Volume 84, Number 3, IN PRESS

Review
Mar Pacheco-Herrero, Luis O. Soto-Rojas, Heidy Reyes-Sabater, Linda Garcés-Ramirez, Fidel de la Cruz López, Ignacio Villanueva-Fierro, José Luna-Muñoz
Current Status and Challenges of Stem Cell Treatment for Alzheimer’s Disease
Abstract: Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.

Review
Xi-Jun Song, He-Yan Zhou, Yu-Ying Sun, Han-Chang Huang
Phosphorylation and Glycosylation of Amyloid-β Protein Precursor: The Relationship to Trafficking and Cleavage in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-β (Aβ) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-β protein precursor (AβPP) through the successive cleaving by β-site AβPP-cleavage enzyme 1 (BACE1) and γ-secretase. AβPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AβPP. In the recent years, about 10 phosphorylation sites of AβPP were identified, and they play complex roles in glycosylation modification and cleavage of AβPP. In this article, we introduced the transport and the cleavage pathways of AβPP, then summarized the phosphorylation and glycosylation sites of AβPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AβPP trafficking and cleavage in order to provide theoretical basis for AD research.

Short Communication
Zan Wang*, Zhengsheng Zhang*, Chunming Xie, Hao Shu, Duan Liu, Zhijun Zhang *These authors contributed equally to this work.
Identification of the Neural Circuit Underlying Episodic Memory Deficit in Amnestic Mild Cognitive Impairment via Machine Learning on Gray Matter Volume
Abstract: Based on whole-brain gray matter volume (GMV), we used relevance vector regression to predict the Rey’s Auditory Verbal Learning Test Delayed Recall (AVLT-DR) scores of individual amnestic mild cognitive impairment (aMCI) patient. The whole-brain GMV pattern could significantly predict the AVLT-DR scores (r=0.54, p<0.001). The most important GMV features mainly involved default-mode (e.g., posterior cingulate gyrus, angular gyrus, and middle temporal gyrus) and limbic systems (e.g., hippocampus and parahippocampal gyrus). Therefore, our results provide evidence supporting the idea that the episodic memory deficit in aMCI patients is associated with disruption of the default-mode and limbic systems.

Short Communication
Janardan P. Pandey, Aryan M. Namboodiri, Paul J. Nietert, Lisa L. Barnes, David A. Bennett
Inhibitory Fcγ Receptor and Paired Immunoglobulin Type 2 Receptor Alpha Genotypes in Alzheimer’s Disease
Abstract: We investigated whether FCGRIIB (rs1050501 C/T) and PILRA (rs1859788 A/G) genotypes contributed to the development of Alzheimer’s disease (AD). We genotyped 209 African American (AA) and 638 European American participants for the FCGRIIB and PILRA alleles. In the AA cohort, subjects homozygous for the C allele of FCGRIIB were more than 4 times as likely to develop AD as those homozygous for the alternative T allele. This SNP also interacted with PILRA: participants who were the carriers of the FCGRIIB C allele and PILRA A allele were 3 times as likely to develop AD as those who lacked these alleles.

Editorial
Markku Kurkinen and Lloyd Tran
Aduhelm: The Best Hope for Alzheimer’s Disease Patients or the Worst Decision the FDA Has Ever Made?

Tian Tian, Xin Qin, Yali Wang, Yan Shi, Xin Yang
40 Hz Light Flicker Promotes Learning and Memory via Long Term Depression in Wild-Type Mice
Abstract: Background: 40 Hz light flicker is a well-known non-invasive treatment that is thought to be effective in treating Alzheimer's disease. However, the effects of 40 Hz visual stimulation on neural networks, synaptic plasticity, and learning and memory in wild-type animals remain unclear. Objective: We aimed to explore the impact of 40 Hz visual stimulation on synaptic plasticity, place cell, and learning and memory in wild-type mice. Methods: c-Fos+ cell distribution and in vivo electrophysiology was used to explore the effects of 40 Hz chronic visual stimulation on neural networks and neuroplasticity in wild-type mice. The character of c-Fos+ distribution in the brain and the changes of corticosterone levels in the blood were used to investigate the state of animal. Place cell analysis and novel location test were utilized to examine the effects of 40 Hz chronic visual stimulation on learning and memory in wild-type mice. Results: We found that 40 Hz light flicker significantly affected many brain regions that are related to stress. Also, 40 Hz induced gamma enrichment within 15 min after light flickers and impaired the expression of long-term potentiation (LTP), while facilitated the expression of long-term depression (LTD) in the hippocampal CA1. Furthermore, 40 Hz light flicker enhanced the expression of corticosterone, rendered well-formed place cells unstable and improved animal’s learning and memory in novel local recognition test, which could be blocked by pre-treatment with the LTD specific blocker Glu2A-3Y. Conclusion: These finding suggested that 40 Hz chronic light flicker contains stress effects, promoting learning and memory in wild-type mice via LTD.

So Yeon Jeon, Jeong Lan Kim
Caregiving for a Spouse with Cognitive Impairment: Effects on Nutrition and Other Lifestyle Factors
Abstract: Background: Being a spousal caregiver (SCG) for a patient with cognitive impairment is well known to be associated with increased risk for dementia and cognitive decline. Objective: This study examined the impact of the care recipient’s cognitive status on lifestyle factors influencing cognitive decline in SCGs, focusing on nutritional status and blood biomarkers. Methods: Fifty-one SCGs participated (mean age 73.5±7.0 years) in this study. All participants underwent clinical assessment including the Mini Nutritional Assessment (MNA), Geriatric Depression Scale, Pittsburgh Sleep Quality Index, and International Physical Activity Questionnaire to evaluate lifestyle factors, and the Mini-Mental State Examination to assess global cognition. Also, nutritional blood biomarkers were measured. Results: SCGs caring for a demented spouse showed significantly higher depression scores (t = -3.608, p = 0.001) and malnutrition risk (t = 2.894, p = 0.006). Decreased care recipients’ cognition was significantly correlated with higher GDS (β = -0.593, t= -4.471, p < 0.001) and higher MNA scores (β = 0.315, t = 2.225, p = 0.031) and lower level of high-density lipoprotein (HDL) cholesterol (β = 0.383, t= 2.613, p = 0.012) in their SCGs. Gender had moderating effects on association of care recipients’ cognition with sleep quality (B[SE]= 0.400[0.189], p = 0.041) and HDL cholesterol (B[SE] = -1.137[0.500], p = 0.028) among SCGs. Poorer care-recipient cognition was associated with worse sleep quality and low HDL cholesterol among wives but not husband caregivers. Conclusion: This study provides substantial evidence that SCGs are at risk for depression and malnutrition, which can further affect cognitive decline. As such, these factors should be well assessed and monitored among SCGs for patient with cognitive impairment.

