Volume 78, Number 4, IN PRESS

Review
Zizhen Si, Xidi Wang (Handling Associate Editor: Wolff Kirsch)
The Neuroprotective and Neurodegeneration Effects of Heme Oxygenase-1 in Alzheimer's Disease
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by complex pathological and biological features. Notably, extracellular amyloid-β deposits as senile plaques and intracellular aggregation of hyperphosphorylated tau as neurofibrillary tangles remain the primary premortem criterion for the diagnosis of AD. Currently, there exist no disease-modifying therapies for AD, and many clinical trials have failed to show its benefits for patients. Heme oxygenase 1 (HO-1) is a 32 kDa enzyme, which catalyzes the degradation of cellular heme to free ferrous iron, biliverdin, and carbon monoxide under stressful conditions. Several studies highlight the crucial pathological roles of HO-1 in the molecular processes of AD. The beneficial roles of HO-1 overexpression in AD brains are widely accepted due to its ability to convert pro-oxidant heme to biliverdin and bilirubin (antioxidants), which promote restoration of a suitable tissue redox microenvironment. However, the intracellular oxidative stress might be amplified by metabolites of HO-1 and exacerbate the progression of AD under certain circumstances. Several lines of evidence have demonstrated that upregulated HO-1 is linked to tauopathies, neuronal damage, and synapse aberrations in AD. Here, we review the aspects of the molecular mechanisms by which HO-1 regulates AD and the latest information on the pathobiology of AD. We further highlight the neuroprotective and neurodystrophic actions of HO-1 and the feasibility of HO-1 as a therapeutic target for AD.

Review
Dona P.W. Jayatunga, Eugene Hone, Prashant Bharadwaj, Manohar Garg, Giuseppe Verdile, Gilles J. Guillemin, Ralph N. Martins
Targeting Mitophagy in Alzheimer’s disease
Abstract: Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer’s disease (AD). Targeting mitophagy pathways has been suggested to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD.

Review
Christopher B. Pople, Ying Meng, Daniel Z. Li, Luca Bigioni, Benjamin Davidson, Laura M. Vecchio, Clement Hamani, Jennifer S. Rabin, Nir Lipsman (Handling Associate Editor: Thibaut Sesia)
Neuromodulation in the Treatment of Alzheimer’s Disease: Current and Emerging Approaches
Abstract: Neuromodulation as a treatment strategy for psychiatric and neurological diseases has grown in popularity in recent years, with the approval of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression being one such example. These approaches offer new hope in the treatment of diseases that have proven largely intractable to traditional pharmacological approaches. For this reason, neuromodulation is increasingly being explored for the treatment of Alzheimer’s disease. However, such approaches have variable, and, in many cases, very limited evidence for safety and efficacy, with most human evidence obtained in small clinical trials. Here we review work in animal models and humans with Alzheimer’s disease exploring emerging neuromodulation modalities. Approaches reviewed include deep brain stimulation, transcranial magnetic stimulation, transcranial electrical stimulation, ultrasound stimulation, photobiomodulation, and visual or auditory stimulation. In doing so, we clarify the current evidence for these approaches in treating Alzheimer’s disease and identify specific areas where additional work is needed to facilitate their clinical translation.

Review
Xinquan Li*, Weiting Xuan*, Dabao Chen*, Huawu Gao, Guangyun Wang, Qiaoru Guo, Yan Wang, Hang Song, Biao Cai *These authors contributed equally to this work.
Research Progress of Alzheimer’s Disease Therapeutic Drugs: Based on Renin-Angiotensin System Axis
Abstract: It is widely recognized that Alzheimer’s disease (AD) has a complicate link to renin-angiotensin system (RAS). It is known that cerebrovascular disease has some connections with AD, but most of the studies are still conducted in parallel or independently. Although previous research came up with large number of hypotheses about the pathogenesis of AD, it does not include the mechanism of RAS-related regulation of AD. It has been found that many components of RAS have been changed in AD. For example, the multifunctional and high-efficiency vasoconstrictor Ang II and Ang III with similar effects are changed under the action of other RAS signal peptides; these signal peptides are believed to help improve nerve injury and cognitive function. These changes may lead to neuropathological changes of AD, and progressive defects of cognitive function, which are association with some hypotheses of AD. The role of RAS in AD gradually attracts our attention, and RAS deserved to be considered carefully in the pathogenesis of AD. This review discusses the mechanisms of RAS participating in the three current hypotheses of AD: neuroinflammation, oxidative stress and amyloid-β protein (Aβ) hypothesis, as well as the drugs that regulate RAS systems already in clinical or in clinical trials. It further demonstrates the importance of RAS in the pathogenesis of AD, not only because of its multiple aspects of participation, which may be accidental, but also because of the availability of RAS drugs, which can be reused as therapies of AD.

Review
Magdalena Rewerska-Juśko, Konrad Rejdak
Social Stigma of People with Dementia
Abstract: In a broad sense, the concept of social stigmatization (from the Greek word “stigma”, or sign) refers to the attitude of social disapproval and the negative reception of a specific group of people due to the characteristic features of this group. The problem of stigma affects many people, and it is also present in medicine and affects people with dementia. Social stigma of people with dementia is a worldwide problem. The severity of this phenomenon depends on several factors, including gender, age, level of education, religiosity, cultural differences, and the severity of cognitive disorders. Stigmatization can have numerous negative consequences. It leads to rejection, discrimination, and exclusion of stigmatized people from participation in various areas of social life. It also affects close relatives. The main goal of this review paper is to present the problem of stigma among people with dementia, discuss the results of represented research that deals with this issue, to approximate the elements that make up this process, and to present the negative consequences of stigma. Detailed knowledge of this phenomenon provides opportunity to reduce the extent of stigma and improve the quality of life people suffering from dementia. It is worth emphasizing the role of an individual approach to the patient and the need to educate the public about dementia.

Review
Akriti Srivastava, Brati Das, Annie Y. Yao and Riqiang Yan
Metabotropic Glutamate Receptors in Alzheimer’s Disease Synaptic Dysfunction: Therapeutic Opportunities and Hope for the Future
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-β (Aβ), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement.

