The administration lasted for eight weeks via oral gavage. After the eighth week, neurobehavior assessments were performed. Rats were sacrificed, and brain and blood samples collected for analysis. Results: There was a significant (p < 0.0001) increase in the duration of motor endurance in AD + CM rats, compared to AD rats. Duration of forced swimming time was lowest (p < 0.0001) in AlCl3 + Taurine rats, compared to that of AD rats. Concentration of Aβ peptide decreased (p < 0.05) in AD rats, treated with CM and/or combination. In taurine-treated rats, superoxide dismutase activity was significantly (p < 0.05) higher than in AD rats. Treatment with taurine + CM increased (p < 0.05) acetylcholinesterase activity compared to controls. Conclusion: Taurine and CM enhanced cognition and sensorimotor activity by decreasing Aβ peptide concentration and increasing superoxide dismutase and acetylcholinesterase activities in AD rats.

Shan Wei*, Suhang Shang*, Liangjun Dang, Fan Gao, Yao Gao, Ling Gao, Chen Chen, Kang Huo, Jingyi Wang, Jin Wang, Qiumin Qu *These authors contributed equally to this work.
Blood Triglyceride and High-Density Lipoprotein Levels Are Associated with Plasma Amyloid-β Transport: A Population-Based Cross-Sectional Study
Abstract: Background: Studies have found that blood lipids are associated with plasma amyloid-β (Aβ) levels, but the underlying mechanism is still unclear. Two Aβ transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aβ transport. Objective: The aim was to investigate the effects of lipids on the relationships between plasma Aβ and transporter levels. Methods: This study included 1,436 adults aged 40 to 88 years old. Blood Aβ, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze the relationships between lipids and plasma Aβ, sLRP1, and sRAGE. Results: After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aβ42 and sRAGE (β=6.158, p=0.049; β=121.156, p<0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aβ40, Aβ42, and sRAGE (β= -48.389, p=0.017; β= -11.142, p=0.020; β= -147.937, p=0.003, respectively). Additionally, positive correlations were found between plasma Aβ and sRAGE in the normal TG (Aβ40: β=0.034, p=0.005; Aβ42: β=0.010, p=0.001) and HDL-c groups (Aβ40: β=0.023, p=0.033; Aβ42: β=0.008, p=0.002) but not in the high TG and low HDL-c groups. Conclusion: Abnormal levels of TG and HDL-c are associated with decreased Aβ and sRAGE levels. Positive correlations between plasma Aβ and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aβ levels might also be involved in peripheral Aβ clearance.

Yasunori Yamada, Kaoru Shinkawa, Masatomo Kobayashi, Vittorio Caggiano, Miyuki Nemoto, Kiyotaka Nemoto, Tetsuaki Arai (Handling Associate Editor: Alexandra König)
Combining Multimodal Behavioral Data of Gait, Speech, and Drawing for Classification of Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: Gait, speech, and drawing behaviors have been shown to be sensitive to the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, previous studies focused on only analyzing individual behavioral modalities, although these studies suggested that each of these modalities may capture different profiles of cognitive impairments associated with AD. Objective: We aimed to investigate if combining behavioral data of gait, speech, and drawing can improve classification performance compared with the use of individual modality and if each of these behavioral data can be associated with different cognitive and clinical measures for the diagnosis of AD and MCI. Methods: Behavioral data of gait, speech, and drawing were acquired from 118 AD, MCI, and cognitively normal (CN) participants. Results: Combining all three behavioral modalities achieved 93.0% accuracy for classifying AD, MCI, and CN, and only 81.9% when using the best individual behavioral modality. Each of these behavioral modalities was statistically significantly associated with different cognitive and clinical measures for diagnosing AD and MCI. Conclusion: Our findings indicate that these behaviors provide different and complementary information about cognitive impairments such that classification of AD and MCI is superior to using either in isolation.