Evangelia Stanitsa, Alexandra Economou, Ion Beratis, Dionysia Kontaxopoulou, Stella Fragkiadaki, Vicky Papastefanopoulou, Dimosthenis Pavlou, Panagiotis Papantoniou, Christos Kroupis, John Papatriantafyllou, Leonidas Stefanis, George Yannis, Sokratis G. Papageorgiou
Effect of Apolipoprotein E4 on the Driving Behavior of Patients with Amnestic Mild Cognitive Impairment or Mild Alzheimer’s Disease Dementia
Abstract: Background: The driving behavior of patients with mild Alzheimer’s disease dementia (ADD) and patients with mild cognitive impairment (MCI) is frequently characterized by errors. A genetic factor affecting cognition is apolipoprotein E4 (APOE4), with carriers of APOE4 showing greater episodic memory impairment than non-carriers. However, differences in the driving performance of the two groups have not been investigated. Objective: To compare driving performance in APOE4 carriers and matched non-carriers. Methods: Fourteen APOE4 carriers and 14 non-carriers with amnestic MCI or mild ADD underwent detailed medical and neuropsychological assessment and participated in a driving simulation experiment, involving driving in moderate and high traffic volume in a rural environment. Driving measures were speed, lateral position, headway distance and their SDs, and reaction time. APOE was genotyped through plasma samples. Results: Mixed two-way ANOVAs examining traffic volume and APOE4 status showed a significant effect of traffic volume on all driving variables, but a significant effect of APOE4 on speed variability only. APOE4 carriers were less variable in their speed than non-carriers; this remained significant after a Bonferroni correction. To further examine variability in the driving performance, coefficients of variation (COV) were computed. Larger headway distance COV and smaller lateral position COV were observed in high compared to moderate traffic. APOE4 carriers had smaller speed COV compared to non-carriers. Conclusion: The lower speed variability of APOE4 carriers in the absence of neuropsychological test differences indicates reduced speed adaptations, possibly as a compensatory strategy. Simulated driving may be a sensitive method for detecting performance differences in the absence of cognitive differences.

Emily A. Largent, Twisha Bhardwaj, Maramawit Abera, Shana D. Stites, Kristin Harkins, Alan J. Lerner, Angela R. Bradbury, Jason Karlawish
Disclosing Genetic Risk of Alzheimer’s Disease to Cognitively Unimpaired Older Adults: Findings from the Study of Knowledge and Reactions to APOE Testing (SOKRATES II)
Abstract: Background: Current practice guidelines recommend against Apolipoprotein E (APOE) testing. However, advances in Alzheimer’s disease (AD) research may soon change this. Objective: To examine longitudinally the experience of learning an APOE result and, if an ε4 carrier, taking a disease-specific treatment to reduce one’s risk of AD. Methods: Fifty ε4 carriers and 20 non-carriers completed semi-structured interviews 3 months and 15 months after APOE disclosure. Results: Individuals generally understand their APOE results. While non-carriers felt relief, ε4 carriers often described themselves as disappointed by their result but nevertheless glad to know. Carriers expressed concerns about stigma and discrimination, including in the workplace. Carriers adopted new health behaviors at higher rates than non-carriers and revised their future plans to account for their increased risk of AD. Individuals participating in research were hopeful that their participation would help them or others; individuals who learned they were at increased risk for AD but who could not participate in research were disappointed. Conclusion: Providers disclosing APOE results should be sensitive to how APOE results shape emotions, self-perceptions, and attitudes about memory; raise concerns about stigma and discrimination in personal and professional relationships; influence health behaviors and decision-making; and can have follow-on effects on family members.

Yan Fu*, Zuo-Teng Wang*, Yi Qu, Xiao-Tong Wang, Ya-Hui Ma, Yan-Lin Bi, Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Sleep Characteristics and Cognitive Function in Older Adults Without Dementia: The CABLE Study
Abstract: Background: The associations between sleep characteristics and cognition are complicated. Alzheimer’s disease (AD) pathologies have been proven to be associated with sleep characteristics. Objective: We aimed to investigate the associations between sleep characteristics and cognitive function and examine the roles of AD pathologies in modulating the association of sleep duration with cognition. Methods: A total of 974 participants who had measurements of cerebrospinal fluid (CSF) amyloid-β (Aβ), phosphorylated tau (P-tau), total tau proteins (T-tau), cognitive function, and sleep characteristics were included from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) study. Linear regression analyses were utilized to explore the associations of sleep characteristics with cognition. Non-linear regression analyses were utilized to explore the associations of sleep habits with cognition. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition. Results: The Pittsburgh Sleep Quality Index (PSQI) total score was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) score (p=0.0176). Long latency (p=0.0054) and low efficiency (p=0.0273) were associated with cognitive impairment. Habitual nap behavior was associated with lower MoCA scores (p=0.0045). U-shaped associations were observed between sleep habits (bedtime and nocturnal sleep duration) and cognition. A causal mediation analysis indicated that P-tau/Aβ42 mediated the association of sleep duration with cognition. Conclusion: These findings showed sleep characteristics were associated with cognitive functions. Sleep habits (duration, bedtime) had U-shaped associations with cognition. AD core pathologies might partially mediate the influence of sleep duration on cognitive impairments.