Commentary
Poul F. Høilund-Carlsen, Jorge R. Barrio, Tom J. Werner, Andrew Newberg, Abass Alavi
Amyloid Hypothesis: The Emperor’s New Clothes?
Abstract: The lengthy debate on the validity of the amyloid hypothesis and the usefulness of amyloid imaging and anti-amyloid therapeutic interventions in dementia continues unabated, even though none of them have been able to convince the medical world of their correctness and clinical value. There are huge financial interests associated with promoting both, but in spite of the large sums of money in their support, no effective anti-amyloid treatments or diagnostic use of amyloid imaging have emerged. There are solid scientific reasons that explain these negative results, and it is time to move forward to other promising options for the benefit of the patients.

Short Communication
Paloma Martín-Jiménez*, Mariana I. Muñoz-García*, David Seoane*, Lucas Roca-Rodríguez*, Ana García-Reyne, Antonio Lalueza, Guillermo Maestro, Dolores Folgueira, Víctor A. Blanco-Palmero, Alejandro Herrero-San Martín, Sara Llamas-Velasco, David A. Pérez-Martínez, Marta González-Sánchez**, Alberto Villarejo-Galende** (Handling Associate Editor: Carla Adelnour) *,**These authors contributed equally to this work.
Cognitive Impairment Is a Common Comorbidity in Deceased COVID-19 Patients: A Hospital-Based Retrospective Cohort Study
Abstract: We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.

Short Communication
Anastasia De Luca, Silvia Fostinelli, Clarissa Ferrari, Giuliano Binetti, Luisa Benussi, Barbara Borroni, Luisa Rossi, Mauro Rongioletti, Roberta Ghidoni, Rosanna Squitti
Iron Serum Markers Profile in Frontotemporal Lobar Degeneration
Abstract: Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative syndrome. Defects of copper (Cu) and iron (Fe) homeostasis are involved in the development of several neurodegenerative diseases and their homeostasis is interconnected by the Cu-protein ceruloplasmin (Cp), responsible for Fe oxidative state. In this study we assessed Fe, transferrin (Trf), ferritin, Cp specific activity (eCp/iCp), Cp/Trf ratio, and Trf saturation in 60 FTLD patients and 43 healthy controls, and discussed the results in relation to Cu homeostasis. The significant decrease of the eCp/iCp in the FTLD patients supports the involvement of Fe imbalance in the onset and progression of FTLD.

Ali Yilmaz, Ilyas Ustun, Zafer Ugur, Sumeyya Akyol, William T. Hu, Massimo S. Fiandaca, Mark Mapstone, Howard Federoff, Michael Maddens, Stewart F. Graham
A Community-Based Study Identifying Metabolic Biomarkers of Mild Cognitive Impairment and Alzheimer’s Disease Using Artificial Intelligence and Machine Learning
Abstract: Background: Currently, there is no objective, clinically available tool for the accurate diagnosis of Alzheimer’s disease (AD). There is a pressing need for a novel, minimally invasive, cost friendly, and easily accessible tool to diagnose AD, assess disease severity, and prognosticate course. Metabolomics is a promising tool for discovery of new, biologically, and clinically relevant biomarkers for AD detection and classification. Objective: Utilizing artificial intelligence and machine learning, we aim to assess whether a panel of metabolites as detected in serum can be used as an objective and clinically feasible tool for the diagnosis of mild cognitive impairment (MCI) and AD. Methods: Using a community-based sample cohort acquired from different sites across the US, we adopted an approach combining Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR), Liquid Chromatography coupled with Mass Spectrometry (LC-MS). and various machine learning statistical approaches to identify a biomarker panel capable of identifying those patients with AD and MCI from healthy controls. Results: Of the 212 measured metabolites, 5 were identified as optimal to discriminate between controls, and individuals with MCI or AD. Our models performed with AUC values in the range of 0.72-0.76, with the sensitivity and specificity values ranging from 0.75-0.85 and 0.69-0.81, respectively. Univariate and pathway analysis identified lipid metabolism as the most perturbed biochemical pathway in MCI and AD. Conclusion: A comprehensive method of acquiring metabolomics data, coupled with machine learning techniques, has identified a strong panel of diagnostic biomarkers capable of identifying individuals with MCI and AD. Further, our data confirm what other groups have reported in that lipid metabolism is significantly perturbed in those individuals suffering with dementia. This work may provide additional insight into AD pathogenesis and encourage more in-depth analysis of the AD lipidome.

Isabelle Pelcher, Christian Puzo, Yorghos Tripodis, Hugo J. Aparicio, Eric G. Steinberg, Alyssa Phelps, Brett Martin, Joseph N. Palmisano, Elizabeth Vassey, Cutter Lindbergh, Ann C. McKee, Thor D. Stein, Ronald J. Killiany, Rhoda Au, Neil W. Kowall, Robert A. Stern, Jesse Mez, Michael L. Alosco
Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures
Abstract: Background: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk. Objective: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS). Methods: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age=72.84, SD=8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n=1,196). Models controlled for age, sex, education, racial identity, APOE ε4 status, and estimated intracranial volume for MRI models. Results: The mean rFSRP probability was 10.42% (min=0.50%, max=95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β=0.02, p=0.028) and worse performance on: Trail Making Test A (β=0.05, p<0.001) and B (β=0.057, p<0.001), and Digit Symbol (β= -0.058, p<0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR=1.02 per quartile, p=0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV. Conclusion: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.

Emilie Blair, Darin Zahuranec, Kenneth M. Langa, Jane Forman, Bailey K. Reale, Colleen Kollman, Bruno Giordani, Deborah A. Levine (Handling Associate Editor: Tatjana Rundek)
Impact of Patient Mild Cognitive Impairment on Physician Decision-Making for Treatment
Abstract: Background: Older patients with mild cognitive impairment (MCI) should receive evidence-based treatments when clinically indicated. However, patients with MCI appear less likely than cognitively normal patients to receive evidence-based treatments. Objective: To explore the influence of a patient's MCI diagnosis on physician decision-making. Methods: Qualitative study of 18 physicians from cardiology, neurology, and internal medicine using semi-structured interviews. We sought to understand whether and how a patient’s having MCI has influenced physicians’ decisions about five categories of treatments or tests (surgery, invasive tests, non-invasive tests, rehabilitation, and preventive medication). We used qualitative content analysis to identify the unifying and recurrent themes. Results: Most physician participants described MCI as influencing their recommendations for at least one treatment or test. We identified two major themes as factors that influenced physician recommendations in patients with MCI: Physicians assume that MCI patients’ decreased cognitive ability will impact treatment; and physicians assume that MCI patients have poor health status and physical functioning that will impact treatment. These two themes were representative of physician beliefs that MCI patients have impaired independent decision-making, inability to adhere to treatment, inability to communicate treatment preferences, and increased risk and burden from treatment. Conclusion: A patient’s MCI diagnosis influences physician decision-making for treatment. Some physician assumptions about patients with MCI were not evidence-based. This phenomenon potentially explains why many patients with MCI get fewer effective treatments or tests than cognitively normal patients. Interventions that improve how physicians understand MCI and make decisions for treatments in patients with MCI are needed.