Filipa Ferreira-Brito, Filipa Ribeiro, Diana Aguiar de Sousa, João Costa, Cátia Caneiras, Luís Carriço, Ana Verdelho
Are Video Games Effective to Promote Cognition and Everyday Functional Capacity in Mild Cognitive Impairment/Dementia Patients? A Meta-Analysis of Randomized Controlled Trials
Abstract: Background: Mild cognitive impairment (MCI) and dementia are associated with increased age. MCI is a clinical entity described as a transitional state between normal cognition and dementia. Video games (VGs) can potentially promote cognition and functional capacity since multiple cognitive domains are recruited during gameplay. However, there is still a lack of consensus regarding the efficacy of VGs as therapeutic tools, particularly in neurodegenerative diseases. Objective: We aimed to analyze the impact of VGs on cognition and functional capacity outcomes in MCI/dementia patients. Methods: We conducted a systematic review and meta-analysis study (PROSPERO [CRD42021229445]). PubMed, Web of Science, Epistemonikos, CENTRAL, and EBSCO electronic databases were searched for RCT (2000-2021) that analyzed the impact of VGs on cognitive and functional capacity outcomes in MCI/dementia patients. Results: Nine studies were included (n = 409 participants), and Risk of Bias (RoB2) and quality of evidence (GRADE) were assessed. Data regarding attention, memory/learning, visual working memory, executive functions, general cognition, functional capacity, quality of life were identified, and pooled analyses were conducted. An effect favoring VGs interventions was observed on Mini-Mental State Examination (MMSE) score (MD = 1.64, 95% CI 0.60 to 2.69). Conclusion: Although promising, the effects observed should be interpreted with caution since serious methodological shortcomings were identified in the studies included. Nonetheless, the effect observed is higher than the minimum clinically important difference (1.4 points) established to MMSE. Future studies on the current topic urge. Recommendations for the design and conduction of cognitive RCT studies are presented.

Wiebke Mohr, Anika Rädke, Adel Afi, David Edvardsson, Franka Mühlichen, Moritz Platen, Martina Roes, Bernhard Michalowsky, Wolfgang Hoffmann
Key Intervention Categories to Provide Person-Centered Dementia Care: A Systematic Review of Person-Centered Interventions
Abstract: Background: Person-centered care (PCC) is an important concept in many countries’ national guidelines and dementia plans. Key intervention categories, i.e., a taxonomy of person-centered (PC)-interventions, to provide person-centered dementia care, are difficult to identify from literature. Objective: This systematic review aimed to identify and categorize published PC-interventions into key intervention categories to guide the provision of person-centered dementia care. Methods: Conduct of this systematic review followed Cochrane guidelines. A search of the dimensions ‘Dementia’, ‘Person-Centered Care’, and ‘Intervention’ combined was performed in PubMed, EMBASE, and Web of Science. Study selection was based on 2-stage screening against eligibility criteria, limited to controlled study designs. Information about interventions and outcomes was extracted into an “Effects Table”. The identified PC-interventions were categorized in intervention categories to provide person-centered dementia care. Results: Searches identified 1,806 records. 19 studies were included. These covered a range of psychosocial interventions, oftentimes multi-component interventions, which followed heterogeneous approaches. Studies were conducted in long-term care/hospital settings. Nine key intervention categories were identified: social contact, physical activities, cognitive training, sensory enhancement, daily living assistance, life history oriented emotional support, training and support for professional caregivers, environmental adjustments, and care organization. Conclusion: Our findings provide a current overview of published PC-interventions in dementia, which followed heterogeneous approaches under the PCC-concept. The heterogeneity made it challenging to identify a well-defined concept of PCC and common key intervention categories. An effectiveness-evaluation of “PC”-including “relationship-centered”-interventions may be valuable, to assess whether an explicit focus on relationships around PCC-interventions yields an added benefit.