Hieronim Jakubowski, Anetta Zioła-Frankowska, Marcin Frankowski, Joanna Perła-Kajan, Helga Refsum, Celeste A. de Jager, A. David Smith
B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment
Abstract: Background: Metals, silicon, and homocysteine are linked to Alzheimer’s disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI). Objective: Examine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vitamins affect these relationships. Methods: MCI participants (n=266, 77.6-year-old, 60.7% female) in VITACOG trial were randomized to receive daily folic acid (0.8 mg)/vitamin B12 (0.5 mg)/vitamin B6 (20 mg) (n=133) or placebo for two years. At baseline and end-of-study, cranial MRIs were obtained from 168 participants, cognition was analyzed by neuropsychological tests, and serum iron, copper, arsenic, aluminum, and silicon quantified by inductively-coupled plasma mass spectrometry in 196 participants. Data were analyzed by bivariate and multiple regression. Results: Baseline iron, cysteine, and homocysteine were significantly associated with brain atrophy rate. Homocysteine effects on brain atrophy rate were modified by iron and cysteine. At baseline, iron, copper, aluminum, and silicon were significantly associated with one or more domains of cognition: semantic memory, verbal episodic memory, attention/processing speed, and executive function. At end-of-study, baseline iron, copper, aluminum, and silicon predicted cognition in at least one domain: semantic memory, verbal episodic memory, visuospatial episodic memory, attention/processing speed, and global cognition in the placebo but not the B vitamin group. Conclusion: Disparate effects of serum iron, copper, aluminum, silicon, and homocysteine on cognition and brain atrophy in MCI suggest that cognitive impairment is independent of brain atrophy. These factors showed domain-specific associations with cognition, which were abrogated by B vitamin therapy.

Luwen Wang*, Mengyu Liu*, Ju Gao, Amber M. Smith, Hisashi Fujioka, Jingjing Liang, George Perry, Xinglong Wang (Handling Editor: Jesus Ávila) *These authors contributed equally to this work.
Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline
Abstract: Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer's disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.

Neda Shafiee, Mahsa Dadar, Simon Ducharme, D. Louis Collins, for the Alzheimer’s Disease Neuroimaging Initiative
Automatic Prediction of Cognitive and Functional Decline Can Significantly Decrease the Number of Subjects Required for Clinical Trials in Early Alzheimer’s Disease
Abstract: Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77% accuracy (81% sensitivity and 75% specificity) to predict cognitive decline at 2 years (74% accuracy at 3 years with 75% sensitivity and 73% specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25% treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression.

Alessia Filippone, Jian-Guo Li, Domenico Praticò (Handling Associate Editor: Patrizia Mecocci)
VPS35 Downregulation Alters Degradation Pathways in Neuronal Cells
Abstract: Background: The vacuolar protein sorting 35 (VPS35) is the main component of the retromer recognition core complex system which regulates intracellular cargo protein sorting and trafficking. Downregulation of VPS35 has been linked to the pathogenesis of neurodegenerative disorders such Alzheimer’s and Parkinson’s diseases via endosome dysregulation. Objective: Here we show that the genetic manipulation of VPS35 affects intracellular degradation pathways. Methods: A neuronal cell line expressing human APP Swedish mutant was used. VPS35 silencing was performed treating cells with VPS35 siRNA or Ctr siRNA for 72 h. Results: Downregulation of VPS35 was associated with alteration of autophagy flux and intracellular accumulation of acidic and ubiquitinated aggregates suggesting that dysfunction of the retromer recognition core leads to a significant alteration in both pathways. Conclusion: Taken together, our data demonstrate that besides cargo sorting and trafficking, VPS35 by supporting the integral function of the retromer complex system plays an important role also as a critical regulator of intracellular degradation pathways.

Ketrin Lengu, Shannon Ryan, Scott J. Peltier, Troy Tyszkowski, Anson Kairys, Bruno Giordani, Benjamin M. Hampstead (Handling Associate Editor: Michael Hornberger)
Effects of High Definition-Transcranial Direct Current Stimulation on Local GABA and Glutamate Levels Among Older Adults with and without Mild Cognitive Impairment: An Exploratory Study
Abstract: Background: Prior research, primarily with young adults, suggests transcranial direct current stimulation (tDCS) effects are driven by the primary excitatory and/or inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA), respectively. Objective: We examined the neurometabolic mechanisms of tDCS in older adults with and without mild cognitive impairment (MCI). Methods: We used data from a double-blind, cross-over, randomized controlled trial (NCT01958437) in 32 older adults to evaluate high definition (HD)-tDCS-induced changes in glutamate and GABA via magnetic resonance spectroscopy (MRS). Participants underwent MRS following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right superior parietal cortex (center anode at P2) and delivered 2mA for 20 minutes. Results: Relative to sham, and when co-varying for MRS voxel overlap and right superior parietal volume, active HD-tDCS significantly increased GABA and decreased the ratio of glutamate to GABA. No changes were observed in a left prefrontal control MRS voxel. Although we did not find a significant correlation between strength of delivered current (measured via MRI-based computational modeling) and neurometabolite change, there was a robust positive relationship between the volume of right superior parietal cortex and neurometabolite change. Conclusion: Our preliminary findings of increased GABA and reduced glutamate/GABA ratio raise the possibility that (HD-)tDCS effects differ by age. Moreover, age- and disease-related regional brain volume loss may be especially important to consider when planning future studies. Replication would emphasize the importance of developing population-specific tDCS parameters that consider structural and physiologic changes associated with “normal” and pathological aging.