Adam O. Ghoweri, Lara Ouillette, Hilaree N. Frazier, Katie L. Anderson, Ruei-Lung Lin, John C. Gant, Rachel Parent, Shannon Moore, Geoffrey G. Murphy, Olivier Thibault (Handling Associate Editor: James Simpkins)
Electrophysiological and Imaging Calcium Biomarkers of Aging in Male and Female 5xFAD Mice
Abstract: Background: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer’s disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. Objective: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5xFAD mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. Methods: Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. Results: Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5xFAD group compared to controls. Deficits in spatial memory, along with increases in Aβ load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. Conclusion: Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5xFAD model and suggests that this surprising result may be a novel biomarker of AD.

Jennifer D. Walker, Grace Spiro, Kassandra Loewen, Kristen Jacklin
Alzheimer’s Disease and Related Dementia in Indigenous Populations: A Systematic Review of Risk Factors
Abstract: Background: There remains a lack of information and understanding of the prevalence and incidence of Alzheimer’s disease or related dementia in Indigenous populations. Little evidence available suggests that Indigenous peoples may have disproportionately high rates of Alzheimer’s disease or related dementia (ADRD). Objective: Given this information, this study systematically explores what risk factors may be associated with ADRD in Indigenous populations. Methods: A search of all published literature was conducted in October 2016, March 2018, and July 2019 using Medline, Embase, and PsychINFO. Subject headings explored were inclusive of all terms related to Indigenous persons, dementia, and risk. All relevant words, phrases, and combinations were used. To be included in this systematic review, articles had to display an association of a risk factor and ADRD. Only studies that reported a quantifiable measure of risk, involved human subjects, and were published in English were included. Results: Of 237 articles originally identified through database searches, 45 were duplicates and 179 did not meet a priori inclusion criteria, resulting in 13 studies eligible for inclusion in this systematic review. Conclusion: The large number of potentially modifiable risk factors reported relative to non-modifiable risk factors illustrates the importance of socioeconomic context in the pathogenesis of ADRD in Indigenous populations. The tendency to prioritize genetic over social explanations when encountering disproportionately high disease rates in Indigenous populations can distract from modifiable proximal, intermediate, and distal determinants of health.

Tyler D. Armstrong*, Usa Suwannasual*, Conner L. Kennedy, Akshaykumar Thasma, Leah J. Schneider, Danielle Phillippi, Amie K. Lund *These authors contributed equally to this manuscript.
Exposure to Traffic-Generated Pollutants Exacerbates the Expression of Factors Associated with the Pathophysiology of Alzheimer’s Disease in Aged C57BL/6 Wild-Type Mice
Abstract: Background: Multiple studies report a strong correlation between traffic-generated air pollution-exposure and detrimental outcomes in the central nervous system (CNS), including Alzheimer’s disease (AD). Incidence of AD is rapidly increasing and, worldwide, many live in regions where pollutants exceed regulatory standards. Thus, it is imperative to identify environmental pollutants that contribute to AD, and the mechanisms involved. Objective: We investigated the effects of mixed gasoline and diesel engine emissions (MVE) on the expression of factors involved in progression of AD in the hippocampus and cerebrum in a young versus aged mouse model. Methods: Young (2 months old) and aged (18 months old) male C57BL/6 mice were exposed to either MVE (300 μg/m3 PM) or filtered air (FA) for 6 h/d, 7 d/wk, for 50 d. Immunofluorescence and RT-qPCR were used to quantify oxidative stress (8-OHdG) and expression of amyloid-β protein precursor (AβPP), β secretase (BACE1), amyloid-β (Aβ), aryl hydrocarbon receptor (AhR), cytochrome P450 (CYP) 1B1, angiotensin-converting enzyme (ACE1), and angiotensin II type 1 (AT1) receptor in the cerebrum and hippocampus, in addition to cerebral microvascular tight junction (TJ) protein expression. Results: We observed age-related increases in oxidative stress, AhR, CYP1B1, Aβ, BACE1, and AT1 receptor in the CA1 region of the hippocampus, and elevation of cerebral AβPP, AhR, and CYP1B1 mRNA, associated with decreased cerebral microvascular TJ protein claudin-5. MVE-exposure resulted in further promotion of oxidative stress, and significant increases in AhR, CYP1B1, BACE1, ACE1, and Aβ, compared to the young and aged FA-exposed mice. Conclusion: Such findings suggest that MVE-exposure exacerbates the expression of factors in the CNS associated with AD pathogenesis in aged populations.

Jan Laczó*, Katerina Cechova*, Martina Parizkova, Ondrej Lerch, Ross Andel, Vaclav Matoska, Vojtech Kaplan, Veronika Matušková, Zuzana Nedelska, Martin Vyhnalek, Jakub Hort *These authors contributed equally to this work.
The Combined Effect of APOE and BDNF Val66Met Polymorphisms on Spatial Navigation in Older Adults
Abstract: Background: The apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory and spatial navigation deficits. The brain-derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment in APOE ɛ4 carriers but its role in APOE ɛ4-related spatial navigation deficits has not been established. Objective: We examined influence of APOE and BDNF Val66Met polymorphism combination on spatial navigation and volumes of selected navigation-related brain regions in cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (aMCI). Methods: 187 participants (aMCI [n=116] and CU [n=71]) from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNFVal/Val, ɛ4–/BDNFMet, ɛ4+/BDNFVal/Val, and ɛ4+/BDNFMet. The participants underwent comprehensive neuropsychological examination, brain MRI, and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real-space human analogue of the Morris water maze. Results: Among the aMCI participants, the ɛ4+/BDNFMet group had the least accurate egocentric navigation performance (p<0.05) and lower verbal memory performance than the ɛ4–/BDNFVal/Val group (p=0.007). The ɛ4+/BDNFMet group had smaller hippocampal and entorhinal cortical volumes than the ɛ4–/BDNFVal/Val (p≤0.019) and ɛ4–/BDNFMet (p≤0.020) groups. Among the CU participants, the ɛ4+/BDNFMet group had less accurate allocentric and allocentric delayed navigation performance than the ɛ4–/BDNFVal/Val group (p<0.05). Conclusion: The combination of APOE ɛ4 and BDNF Met polymorphisms is associated with more pronounced egocentric navigation impairment and atrophy of the medial temporal lobe regions in individuals with aMCI and less accurate allocentric navigation in CU older adults.