Quan Wang*, Ning Su*, Jin Huang, Xinyu Liang, Jing Yuan, Ming Yao, Li-Xin Zhou, Zheng-Yu Jin, Shu-Yang Zhang, Li-Ying Cui, Gaolang Gong, Feng Tian, Yi-Cheng Zhu**, Jun Ni** (Handling Associate Editor: Rhoda Au) *,**These authors contributed equally to this study.
White Matter but not Gray Matter Volumes Are Associated with Cognition in Community-Dwelling Chinese Populations
Abstract: Background: Few studies have investigated the association between cognition and brain volume associated with cerebral small vessel disease (CSVD). Objective: We investigated the association between cognition and brain volume and neuroimaging markers of CSVD in a community-dwelling population. Methods: Participants (n=993, age ≥35 years) from the community-based Shunyi Study were included to investigate the association between neuroimaging markers and cognition cross-sectionally. Magnetic resonance imaging markers included brain volume measurements of the total cerebrum, white matter, gray matter, and CSVD imaging markers. Cognitive performance was assessed using neuropsychological tests of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Fuld Object Memory, digit span, Trail Making Test (TMT)-A, and TMT-B. Results: For brain volume measurement, subcortical white matter fraction was positively associated with MMSE score (β=0.034, p=0.0062) and MoCA score (β=0.034, p=0.0174), and negatively associated with TMT-A and TMT-B completion time (β=-2.319, p=0.0002; β=-2.827, p=0.0073, respectively). For evaluation of CSVD imaging markers, the presence of lacunes was positively associated with TMT-B completion time (β=17.241, p=0.0028). Conclusion: In community-dwelling populations, reduced white matter volumes, as a consequence of aging and vascular damage, are associated with worse global cognition and executive function. Our findings provide potential insights into the correlation between cognition and CSVD-associated subcortical white matter injury.

Seung-Jun Seo*, Won-Seok Chang*, Jae-Geun Jeon, Younshick Choi, EunHo Kim, Jong-Ki Kim *These authors contributed equally to this work.
Proton Stimulation Targeting Plaque Magnetite Reduces Amyloid-β Plaque and Iron Redox Toxicity and Improves Memory in an Alzheimer’s Disease Mouse Model
Abstract: Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer’s disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function. Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. Results: Single PS induced a 48-87% reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68-82%) and (94-97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p < 0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils. Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery.

Alessandra Cianflone, Luigi Coppola, Peppino Mirabelli, Marco Salvatore (Handling Associate Editor: Anette Hall)
Predictive Accuracy of Blood-Derived Biomarkers for Amyloid-β Brain Deposition Along with the Alzheimer’s Disease Continuum: A Systematic Review
Abstract: Background: An amyloid-β (Aβ) positron emission tomography (Aβ-PET) scan of the human brain could lead to an early diagnosis of Alzheimer’s disease (AD) and estimate disease progression. However, Aβ-PET imaging is expensive, invasive, and rarely applicable to cognitively normal subjects at risk for dementia. The identification of blood biomarkers predictive of Aβ brain deposition could help the identification of subjects at risk for dementia and could be helpful for the prognosis of AD progression. Objective: This study aimed to analyze the prognostic accuracy of blood biomarkers in predicting Aβ-PET status along with progression toward AD. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, we searched bibliographic databases from 2010 to 2020. The quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Results: A total of 8 studies were retrieved. The prognostic accuracy of Aβ-PET status was calculated by obtaining ROCs for the following biomarkers: free, total, and bound Aβ42 and Aβ40; Aβ42/40 ratio; neurofilaments (NFL); total tau (T-tau); and phosphorylated-Tau181 (P-tau181). Higher and lower plasma baseline levels of P-tau181 and the Aβ42/40 ratio, respectively, showed consistently good prognostication of Aβ-PET brain accumulation. Only P-tau181 was shown to predict AD progression. Conclusion: In conclusion, the Aβ42/40 ratio and plasma P-tau181 were shown to predict Aβ-PET status. Plasma P-tau181 could also be a preclinical biomarker for AD progression.

Scherazad Kootar, Md Hamidul Huque, Richard Arthur, Moyra Mortby, Kaarin J. Anstey (Handling Associate Editor: Joshua Stott)
Association Between Anxiety and Cognitive Decline Over 12 Years in a Population-Based Cohort
Abstract: Background: Findings on the associations between anxiety and cognitive decline are mixed and often confounded. Objective: We studied whether anxiety symptoms were associated with the risk of cognitive decline after adequate adjustment of confounding factors. Methods: Our study consists of 2,551 community-dwelling older adults recruited between the ages of 60-64 years and followed up for 12 years in the PATH Through Life cohort study. Anxiety symptoms were measured using the Goldberg Anxiety Scale (GAS; range 0-9). General cognitive function, episodic memory, working memory, verbal intelligence, processing speed, and psychomotor speed were measured. Multilevel analyses were carried out to investigate the association between anxiety symptoms and cognitive decline over 12 years, taking into account confounding variables. Results: We did not find a significant association between baseline anxiety symptoms and cognitive decline over 12 years. Although some associations between anxiety symptoms with psychomotor speed (β= -0.04, 99% CI: -0.08, 0.00) and processing speed (β= -0.27, 99% CI: -0.48, -0.07) were found, these were attenuated after adjusting for depression. We also did not find an association between cumulative anxiety and decline in cognitive performance. Conclusion: In this sample of cognitively healthy men and women aged 60 years and above, anxiety symptoms were not associated with the risk of cognitive decline. Long follow-up study time, appropriate selection of confounding factors, and estimating the effect of cumulative anxiety are important to establish the association between anxiety and cognitive symptoms.