Kazuo Washida*, Erika Kitajima*, Tomotaka Tanaka, Shuhei Ikeda, Tetsuya Chiba, Kotaro Noda, Takeshi Yoshimoto, Kazuki Fukuma, Satoshi Saito, Masafumi Ihara (Handling Associate Editor: Robert Friedland) *These authors contributed equally to this work.
A Nationwide Multi-Center Questionnaire Survey on the Real-World State and Clinical Management of Poststroke Dementia in Japan
Abstract: Background: Poststroke dementia (PSD) is a serious problem for stroke survivors. However, there is still limited data on the real-world state and clinical management of PSD worldwide, and several countries already have a super-aged society. Objective: We conducted a nationwide questionnaire survey to examine the real-world state and management of PSD in Japan. Methods: A survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated between July 2018 and August 2019. Thirteen questions regarding PSD were mailed to doctors responsible for stroke management. Results: Responses were obtained from 251 hospitals (50.2%). The chief doctors responsible for stroke management answered the questionnaires. The median numbers of patients admitted annually with stroke in the departments of neurology and neurosurgery in the hospitals were 281.0 (interquartile range [IQR], 231.8–385.3) and 253.5 (IQR, 210.0–335.3), respectively, and most hospitals were acute care hospitals. Executive dysfunction was the most common cognitive dysfunction (10.9%), followed by amnesia (9.5%) and apathy (4.1%). Surprisingly, many stroke survivors lived alone at home (23.7%). Montreal Cognitive Assessment was significantly uncommon compared to Mini-Mental State Examination (p<0.01). Furthermore, objective evaluation tests for behavioral and psychological symptoms of dementia were not often performed. Cognitive rehabilitation treatments were performed more often and earlier than drug treatments. The first drug of choice for PSD was predominantly donepezil (79.1%), followed by galantamine (6.1%), cilostazol (4.9%), memantine (2.5%), and rivastigmine (1.8%). Conclusion: Our study provides real-world evidence for the state of clinical practice related to PSD in Japan.

Fiona Höbler, Katherine S. McGilton, Walter Wittich, Kate Dupuis, Marilyn Reed, Shirley Dumassais, Paul Mick, M. Kathleen Pichora-Fuller
Hearing Screening for Residents in Long-Term Care Homes Who Live with Dementia: A Scoping Review
Abstract: Background: Hearing loss is highly prevalent in older adults, particularly among those living with dementia and residing in long-term care homes (LTCHs). Sensory declines can have deleterious effects on functioning and contribute to frailty, but the hearing needs of residents are often unrecognized or unaddressed. Objective: To identify valid and reliable screening measures that are effective for the identification of hearing loss and are suitable for use by nursing staff providing care to residents with dementia in LTCHs. Methods: Electronic databases (Embase, Medline, PsycINFO, CENTRAL, and CINAHL) were searched using comprehensive search strategies, and a stepwise approach based on Arksey & O'Malley’s scoping review and appraisal process was followed. Results: There were 193 scientific papers included in the review. Pure-tone audiometry was the most frequently reported measure to test hearing in older adults living with dementia. However, measures including self- or other-reports and questionnaires, review of medical records, otoscopy, and the whisper test were found to be most suitable for use by nurses working with older adults living with dementia in LTCHs. Conclusion: Although frequently used, the suitability of pure-tone audiometry for use by nursing staff in LTCHs is limited, as standardized audiometry presents challenges for many residents, and specific training is needed to successfully adapt test administration procedures and interpret results. The whisper test was considered to be more suitable for use by staff in LTCH; however, it yields a limited characterization of hearing loss. There remains an urgent need to develop new approaches to screen hearing in LTCHs.

Deepika Shukla, Pravat K. Mandal, Ritwick Mishra, Khushboo Punjabi, Divya Dwivedi, Manjari Tripathi, Vaishali Badhautia
Hippocampal Glutathione Depletion and pH Increment in Alzheimer's Disease: An in vivo MRS Study
Abstract: Background: Oxidative stress plays a major role in Alzheimer’s disease (AD) pathogenesis, and thus, antioxidant glutathione (GSH) has been actively investigated in mitigating the oxidative load. Significant hippocampal GSH depletion has been correlated with cognitive impairment in AD. Furthermore, postmortem studies indicated alterations in cellular-energy metabolism and hippocampal pH change toward alkalinity in AD. Objective: Concurrent analysis of hippocampal GSH and pH interplay in vivo on the same individual is quite unclear and hence requires investigation to understand the pathological events in AD. Methods: Total 39 healthy old (HO), 22 mild cognitive impairment (MCI), and 37 AD patients were recruited for hippocampal GSH using 1H-MRS MEGA-PRESS and pH using 2D 31P-MRSI with dual tuned (1H/31P) transmit/receive volume head coil on 3T-Philips scanner. All MRS data processing using KALPANA package and statistical analysis were performed MedCalc, respectively and NINS-STAT package. Results: Significant GSH depletion in the left and right hippocampus (LH and RH) among MCI and AD study groups as compared to HO was observed, whereas pH increased significantly in the LH region between HO and AD. Hippocampal GSH level negatively correlated with pH in both patient groups. The ROC analysis on the combined effect of GSH and pH in both hippocampal regions give accuracy for MCI (LH: 78.27%; RH: 86.96%) and AD (LH: 88%; RH: 78.26%) groups differentiating from HO. Conclusion: Outcomes from this study provide further insights to metabolic alterations in terms of concurrent assessment of hippocampal GSH and pH levels in AD pathogenesis, aiding in early diagnosis of MCI and AD.

Sterre C.M. de Boer, Lina Riedl, Sven J. van der Lee, Markus Otto, Sarah Anderl-Straub, Ramon Landin-Romero, Federica Sorrentino, Jay L.P. Fieldhouse, Lianne M. Reus, Blanca Vacaflor, Glenda Halliday, Daniela Galimberti , Janine Diehl-Schmid, Simon Ducharme, Olivier Piguet, Yolande A.L. Pijnenburg
Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia
Abstract: Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n=654), non-fluent variant primary progressive aphasia (nfvPPA; n=99), semantic variant primary progressive aphasia (svPPA; n=117), and right temporal variant frontotemporal dementia (rtvFTD; n=40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p=0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p=0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases sex distribution was somewhat equal. Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.