Masayuki Satoh, Jun-ichi Ogawa, Tomoko Tokita, Yoshimi Matsumoto, Koji Nakao, Ken-ichi Tabei, Natsuko Kato, Hidekazu Tomimoto
The Effects of a 5-Year Physical Exercise Intervention with Music in Community-Dwelling Normal Elderly People: The Mihama-Kiho Follow-Up Project
Abstract: Background: We previously reported the enhanced effects of physical exercise when combined with music (ExM) on cognitive function in community-dwelling normal elderly people compared to exercise alone. Following that study, participants voluntarily continued the ExM classes for 5 years. Objective: To identify the effects of a 5-year ExM intervention on cognitive function in normal elderly people. Methods: Fifty-four subjects continued the ExM classes once a week for 5 years (ExM group). Thirty-three subjects retired from the ExM class during the 5 years (Retired group). Twenty-one subjects never participated in any intervention over the 5 years (No-exercise group). Cognitive function and ADLs were assessed using neuropsychological batteries and the functional independence measure (FIM), respectively. The voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) was used to investigate medial temporal lobe atrophy. Results: Analyses of the raw scores after the 5-year intervention showed significant differences between the ExM and No-exercise groups in their MMSE scores, Raven’s colored progressive matrices (RCPM) time, logical memory (LM)-I, as well as the total and physical exercise sub-scores of the FIM. Analysis of subjects aged 70-79 years at the beginning of this project showed significantly quicker performance on the RCPM in the ExM compared to No-exercise groups. The correlation coefficients between the total number of ExM sessions attended and the degree of changes in physical, neuropsychological, and VSRAD scores were significant for RCPM performance time and LM-I scores. Conclusion: Long-term ExM intervention reinforces multifaceted cognitive function in normal elderly people, and is especially beneficial for psychomotor speed.

Tong Yang, Hualou Wang, Ying Xiong, Chong Chen, Keran Duan, Jingya Jia, Fei Ma
Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial
Abstract: Background: Cognitive decline in older adults is a serious public health problem today. Association between vitamin D supplementation and cognition remains controversial. Objective: To determine whether a 12-month vitamin D supplementation improves cognitive function in elderly subjects with mild cognitive impairment (MCI), and whether it is mediated through the mechanism in which telomere length (TL) regulate oxidative stress. Methods: This was a double-blind, randomized, placebo-controlled trial in Tianjin, China. Participants were all native Chinese speakers aged 65 years and older with MCI. 183 subjects were randomized to an intervention group (vitamin D 800 IU/day, n=93) or a placebo group (the matching starch granules, n=90), and followed up for 12 months. Tests of cognitive function and mechanism-related biomarkers were evaluated at baseline, 6 months, and 12 months. Results: Repeated-measures ANOVA showed substantial improvements in the full scale intelligence quotient (FSIQ), information, digit span, vocabulary, block design, and picture arrangement scores in the vitamin D group over the placebo group (p<0.001). Leukocyte TL was significantly higher, while serum 8-OXO-dG, OGG1mRNA, and P16INK4amRNA revealed greater decreases in the vitamin D group over the placebo group (p<0.001). According to mixed-model repeated-measures ANOVA analysis, vitamin D group showed a significant enhancement in the FSIQ score for 12 months compared with the control (estimate value=5.132, p<0.001). Conclusion: Vitamin D supplementation for 12 months appears to improve cognitive function through reducing oxidative stress regulated by increased TL in order adults with MCI. Vitamin D may be a promising public health strategy to prevent cognitive decline.

J.Q. Alida Chen, Philip Scheltens, Colin Groot, Rik Ossenkoppele
Associations Between Caffeine Consumption, Cognitive Decline, and Dementia: A Systematic Review
Abstract: Background: Epidemiologic studies have provided inconclusive evidence for a protective effect of caffeine consumption on risk of dementia and cognitive decline. Objective: To summarize literature on the association between caffeine and 1) the risk of dementia and/or cognitive decline, and 2) cognitive performance in individuals with mild cognitive impairment (MCI) or dementia, and 3) to examine the effect of study characteristics by categorizing studies based on caffeine source, quantity and other possible confounders. Methods: We performed a systematic review of caffeine effects by assessing overall study outcomes; positive, negative or no effect. Our literature search identified 61 eligible studies performed between 1990 and 2020. Results: For studies analyzing the association between caffeine and the risk of dementia and/or cognitive decline, 16/57 (28%) studies including a total of 40,707/153,070 (27%) subjects reported positive study outcomes, and 30/57 (53%) studies including 71,219/153,070 (47%) subjects showed positive results that were dependent on study characteristics. Caffeine effects were more often positive when consumed in moderate quantities (100-400 mg/d), consumed in coffee or green tea, and in women. Furthermore, four studies evaluated the relationship between caffeine consumption and cognitive function in cognitively impaired individuals and the majority (3/4 [75%]) of studies including 272/289 subjects (94%) reported positive outcomes. Conclusion: This review suggests that caffeine consumption, especially moderate quantities consumed through coffee or green tea and in women, may reduce the risk of dementia and cognitive decline, and may ameliorate cognitive decline in cognitively impaired individuals.