Hadeel Y. Tarawneh, Wilhelmina H.A.M. Mulders, Hamid R. Sohrabi, Ralph N. Martins, Dona M.P. Jayakody
Investigating Auditory Electrophysiological Measures of Participants with Mild Cognitive Impairment and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Event-Related Potential Studies
Abstract: Background: Objectively measuring auditory functions has been proposed as an avenue in differentiating normal age-related cognitive dysfunction from Alzheimer’s disease (AD) and its prodromal states. Previous research has suggested auditory event-related potentials (AERPs) to be non-invasive, cost-effective, and efficient biomarkers for the diagnosis of AD. Objective: The objective of this paper is to review the published literature on AERPs measures in older adults diagnosed with AD and those at higher risk of developing AD, i.e., mild cognitive impairment (MCI) and subjective cognitive decline. Methods: The search was performed on six major electronic databases (Ovid MEDLINE, OVID EMBASE, PsycINFO, PubMed, Scopus, and CINAHL Plus). Articles identified prior to 7 May 2019 were considered for this review. A random effects meta-analysis and analysis of between study heterogeneity was conducted using the Comprehensive Meta-Analysis software. Results: The search identified 1,076 articles; 74 articles met the full inclusion criteria and were included in the systematic review, and 47 articles were included into the analyses. Pooled analysis suggests that AD participants can be differentiated from controls due to significant delays in ABR, N100, P200, N200, and P300 latencies. P300 amplitude was significantly smaller in AD participants compared to controls. P300 latencies differed significantly between MCI participants and controls based on the pooled analysis. Conclusion: The findings of this review indicate that some AERPs may be valuable biomarkers of AD. In conjunction with currently available clinical and neuropsychological assessments, AERPs can aid in screening and diagnosis of prodromal AD.

Kinjal Doshi, Stacey Lee Henderson, Qianqian Fan, Kian Foong Wong, Julian Lim
Mindfulness-Based Training Does Not Improve Neuropsychological Outcomes in Mild Cognitive Impairment More Than Spontaneous Reversion Rates: A Randomized Controlled Trial
Abstract: Background: Current pharmacological and behavioral treatment options for mild cognitive impairment (MCI) are limited, motivating a search for alternative therapies that might slow the progression of cognitive decline. Objective: We investigated the effectiveness of a cognition-focused mindfulness-based intervention. Methods: An open-label, three arm randomized controlled trial was conducted at a public tertiary medical center. Older persons (ages 45-75; N = 76) diagnosed with MCI were recruited and randomized into either Mindfulness-based training (MBT), cognitive rehabilitation therapy (CRT), or treatment as usual (TAU). Participants in the intervention arms received 8 weekly 2-h sessions delivered in a group setting and engaged in home practice. Primary outcomes measures included changes in index scores for attention, immediate memory, and delayed memory as measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Depression was a secondary outcome. Results: Using intent-to-treat analysis, we found that participants receiving MBT showed significant improvements in global cognition (d = 0.26; [95% CI 0.03 - 0.56]) and delayed memory (d = 0.36; [95% CI 0.17 - 0.57]), with significantly greater improvements in delayed memory than CRT (ηp2 = 0.10). However, there was no benefit of MBT over TAU. No change in depression was observed in the MBT group. Reductions in depression were associated with improvements in cognitive functioning in the MBT group only. Conclusion: Our results suggest that a cognition-focused MBT did not improve cognitive functioning in MCI patients substantially more than spontaneous reversion rates, possibly as mood symptoms were not significantly alleviated in this group.