Heeyoung Kim, Sungmin Jun, Bum Soo Kim, In-Joo Kim; Alzheimer’s Disease Neuroimaging Initiative
Serum Adiponectin in Alzheimer’s Disease (AD): Association with AD Biomarkers and Cognitive Outcome
Abstract: Background: The association between dementia and serum adiponectin has been evaluated in many studies; however, conclusions remain mixed. Objective: We investigated the cross-sectional associations of adiponectin with cognitive function and Alzheimer’s disease (AD) biomarkers and whether serum adiponectin levels can predict cognitive outcomes. Methods: This study included 496 participants from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI1) with available serum adiponectin levels at baseline and ≥65 years of age. Subjects were stratified based on sex and apolipoprotein ε4 (APOE4) carrier status to determine associations between adiponectin and cognitive function. The linear mixed model was used to analyze associations between adiponectin level and cognitive outcome in amnestic mild cognitive impairment (aMCI) patients. Results: Serum adiponectin levels were higher in aMCI and AD than in CN subjects among APOE4 non-carrier males (adiponectin in CN, aMCI, and AD: 0.54 ± 0.24, 0.74 ± 0.25, and 0.85 ± 0.25, respectively, p < 0.001). In this group, serum adiponectin levels were associated with age (p = 0.001), ADAS13 (p < 0.001), memory function (p < 0.001), executive function (p < 0.001), total tau (p < 0.001), and phosphorylated tau (p < 0.001) measures in cerebrospinal fluid (CSF). Higher adiponectin level was not associated with cognitive outcome in aMCI patients in the linear mixed model analysis over 5.3 ± 2.6 years of mean follow-up. Conclusion: Serum adiponectin level was associated with cognitive function and CSF AD biomarkers among APOE4 non-carrier males. However, serum adiponectin level was not associated with longitudinal cognitive function outcome in aMCI.

Jeanine J.S. Rutten, Janine van Kooten, Anouk M. van Loon, Laura W. van Buul, Karlijn J. Joling, Martin Smalbrugge, Cees M.P.M. Hertogh (Handling Associate Editor: Alba Malara)
Dementia and Parkinson’s Disease: Risk Factors for 30-Day Mortality in Nursing Home Residents with COVID-19
Abstract: Background: The COVID-19 pandemic has led to high mortality rates in nursing homes (NHs) in Europe. For adequate risk management and good prognostications, it is essential to identify mortality risk factors. Objective: This study aimed to determine whether previously identified risk factors for 30-day mortality in Dutch NH residents with COVID-19 are unique to COVID-19. Methods: In this cohort study, we included 1,294 NH residents with COVID-19 (cases) and 17,999 NH residents without COVID-19 (controls, from the pre-COVID-19 period). We used descriptive statistics and Cox proportional hazard models to compare mortality rates in residents with and without COVID-19, categorized by risk factors. Results: Cases had a more than 18 times higher hazard of death within 30 days compared to controls (HR 18, 95% CI: 16-20). For residents with COVID-19, being male, having dementia, and having Parkinson’s disease (PD) were all associated with a higher 30-day mortality (HR 1.8 versus 1.3 versus 1.7). Being male was also associated with a higher mortality (HR 1.7) in the control group, whereas having dementia and PD were not. COVID-19 symptomatology was very similar for residents with and without dementia or PD, except for delirium and malaise which was more frequent in residents with dementia. Conclusion: Dementia and PD were significant additional risk factors for mortality in Dutch NH residents with COVID-19, whereas male gender was not unique to residents with COVID-19. The frailty of PD and dementia in NH residents with COVID-19 are relevant to consider in prognostication, communication, and care planning with residents and their families.

Chorong Oh (Handling Associate Editor: Manuel Montero-Odasso)
Single-Task or Dual-Task? Gait Assessment as a Potential Diagnostic Tool for Alzheimer’s Disease
Abstract: Background: A person’s gait performance requires the integration of sensorimotor and cognitive systems. Therefore, a person’s gait may be influenced by concurrent cognitive load such as simultaneous talking. Although it has been known that gait performance of people with Alzheimer’s dementia (AD) is compromised when they attempt a dual-task walking task, it is unclear if using a dual-task gait performance during an AD assessment yields higher diagnostic accuracy. Objective: This study was designed to investigate the predictive power for AD of dual-task gait performance in an AD assessment. Methods: Participants (14 with AD and 15 healthy controls) walked across the GAITRite© Portable Walkway mat under three different cognitive load conditions: no simultaneous cognitive load, walking while counting numbers by ones, and walking while completing category naming. Results: Multiple logistic regression revealed that the high cognitive load (i.e., category naming) with or without the low cognitive load (i.e., concurrent counting) increased the proportion of variance explained by the FAP, SL, and DST. Conclusion: Dual-task walking and talking may be a more effective diagnostic feature than single-task walking in a comprehensive AD diagnostic assessment.

Carolin Hofmann, Annika Sander, Xing Xing Wang, Martina Buerge, Bettina Jungwirth, Laura Borgstedt, Matthias Kreuzer, Claudia Kopp, Kenji Schorpp, Kamyar Hadian, Carsten T. Wotjak, Tim Ebert, Maarten Ruitenberg, Christopher G. Parsons, Gerhard Rammes (Handling Associate Editor: Daniela Puzzo)
Inhalational Anesthetics Do Not Deteriorate Amyloid-β-Derived Pathophysiology in Alzheimer’s Disease: Investigations on the Molecular, Neuronal, and Behavioral Level
Abstract: Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer’s disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. Objective: In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. Methods: Oligomerization of Aβ1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ1-42, Aβ1-40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. Results: Whereas isoflurane and sevoflurane did not affect Aβ1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ1-42-induced spine density attenuation. In the presence of Aβ1-40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ1-42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. Conclusion: None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ1-42 aggregation, LTP, and spine density.