Sofia de la Fuente Garcia, Craig Ritchie, Saturnino Luz
Artificial Intelligence, Speech, and Language Processing Approaches to Monitoring Alzheimer’s Disease: A Systematic Review
Abstract: Background: Language is a valuable source of clinical information in Alzheimer’s Disease, as it declines concurrently with neurodegeneration. Consequently, speech and language data have been extensively studied in connection with its diagnosis. Objective: Firstly, to summarize the existing findings on the use of artificial intelligence, speech, and language processing to predict cognitive decline in the context of Alzheimer’s disease. Secondly, to detail current research procedures, highlight their limitations, and suggest strategies to address them. Methods: Systematic review of original research between 2000 and 2019, registered in PROSPERO (reference CRD42018116606). An interdisciplinary search covered six databases on engineering (ACM and IEEE), psychology (PsycINFO), medicine (PubMed and Embase), and Web of Science. Bibliographies of relevant papers were screened until December 2019. Results: From 3,654 search results, 51 articles were selected against the eligibility criteria. Four tables summarize their findings: study details, (aim, population, interventions, comparisons, methods, and outcomes), data details (size, type, modalities, annotation, balance, availability, and language of study), methodology (pre-processing, feature generation, machine learning, evaluation, and results), and clinical applicability (research implications, clinical potential, risk of bias, and strengths/limitations). Conclusion: Promising results are reported across nearly all 51 studies, but very few have been implemented in clinical research or practice. The main limitations of the field are poor standardization, limited comparability of results, and a degree of disconnect between study aims and clinical applications. Active attempts to close these gaps will support translation of future research into clinical practice.

Stelios Zygouris, Mara Gkioka, Despina Moraitou, Birgit Teichmann, Thrasyvoulos Tsiatsos, Sotirios Papagianopoulos, Magda Tsolaki
Assessing the Attitudes of Greek Nurses Toward Computerized Dementia Screening
Abstract: Background: Despite the abundance of research on computerized dementia screening tests, the attitudes of hospital personnel toward this screening method have not been investigated. Objective: 1) To conduct a confirmatory factor analysis of the first part of a two-part questionnaire about computerized dementia screening. 2) To assess the attitudes of Greek nurses toward computerized dementia screening. 3) To assess barriers to future implementation of computerized dementia screening in the Greek healthcare system, as reported by nurses. Methods: 161 Greek nurses from two urban public general hospitals who participated in a dementia training program were recruited. They were asked to complete a two-part questionnaire about computerized dementia screening. The first part of the questionnaire assesses attitudes toward dementia screening while the second part of the questionnaire assesses barriers to its implementation. Results: Confirmatory factor analysis on the first part of the questionnaire suggested a two-factor structure (feasibility/acceptability). The total score of all items loading on each factor was calculated. For feasibility, scores ranged between 10 and 25 (M = 19.38, SD = 3.80). For acceptability, scores ranged between 6 and 20 (M = 15.27, SD = 2.76). The main barriers to implementation were cost of equipment, insufficient training, lack of a plan for the integration of computerized screening tests in the daily routine of the hospital and time needed for staff training. Conclusion: The positive attitude of nurses supports the implementation of computerized dementia screening in public hospitals as long as identified barriers are addressed.

Jen-Hau Chen, Tsung-Yu Kuo, Hwa-Lung Yu, Charlene Wu, Su-Ling Yeh, Jeng-Min Chiou, Ta-Fu Chen, Yen-Ching Chen
Long-Term Exposure to Air Pollutants and Cognitive Function in Taiwanese Community-Dwelling Older Adults: A Four-Year Cohort Study
Abstract: Background: Previous studies have assessed limited cognitive domains with relatively short exposure to air pollutants, and studies in Asia are limited. Objective: This study aims to explore the association between long-term exposure to air pollutants and cognition in community-dwelling older adults. Methods: This four-year prospective cohort study recruited 605 older adults at baseline (2011-2013) and 360 participants remained at four-year follow-up. Global and domain-specific cognition were assessed biennially. Data on PM2.5 (particulate matter≤2.5 μm diameter, 1993-2015), PM10 (2005-2015), and nitrogen dioxide (NO2, 2005-2015) were obtained from Environmental Protection Administration. Bayesian Maximum Entropy was utilized to estimate the spatiotemporal distribution of levels of these pollutants. Results: Exposure to high-level PM2.5 (>29.98 μg/m3) was associated with an increased risk of global cognitive impairment (adjusted odds ratio=4.56; β=-0.60). High-level PMcoarse exposure (>26.50 μg/m3) was associated with poor verbal fluency (β=-0.19]. High-level PM10 exposure (>51.20 μg/m3) was associated with poor executive function (β=-0.24). Medium-level NO2 exposure (>28.62 μg/m3) was associated with better verbal fluency (β=0.12). Co-exposure to high concentrations of PM2.5, PMcoarse or PM10 and high concentration of NO2 were associated with poor verbal fluency (PM2.5 and NO2: β=-0.17; PMcoarse and NO2: β=-0.23; PM10 and NO2: β=-0.21) and poor executive function (PM10 and NO2: β=-0.16). These associations became more evident in women, apolipoprotein ε4 non-carriers, and those with education >12 years. Conclusion: Long-term exposure to PM2.5 (higher than TEPA guidelines), PM10 (lower than TEPA guidelines) or co-exposure to PMx and NO2 were associated with poor global, verbal fluency, and executive function over 4 years.

Nils Richter, Gérard Bischof, Julian Dronse, Nils Nellessen, Bernd Neumaier, Karl-Josef Langen, Alexander Drzezga, Gereon R. Fink, Thilo van Eimeren, Juraj Kukolja, Oezguer A. Onur (Handling Associate Editor: Raffaella Migliaccio)
Entorhinal Tau Predicts Hippocampal Activation and Memory Deficits in Alzheimer’s Disease
Abstract: Background: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer’s disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD. Objective: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild dementia due to AD. Methods: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [18F]-AV-1451. Results: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation. Conclusion: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory in AD.

Hans Drenth, Sytse Zuidema, Ivan Bautmans, Lucio Marinelli, Galit Kleiner, Hans Hobbelen (Handling Associate Editor: Teresa Liu-Ambrose)
Paratonia in Dementia: A Systematic Review
Abstract: Background: Paratonia is a dementia-induced motor abnormality. Although paratonia affects virtually all people with dementia, it is not well known among clinicians and researchers. Objective: The aim of this study was to perform a systematic review of the literature on the definition, pathogenesis, diagnosis, and intervention of paratonia as well as to propose a research agenda for paratonia. Methods: In this systematic review, the Embase, PubMed, CINAHL, and Cochrane CENTRAL databases were searched for articles published prior to December 2019. Two independent reviewers performed data extraction and assessed the risk of bias of the studies. The following data were extracted: first author, year of publication, study design, study population, diagnosis, assessment, pathogenesis, therapy and interventions. Results: Thirty-five studies met the inclusion criteria and were included. Most studies included in the review mention clinical criteria for paratonia. Additionally, pathogenesis, method of assessment, diagnosis, and paratonia severity as are interventions to address paratonia are also discussed. Conclusion: This systematic review outlines what is currently known about paratonia, as well as discusses the preliminary research on the underlying mechanisms of paratonia. Although paratonia has obvious devastating impacts on health and quality of life, the amount of research to date has been limited. In the last decade, there appears to have been increased research on paratonia, which hopefully will increase the momentum to further advance the field.