Ioulietta Lazarou, Despina Moraitou, Marianna Papatheodorou, Isaak Vavouras, Chrysanthi Lokantidou, Christina Agogiatou, Moses Gialaoutzis, Spiros Nikolopoulos, Thanos G. Stavropoulos, Ioannis Kompatsiaris (Yiannis), Magda Tsolaki
Adaptation and Validation of the Memory Alteration Test (M@T) in Greek Middle-Aged, Older, and Older-Old Population with Subjective Cognitive Decline and Mild Cognitive Impairment
Abstract: Background: The Memory Alteration Test (M@T) is a verbal episodic and semantic memory screening test able to detect subjective cognitive decline (SCD). Objective: To adapt M@T, creating a Greek version of the Memory Alteration Test (M@T-GR), and to validate M@T-GR compared to the Mini-Mental State Examination (MMSE), SCD-Q MyCog and TheirCog. Methods: 232 people over 55 years old participated in the study and they were classified as healthy controls (HC, n = 65), SCD (n = 78), or MCI (n = 89). Results: The ANCOVA showed that the M@T-GR’s total score was significantly different in HC and SCD (I–J = 2.26, p=0.032), HC and MCI (I–J = 6.16, p<0.0001), and SCD compared to MCI (I–J = 3.90, p<0.0001). In particular, a cut-off score of 46.50 points had an 81% sensitivity and 61% specificity for discriminating HC from SCD (AUC=0.76, p<0.0001), while a cut-off score of 45.50 had a sensitivity of 92% and a specificity of 73% for discriminating MCI (AUC=0.88, p<0.0001), and a cut-off score of 45.50 points had a sensitivity of 63% and a specificity of 73% for discriminating SCD from those with MCI (AUC=0.69, p<0.0021). Exploratory factor analysis indicated that there was one factor explaining 38.46% of the total variance. Internal consistency was adequate (α = 0.75), while convergent validity was found between M@T-GR and MMSE (r = 0.37, p<0.0001) and SCD-Q TheirCog (r= -0.32, p<0.0001). Conclusion: The M@T-GR is a good to fair screening tool with adequate discriminant validity for administration in people with SCD and MCI in Greece.

Naoko Nakahata, Takumi Nakamura, Takeshi Kawarabayashi, Yusuke Seinoe, Sadanobu Ichii, Yoshio Ikeda, Masakuni Amari, Masamitsu Takatama, Koichi Murashita, Kazunari Ihara, Ken Itoh, Shigeyuki Nakaji, Mikio Shoji
Age-Related Cognitive Decline and Prevalence of Mild Cognitive Impairment in the Iwaki Health Promotion Project
Abstract: Background: The Iwaki Health Promotion Project (IHPP) is a community-based study for the prevention of lifestyle-related diseases and improvement of quality of life. Objective: Between 2014 and 2017, a total of 4,442 Iwaki town residents from 19 to 93 years of age participated in annual surveys to clarify the natural course of age-related cognitive decline and mild cognitive impairment (MCI). Methods: Modified OLD and SED-11Q questionnaires, MMSE, Logical Memory II, educational history, and APOE genotypes were examined at the first screening. MCI and dementia were diagnosed at the second examination by detailed neurological examination, CDR, and MRI, and followed for 3 years. Spline regression analyses based on a linear mixed model was adopted for statistical analysis. Results: MMSE scores declined with age from 55 to 64 years. There was also interaction between levels of education and ages. At the second examination, 56 MCI and 5 dementia patients were identified. None of the MCI cases progressed to dementia during the 3 years. During follow-up examinations, 13 cases showed improved MMSE scores (0.95 point/year), 5 remained stable, and 7 deteriorated (-0.83 point/year). Five cases showed improved CDR-SOB scores (-0.28 point/year), 9 remained stable, and 6 deteriorated (0.3 point/year). Conclusion: IHPP revealed that age- and education-related cognitive decline began and advanced from 55 years of age. The prevalence of MCI and dementia was estimated to be 5.9% in the Iwaki town cohort over 60 yeas of age. About 30% of MCI cases showed progression of cognitive decline.

Jennifer Stargatt, Sunil Bhar, Tanya Petrovich, Jahar Bhowmik, David Sykes, Kelly Burns (Handling Associate Editor: Meghan Mattos)
The Effects of Virtual Reality-Based Education on Empathy and Understanding of the Physical Environment for Dementia Care Workers in Australia: A Controlled Study
Abstract: Background: There is support for the effectiveness of virtual reality (VR) technology in dementia education. However, it is not yet known if VR is a useful tool for improving empathy and understanding of dementia care environments among dementia care workers. Objective: This study compared learning outcomes of VR versus non-VR (control) workshops for dementia care workers of different ages and English-speaking backgrounds. Methods: Dementia care workers enrolled in workshops on dementia care principles. Once participants were enrolled, workshops were assigned at random to deliver non-VR or VR-based education. Participants (N = 114, 91.8% female, mean age = 46.4; SD = 13.2; n = 60VR condition, 54control condition) completed self-report measures of empathy towards people living with dementia, understanding of dementia care environments, dementia knowledge, and attitudes towards dementia at pre- and post-workshop. Results: Significant pre-post main effects were observed for empathy, understanding of dementia care environments, and attitudes. Interaction effects were not found; improvements in outcomes were similar between conditions. However, interaction effects were observed for subgroups. Empathy improved significantly more in the VR condition for older participants. Understanding of dementia care environments improved more in the VR condition for younger and non-English-speaking background participants. Conclusion: Using VR may not augment teaching outcomes for all learners. VR may differentially assist leaners of different ages and English-speaking backgrounds. More research is needed to understand for which variables and for whom VR is a useful teaching tool.

David Silhan, Olga Pashkovska, Ales Bartos, for the Alzheimer’s Disease Neuroimaging Initiative
Hippocampo-Horn Percentage and Parietal Atrophy Score for Easy Visual Assessment of Brain Atrophy on Magnetic Resonance Imaging in Early- and Late-Onset Alzheimer’s Disease
Abstract: Background: Magnetic resonance imaging (MRI) visual scales of brain atrophy are important for differential diagnosis of dementias in routine clinical practice. Atrophy patterns in early- and late-onset Alzheimer’s disease (AD) can be different according to some studies. Objective: Our goal was to assess brain atrophy patterns in early- and late-onset AD using our recently developed simple MRI visual scales and evaluate their reliability. Methods: We used Hippocampo-horn percentage (Hip-hop) and Parietal Atrophy Score (PAS) to compare mediotemporal and parietal atrophy on brain MRI among 4 groups: 26 patients with early-onset AD, 21 younger cognitively normal persons, 32 patients with late-onset AD, and 36 older cognitively normal persons. Two raters scored all brain MRI to assess reliability of the Hip-hop and PAS. Brain MRIs were obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Results: The patients with early-onset AD had significantly more pronounced mediotemporal and also parietal atrophy bilaterally compared to the controls (both p < 0.01). The patients with late-onset AD had significantly more pronounced only mediotemporal atrophy bilaterally compared to the controls (p < 0.000001), but parietal lobes were the same. Intra-rater and inter-rater reliability of both visual scales Hip-hop and PAS were almost perfect in all cases (weighted-kappa value ranged from 0.90 to 0.99). Conclusion: While mediotemporal atrophy detected using Hip-hop is universal across the whole AD age spectrum, parietal atrophy detected using PAS is worth rating only in early-onset AD. Hip-hop and PAS are very reliable MRI visual scales.