Tai Hong, Shigeki Hirano, Toru Sakurai, Yoshikazu Nakano, Ai Ishikawa, Kazuho Kojima, Hongliang Li, Hitoshi Shimada, Koichi Kashiwado, Hiroki Mukai, Takuro Horikoshi, Atsuhiko Sugiyama, Takashi Uno, Satoshi Kuwabara (Handling Associate Editor: Masamichi Imai)
The Neuropsychological Correlates of Brain Perfusion and Gray Matter Volume in Alzheimer’s Disease
Abstract: Background: Neuropsychological tests, structural neuroimaging, and functional neuroimaging are employed as diagnostic and monitoring biomarkers of patients with Alzheimer’s disease (AD). Objective: We aimed to elucidate the similarities and differences in neuropsychological tests and neuroimaging with the use of the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog), structural magnetic resonance image (MRI), and perfusion single photon emission computed tomography (SPECT), and parametric image analyses to understand its role in AD. Methods: Clinically-diagnosed AD patients (n=155) were scanned with three-dimensional T1-weighted MRI and N-isopropyl-p-[123I] iodoamphetamine SPECT. Statistical parametric mapping 12 was used for preprocessing images, statistical analyses, and voxel-based morphometry for gray matter volume analyses. Group comparison (AD versus healthy controls), multiple regression analyses with MMSE, ADAS-cog total score, and ADAS-cog subscores as variables, were performed. Results: The AD group showed bilateral hippocampal volume reduction and hypoperfusion in the bilateral temporo-parietal lobe and posterior midline structures. Worse MMSE and ADAS-cog total score were associated with bilateral temporo-parietal volume loss and hypoperfusion. MMSE, but not ADAS-cog, was associated with the posterior midline structures. The ADAS-cog subscores were associated with the temporal volume, while perfusion analyses were linked to the left temporo-parietal region with the language function and right analogous region with the constructional praxis subscore. Conclusion: MMSE and ADAS-cog are associated with temporo-parietal regions, both in volume and perfusion. The MMSE score is associated with posterior midline structures and linked to an abnormal diagnostic AD pattern. Perfusion image analyses better represents the cognitive function in AD patients.

Hannah Gardener, Michelle Caunca, Chuanhui Dong, Ying Kuen Cheung, Tatjana Rundek, Mitchell S.V. Elkind, Clinton B. Wright, Ralph L. Sacco
Obesity Measures in Relation to Cognition in the Northern Manhattan Study
Abstract: Background: Mid-life obesity is associated with cognitive impairment, though the relationship for late-life obesity is equivocal, and may depend on the anthropometric measure. Objective: We examined the relationship between adiposity and cognition across age categories, cognitive domains, and by measures of obesity in a multi-ethnic population-based cohort. Methods: The study included 1,179 Northern Manhattan Study participants with obesity measures at baseline (44% overweight, 30% obese), an initial neuropsychological assessment conducted within 7 years (mean age=70), and a second cognitive assessment conducted on average 6 years later. Z-scores were derived for cognitive domains (episodic and semantic memory, executive function, processing speed) and averaged to calculate global cognition. Body mass index (BMI) and waist:hip ratio (WHR) were examined in relation to cognitive performance and change over time, stratified by age, using linear regression models adjusting for vascular risk factors. Results: Among those age < 65 years at baseline, greater WHR was associated with worse global cognitive performance at initial assessment and directly associated with decline in performance between assessments. The association with initial performance was strongest for non-Hispanic Whites (beta=-0.155/standard deviation, p=0.04), followed by non-Hispanic Black/African Americans (beta=-0.079/standard deviation, p=0.07), and Hispanics (beta=-0.055/standard deviation, p=0.03). The associations were most apparent for the domains of processing speed and executive function. There was no association for BMI among those < 65 years. Among those age ≥65, there was no association for BMI or WHR with cognitive performance at initial assessment nor decline over time. Conclusion: Our results support the detrimental effect of mid-life rather than later life obesity, particularly abdominal adiposity, on cognitive impairment and decline.

Ayush Singh, Dyron Allen, Anna Fracassi, Batbayar Tumurbaatar, Chandramouli Natarajan, Pietro Scaduto, Randy Woltjer, Rakez Kayed, Agenor Limon, Balaji Krishnan*, Giulio Taglialatela* (Handling Associate Editor: Jose Abisambra) *Co-senior authors
Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer’s Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers
Abstract: Background: Certain individuals, here referred to as Non-Demented with Alzheimer Neuropathology (NDAN), do not show overt neurodegeneration (N-) and remain cognitively intact despite the presence of plaques (A+) and tangles (T+) that would normally be consistent with fully symptomatic Alzheimer’s disease (AD). Objective: The existence of NDAN (A+T+N-) subjects suggests that the human brain utilizes intrinsic mechanisms that can naturally evade cognitive decline normally associated with the symptomatic stages of AD (A+T+N+). Deciphering the underlying mechanisms would prove relevant to develop complementing therapeutics to prevent progression of AD-related cognitive decline. Methods: Previously, we have reported that NDAN present with preserved neurogenesis and synaptic integrity paralleled by absence of amyloid oligomers at synapses. Using postmortem brain samples from age-matched control subjects, demented AD patients and NDAN individuals, we performed immunofluorescence, western blots, micro transplantation of synaptic membranes in Xenopus oocytes followed by twin electrode voltage clamp electrophysiology and fluorescence assisted single synaptosome-long term potentiation studies. Results: We report decreased tau oligomers at synapses in the brains of NDAN subjects. Furthermore, using novel approaches we report, for the first time, that such absence of tau oligomers at synapses is associated with synaptic functional integrity in NDAN subjects as compared to demented AD patients. Conclusion: Overall, these results give further credence to tau oligomers as primary actors of synaptic destruction underscoring cognitive demise in AD and support their targeting as a viable therapeutic strategy for AD and related tauopathies.