Ramon Casanova, Sarah A. Gaussoin, Robert Wallace, Laura Baker, Jiu-Chiuan Chen, JoAnn E. Manson, Victor W. Henderson, Bonnie C. Sachs, Jamie Justice, Eric A. Whitsel, Kathleen M. Hayden, Stephen R. Rapp
Investigating Predictors of Preserved Cognitive Function in Older Women Using Machine Learning: Women’s Health Initiative Memory Study
Abstract: Background: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge. Objective: We used data from the longitudinal Women’s Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life. Methods: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≤39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≤39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score <31. Random Forests was used to rank the predictors of preserved cognitive function. Results: Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76-0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels. Conclusion: The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors.

Yi Liu*, Zhuoyuan Li*, Xueyan Jiang, Wenying Du, Xiaoqi Wang, Can Sheng, Jiehui Jiang, Ying Han (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Differences in Functional Brain Networks Between Subjective Cognitive Decline with and without Worry Groups: A Graph Theory Study from SILCODE
Abstract: Background: Evidence suggests that subjective cognitive decline (SCD) individuals with worry have a higher risk of cognitive decline. However, how SCD-related worry influences the functional brain network is still unknown. Objective: In this study, we aimed to explore the differences in functional brain networks between SCD subjects with and without worry. Methods: A total of 228 participants were enrolled from the Sino Longitudinal Study on Cognitive Decline (SILCODE), including 39 normal control (NC) subjects, 117 SCD subjects with worry, and 72 SCD subjects without worry. All subjects completed neuropsychological assessments, APOE genotyping, and resting-state functional magnetic resonance imaging (rs-fMRI). Graph theory was applied for functional brain network analysis based on both the whole brain and default mode network (DMN). Parameters including the clustering coefficient, shortest path length, local efficiency, and global efficiency were calculated. Two-sample T-tests and chi-square tests were used to analyze differences between two groups. In addition, a false discovery rate-corrected post hoc test was applied. Results: Our analysis showed that compared to the SCD without worry group, SCD with worry group had significantly increased functional connectivity and shortest path length (p=0.002) and a decreased clustering coefficient (p=0.013), global efficiency (p=0.001), and local efficiency (p<0.001). The above results appeared in both the whole brain and DMN. Conclusion: There were significant differences in functional brain networks between SCD individuals with and without worry. We speculated that worry might result in alterations of the functional brain network for SCD individuals and then result in a higher risk of cognitive decline.

Jovana Aranđelović, Anja Santrač, Bojan Batinić, Lidija Todorović, Md Zubair Ahmed Khan, Farjana Rashid, Michael M. Poe, Aleksandar Obradović, James M. Cook, Miroslav M. Savić
Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease
Abstract: Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising.

Yume Imahori, Davide L. Vetrano, Petter Ljungman, Chengxuan Qiu
Electrocardiographic Predictors of Cognitive Decline and Dementia: A Systematic Review
Abstract: Background: Markers of altered cardiac function might predict cognitive decline and dementia. Objective: This systematic review aims to review the literature that examines the associations of various electrocardiogram (ECG) markers with cognitive decline and dementia in middle-aged and elderly populations. Methods: We searched PubMed, Embase, and Web of Science through 1 July 2020 for literature and conducted a systematic literature review. We included studies examining the associations of ECG markers (e.g., left ventricular hypertrophy [LVH], spatial QRS-T angle, and QT prolongation) with cognitive function and dementia in adult populations regardless of study setting and design, but excluded studies examining atrial fibrillation and heart rate variability. Results: Fourteen community-based cross-sectional and longitudinal studies were identified. ECG markers were investigated in association with dementia in four prospective studies, and with cognitive decline in ten prospective studies. ECG-assessed LVH was associated with dementia in one study while five heterogeneous prospective studies yielded inconsistent associations with cognitive decline. Regarding ventricular repolarization markers, spatial QRS-T angle was associated with cognitive decline in one study while another study found no association between QT prolongation and cognitive decline. High resting heart rate was associated with both dementia and cognitive decline in one study but not associated with dementia in another study. P-wave abnormality was significantly associated with incident dementia and cognitive decline in one prospective study. Conclusion: Some ECG markers were associated with incident dementia and cognitive decline. However, limited number of heterogeneous studies did not allow us to make firm conclusions. Further studies are needed.

Hongliang Liu, Michael Lutz, Sheng Luo, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Jin-Tai Yu)
Association Between Polygenic Risk Score and the Progression from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer’s disease (AD). Objective: In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging. Methods: We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed. Results: We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, se = 0.061, p = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, se = 0.037, p = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PIB and AV45), but decreased hippocampus and entorhinal cortex volumes (p < 0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ42 (beta = 0.056, SE = 0.026, p = 0.036). Conclusion: Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI.

Youjin Jung, Raymond P. Viviano, Sanneke van Rooden, Jeroen van der Grond, Serge A.R.B. Rombouts, Jessica S. Damoiseaux
White Matter Hyperintensities and Apolipoprotein E Affect the Association Between Mean Arterial Pressure and Objective and Subjective Cognitive Functioning in Older Adults
Abstract: Background: White matter hyperintensities (WMH) show a robust relationship with arterial pressure as well as objective and subjective cognitive functioning. In addition, APOE ε4 carriership may influence how arterial pressure affects cognitive functioning. Objective: To determine the role of region-specific WMH burden and APOE ε4 carriership on the relationship between mean arterial pressure (MAP) and cognitive function as well as subjective cognitive decline (SCD). Methods: The sample consisted of 87 cognitively unimpaired middle-aged to older adults aged 50-85. We measured WMH volume for the whole brain, anterior thalamic radiation (ATR), forceps minor, and superior longitudinal fasciculus (SLF). We examined whether WMH burden mediated the relationship between MAP and cognition (i.e., TMT-A score for processing speed; Stroop performance for executive function) as well as SCD (i.e., Frequency of Forgetting (FoF)), and whether APOE ε4 carriership moderated that mediation. Results: WMH burden within SLF mediated the effect of MAP on Stroop performance. Both whole brain and ATR WMH burden mediated the effect of MAP on FoF score. In the MAP–WMH–Stroop relationship, the mediation effect of SLF WMH and the effect of MAP on SLF WMH were significant only in APOE ε4 carriers. In the MAP–WMH–FoF relationship, the effect of MAP on whole brain WMH burden was significant only in ε4 carriers. Conclusion: WMH burden and APOE genotype explain the link between blood pressure and cognitive function and may enable a more accurate assessment of the effect of high blood pressure on cognitive decline and risk for dementia.