Yu-Xiang Yang, Kevin Kuo, Hong-Qi Li, Xue-Ning Shen, Shi-Dong Chen, Mei Cui, Qiang Dong, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Investigating Causal Relations Between Risk Tolerance, Risky Behaviors, and Alzheimer’s Disease: A Bidirectional Two-Sample Mendelian Randomization Study
Abstract: Background: Several studies have shown risky behaviors and risk tolerance are associated with Alzheimer’s disease. However, the underlying causality remains unclear. Risky behavior and risk tolerance may induce the onset of Alzheimer’s disease, and/or vulnerability to Alzheimer’s disease may result in more risky behaviors. Objective: To examine bidirectional relationships between risky behavior, risk tolerance, and Alzheimer’s disease using Mendelian randomization method for assessing potential causal inference. Methods: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with risky behaviors and risk tolerance (n = 370,771–939,908), and Alzheimer’s disease (n = 71,880 -37,613) as genetic instruments from large meta-analyses of genome-wide association studies. Results: Our results support a strong protective casual effect of risk-taking tendency on AD (odds ratio [OR] = 0.79; 95%CI, 0.67-0.94, p = 0.007). There was weak statistically significant relationship between number of sexual partners and AD (OR = 0.50, 95%CI, 0.27-0.93, p = 0.04), and between family history of AD and automobile speeding propensity (OR = 1.018, 95% CI, 1.005 to 1.031; p = 0.007). Contrary to expectations, there was no statistically significant causal effect of AD on risk-taking tendency (β = 0.015, 95% CI, −0.005 to 0.04; p = 0.14). Conclusion: Under Mendelian randomization assumptions, our results suggest a protective relationship between risk-taking tendency and the risk of AD. This finding may provide valuable insights into Alzheimer’s disease pathogenesis and the development of preventive strategies.

Wolf E. Mehling, Travis M. Scott, James Duffy, Rachel A. Whitmer, Margaret A. Chesney, W. John Boscardin, Deborah E. Barnes (Handling Associate Editor: Kaarin Anstey)
Dyadic Group Exercises for Persons with Memory Deficits and Care Partners: Mixed-Method Findings from the Paired Preventing Loss of Independence through Exercise (PLIÉ) Randomized Trial
Abstract: Background: Non-pharmacological therapies for persons with dementia (PWD) are needed. Objective: To develop and test the Paired Preventing Loss of Independence through Exercise (PLIÉ) program, an integrative group movement program for PWD and care partners (CPs). Methods: Participants were randomized to immediate or delayed start to Paired PLIÉ in community-based classes (1 hour, 2 days/week, 12 weeks, 3 home visits). Co-primary outcomes included standard measures of cognition, physical function, and quality of life (PWD) and caregiver burden (CPs) assessed by blinded assessors, analyzed using linear mixed models to calculate effect sizes for outcome changes during Paired PLIÉ, controlling for randomization group. Anonymous satisfaction surveys included satisfaction ratings and thematic analysis of open-ended responses. Results: Thirty dyads enrolled, 24 (80%) completed. PWD (mean age 80; 55% female) experienced significant improvement in self-rated quality of life (Effect Size +0.23; p=0.016) when participating in Paired PLIÉ, while CPs experienced a non-significant increase in burden (-0.23, p=0.079). Changes in physical and cognitive function in PWD were not significant. All CPs returning the satisfaction survey (n=20) reported being moderately-to-highly satisfied with the program. Thematic analyses identified physical (e.g., sit-to-stand, more energy), emotional (enjoyment), and social benefits (peer-to-peer interaction) for PWD and CPs; challenges were primarily related to getting to the in-person classes. Conclusion: Paired PLIÉ is a promising integrative group movement program that warrants further study. It is feasible and may improve self-rated quality of life in PWD. Although CPs may experience increased burden due to logistical challenges, most reported high satisfaction and physical, emotional, and social benefits.

Biancamaria Guarnieri, Michelangelo Maestri, Federico Cucchiara, Annalisa Lo Gerfo, Alessandro Schirru, Dario Arnaldi, Pietro Mattioli, Flavio Nobili, Gemma Lombardi, Gianluigi Cerroni, Antonella Bartoli, Raffaele Manni, Elena Sinforiani, Michele Terzaghi, Maria Grazia Arena, Rosalia Silvestri, Chiara La Morgia, Maria Caterina Di Perri, Ferdinando Franzoni, Gloria Tognoni, Michelangelo Mancuso, Sandro Sorbi, Ubaldo Bonuccelli, Gabriele Siciliano, Ugo Faraguna, Enrica Bonanni
Multicenter Study on Sleep and Circadian Alterations as Objective Markers of Mild Cognitive Impairment and Alzheimer’s Disease Reveals Sex Differences
Abstract: Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. Results: Wake after sleep onset (WASO) was higher (p<0.001) and sleep efficiency (SE) lower (p=0.003) in MCI, and Sleep Regularity Index (SRI) was lower in AD patients compared to controls (p=0.004). SE was lower in male AD compared to female AD (p=0.038) and SRI lower in male AD compared to male controls (p=0.008), male MCI (p=0.047), but also female AD subjects (p=0.046). Mesor was significantly lower in males in the overall population. Age reduced the dissimilarities for WASO and SE but demonstrated sex differences for amplitude (p=0.009) in the overall population, controls (p=0.005), and AD subjects (p=0.034). The confusion-matrices showed good predictive power of actigraphic data. Conclusion: Actigraphic data could help identify disease or health status. Sex (possibly gender) differences could impact on neurodegeneration and disease trajectory with potential clinical applications.

Lars Frings, Bernhard Heimbach, Philipp T. Meyer, Sabine Hellwig (Handling Associate Editor: Michael Hornberger)
Intrinsic Alertness Is Impaired in Patients with Nigrostriatal Degeneration: A Prospective Study with Reference to [123I]FP-CIT SPECT and [18F]FDG PET
Abstract: Background: Variations in alertness and attention are common in Lewy body diseases (LBD) and among the core features of dementia with Lewy bodies (DLB). Dopamine transporter SPECT is an accurate biomarker of nigrostriatal degeneration (NSD) in LBD. Objective: The present study investigated performance on a computerized alertness test as a potential measure of attention in patients with NSD compared to patients without NSD. Methods: Thirty-six patients with cognitive impairment plus at least one core feature of DLB referred for [123I]FP-CIT SPECT imaging were prospectively recruited. Performance in a computerized test of intrinsic alertness was compared between patients with and those without NSD as assessed by [123I]FP-CIT SPECT. Results: Reaction times to auditory stimuli (adjusted for age, sex, and education) were significantly longer in patients with NSD compared to those with a normal [123I]FP-CIT SPECT scan (p < 0.05). Statistical analyses revealed no significant differences comparing reaction times to visual stimuli or dispersion of reaction times between groups. Exploratory analysis in a subgroup of patients with available [18F]FDG PET revealed that longer reaction times were associated with decreased glucose metabolism in the prefrontal cortex (statistical parametric mapping, adjusted for age and sex; p < 0.005, cluster extent > 50 voxels). Conclusion: Computerized assessment of auditory reaction times is able to detect alertness deficits in patients with NSD and might help to measure alertness deficits in patients with LBD and NSD. Future studies in larger samples are needed to evaluate the diagnostic utility of computerized alertness assessment for the differential diagnosis of LBD.