Di Hu, Chuning Liu, Kai Xia, Amy Abramowitz, Guorong Wu, and Alzheimer's Disease Neuroimaging Initiative (ADNI)
Characterizing the Resilience Effect of Neurodegeneration for the Mechanistic Pathway of Alzheimer’s Disease
Abstract: Background: With the rapid development of neurobiology and neuroimaging technologies, mounting evidence shows that Alzheimer's disease (AD) is caused by the build-up of two abnormal proteins, amyloid-β plaques (A) and neurofibrillary tangles (T). Over time, these AD-related neuropathological burdens begin to spread throughout the brain, which results in the characteristic progression of symptoms in AD. Objective: Although tremendous efforts have been made to link biological indicators to the progression of AD, limited attention has been paid to investigate the multi-factorial role of socioeconomic status (SES) in the prevalence or incidence of AD. There is high demand to explore the synergetic effect of sex and SES factors in moderating the neurodegeneration process caused by the accumulation of A and T biomarkers. Methods: We carry out a meta-data analysis on the longitudinal neuroimaging data, clinical outcomes, genotypes, and demographic data in Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). Results: Our major findings include 1) education and occupation show resilience effects at the angular gyrus, superior parietal lobule, lateral occipital-temporal sulcus, and posterior transverse collateral sulcus where we found significant slowdown of neurodegeneration due to higher education level or more advanced occupation rank; 2) A and T biomarkers manifest different spatial patterns of brain resilience; 3) BDNF (brain-derived neurotrophic factor) single nucleotide polymorphism (SNP) rs10835211 shows strong association to the identified resilience effect; 4) the identified resilience effect is associated with the clinical manifestation in memory, learning, and organization performance. Conclusion: Several brain regions manifest resilience from SES to A and T biomarkers. BDNF SNPs have a potential association with the resilience effect from SES. In addition, cognitive measures of learning and memory demonstrate the resilience effect.

Emma Lindgren, Josephine Sörenson, Carina Wattmo, Ingemar Kåreholt, Katarina Nägga
Differences in Dementia Care Between Swedish-Born and Foreign-Born from Countries with Different Country Level Socioeconomic Position: A Nationwide Register-Based Study
Abstract: Background: With a growing elderly population worldwide, the prevalence of dementia is rapidly increasing. Studies from high income countries have shown that belonging to a minority ethnic group increases the risk of health disadvantages. Objective: The aim of the present registry-based study was to identify potential differences in diagnostics, treatment, and care of individuals with dementia focusing on foreign-born in Sweden and the impact of country level socioeconomic position (SEP). Methods: The study was based on a large dataset from the Swedish Dementia Registry (SveDem) and the Swedish Tax Agency's population registry. Data on demographic variables, cognitive tests, clinical assessments, medication, diagnosis, and interventions initiated at diagnosis were collected. Country level SEP was determined by country of birth as classified by World Bank Country and Lending groups. Results: Of 57,982 patients with dementia registered in SveDem, 7,171 (12.4%) were foreign-born. The foreign-born were significantly younger at diagnosis (p<0.001), had a lower MMSE score (p<0.001), lower odds of receiving a specific dementia diagnosis (p<0.001), lower use of acetylcholinesterase inhibitors (p<0.001), and overall a higher use of neuroleptics compared with the Swedish-born group. The lower SEP, the greater differences to Swedish-born were seen in many of the examined variables. Conclusion: There were significant differences in dementia diagnostics, treatment, and care between foreign-born and Swedish-born, a lower SEP indicating greater differences. Further research should focus on various socioeconomic aspects and health care outcomes for a more profound analysis of equity in dementia care.

Danielle Newby, Laura Winchester, William Sproviero, Marco Fernandes, Di Wang, Andrey Kormilitzin, Lenore J. Launer, Alejo J. Nevado-Holgado (Handling Associate Editor: Hélène Girouard)
Associations Between Brain Volumes and Cognitive Tests with Hypertensive Burden in UK Biobank
Abstract: Background: Mid-life hypertension is an established risk factor for cognitive impairment and dementia and related to greater brain atrophy and poorer cognitive performance. Previous studies often have small sample sizes from older populations that lack utilizing multiple measures to define hypertension such as blood pressure, self-report information, and medication use; furthermore, the impact of the duration of hypertension is less extensively studied. Objective: To investigate the relationship between hypertension defined using multiple measures and length of hypertension with brain measure and cognition. Methods: Using participants from the UK Biobank MRI visit with blood pressure measurements (n = 31,513), we examined the cross-sectional relationships between hypertension and duration of hypertension with brain volumes and cognitive tests using generalized linear models adjusted for confounding. Results: Compared with normotensives, hypertensive participants had smaller brain volumes, larger white matter hyperintensities (WMH), and poorer performance on cognitive tests. For total brain, total grey, and hippocampal volumes, those with greatest duration of hypertension had the smallest brain volumes and the largest WMH, ventricular cerebrospinal fluid volumes. For other subcortical and white matter microstructural regions, there was no clear relationship. There were no significant associations between duration of hypertension and cognitive tests. Conclusion: Our results show hypertension is associated with poorer brain and cognitive health however, the impact of duration since diagnosis warrants further investigation. This work adds further insights by using multiple measures defining hypertension and analysis on duration of hypertension which is a substantial advance on prior analyses—particularly those in UK Biobank which present otherwise similar analyses on smaller subsets.