Ester Esteban de Antonio, Jorge López-Álvarez, Alberto Rábano, Luis Agüera-Ortiz, Antonio Sánchez-Soblechero, Laura Amaya, Sofía Portela, Carlos Cátedra, Javier Olazarán
Pathological Correlations of Neuropsychiatric Symptoms in Institutionalized People with Dementia
Abstract: Background: Comprehensive clinicopathological studies of neuropsychiatric symptoms (NPS) in dementia are lacking. Objective: To describe the pathological correlations of NPS in a sample of institutionalized people with dementia. Methods: We studied 59 people who were consecutively admitted to a nursing home and donated their brain. Correlations between pathological variables and NPS upon admission (n=59) and at one-year follow-up assessment (n=46) were explored and confirmed using bivariate and multivariate statistical methods. Results: Mean (SD) age at admission was 83.2 (6.4) years and mean (SD) age at demise was 85.4 (6.6); 73% of the subjects were female and 98% presented advanced dementia. The most frequent etiological diagnosis was Alzheimer’s disease (AD; 74.6% clinical diagnosis, 67.8% pathological diagnosis). The pathological diagnosis of AD was associated with aggression (βest 0.31), depression (βest 0.31), anxiety (βest 0.38), and irritability (βest 0.28). Tau stage correlated with aggressive symptoms (βest 0.32) and anxiety (βest 0.33). Coexistence of AD and Lewy body pathology was associated with depression (βest 0.32), while argyrophilic grains were associated with eating symptoms (βest 0.29). Predictive models were achieved for apathy, including cognitive performance, basal ganglia ischemic lesions, and sex as predictors (R2 0.38) and for sleep disorders, including pathological diagnosis of AD and age at demise (R2 0.18) (all p-values <0.05, unadjusted). Conclusion: AD was the main pathological substrate of NPS in our sample of very elderly people with advanced dementia. However, correlations were mild, supporting a model of focal/asymmetric rather than diffuse brain damage, along with relevance of environmental and other personal factors, in the genesis of those symptoms.

Jarrod Flax, Heather M. Wilkins, Reegan Miller, Sarah Griffith, Gentry K. Cork, Amy Qiang, Jeffrey Thompson, Russell H. Swerdlow, Chad Slawson
OGA Inhibition Alters Energetics and Nutrient Sensing in Alzheimer’s Disease Cytoplasmic Hybrids
Abstract: Background: Alzheimer’s disease (AD) features reductions in key bioenergetic fluxes and perturbed mitochondrial function. Cytoplasmic hybrids (cybrids) generated through the transfer of AD subject mitochondria to mtDNA-depleted SH-SY5Y neuroblastoma cells recapitulate some of these features in an in vitro setting. Objective: For this study, we used the AD cybrid model to assess the impact of a nutrient-excess like-state via increasing O-GlcNAcylation on whole cell and mitochondrial homeostasis. Methods: We induced increased O-GlcNAc by treating AD and control cybrid cell lines with Thiamet G (TMG), an inhibitor of the O-GlcNAcase enzyme that mediates removal of the nutrient-dependent O-GlcNAc modification. Results: Relative to control cybrid cell lines, AD cybrid lines showed a blunted response to TMG-induced O-GlcNAcylation. At baseline, AD cybrid cell line mitochondria showed partial activation of several proteins that help maintain bioenergetic homeostasis such as AMP-Regulated Kinase suggesting that AD mitochondria initiate a state of nutrient stress promoting energetic compensation; however, this compensation reduces the capacity of cells to respond to additional nutrient-related stresses such as TMG treatment. Also, TMG caused disruptions in acetylation and Sirtuin 3 expression, while lowing total energetic output of the cell. Conclusion: Together, these findings suggest that modulation of O-GlcNAc is essential for proper energetic function of the mitochondria, and AD mitochondrial capacity to handle nutrient-excess is limited.

Shahram Oveisgharan, Ana W. Capuano, Alifiya Kapasi, Aron S. Buchman, Julie A. Schneider, David A. Bennett, Zoe Arvanitakis
Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau
Abstract: Background: Vascular mechanisms may contribute to the accumulation of AD pathology. Objective: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association. Methods: We examined the brains of 1,585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau. Results: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r = -0.00, p=0.918) or tau (r = 0.01, p=0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p=0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p=0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP. Conclusion: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

Yuichiro Ii, Hidehiro Ishikawa, Hirofumi Matsuyama, Akihiro Shindo, Keita Matsuura, Kimiko Yoshimaru, Masayuki Satoh, Akira Taniguchi, Kana Matsuda, Maki Umino, Masayuki Maeda, Hidekazu Tomimoto (Handling Associate Editor: Masahito Yamada)
Hypertensive Arteriopathy and Cerebral Amyloid Angiopathy in Patients with Cognitive Decline and Mixed Cerebral Microbleeds
Abstract: Background: Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. Objective: We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. Methods: Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. Results: The two scores were positively correlated (ρ = 0.449, p < 0.001). The prevalence of lobar dominant CMB distribution (p < 0.001) and lacunes in the centrum semiovale (p < 0.001) and the severity of WMH in the parieto-occipital lobes (p = 0.004) were significantly higher in the high CAA-SVD score group. cSS was found in four patients with high CAA-SVD score who showed lobar-dominant CMB distribution and severe posterior WMH. Conclusion: Mixed CMBs are mainly due to HA. Assessing both two scores may predict the overlap of HA and CAA in individuals with mixed CMBs. Patients with a high CAA-SVD score may have some degree of advanced CAA, especially when lobar predominant CMBs, severe posterior WMH, lobar lacunes, or cSS are observed.