Volume 77, Number 2, 2020

Pages 459-504

Vicky Yamamoto*, Joe F. Bolanos*, John Fiallos, Susanne E. Strand, Kevin Morris, Sanam Shahrokhinia, Tim R. Cushing, Lawrence Hopp, Ambooj Tiwari, Robert Hariri, Rick Sokolov, Christopher Wheeler, Ajeet Kaushik, Ashraf Elsayegh, Dawn Eliashiv, Rebecca Hedrick, Behrouz Jafari, J. Patrick Johnson, Mehran Khorsandi, Nestor Gonzalez, Guita Balakhani, Shouri Lahiri, Kazem Ghavidel, Marco Amaya, Harry Kloor, Namath Hussain, Edmund Huang, Jason Cormier, J. Wesson Ashford, Jeffrey C. Wang, Shadi Yaghobian, Peyman Khorrami, Bahman Shamloo, Charles Moon, Jonathan Dang, Payam Shadi, Babak Kateb *These authors contributed equally to this work.
COVID-19: Review of a 21st Century Pandemic from Etiology to Neuro-psychiatric Implications
Abstract: COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients’, families’, and society’s mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University’s library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer’s disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

Pages 505-521

Eva Mª Arroyo-Anlló, Jorge Chamorro Sánchez, Roger Gil
Could Self-Consciousness Be Enhanced in Alzheimer's Disease? An Approach from Emotional Sensorial Stimulation
Abstract: Alzheimer's disease (AD) provides a valuable field of research into impairment of self-consciousness (SC), because AD patients have a reduced capacity to understand their mental world, to experience and relive previous personal events, as well as to interpret thoughts, feelings, and beliefs about themselves. Several studies observed that AD patients had an altered SC, but not a complete abolition of it. Emotions are an integral part of the construction of personal identity, therefore of Self. In general, most studies on emotion in AD patients have observed that emotion is not completely abolished and it lets them better remember autobiographical events with greater emotional charge. The positive effect of autobiographical memories rich in emotional content, evoked directly/automatically by sensorial stimuli such as familiar odors or music, could be used to reestablish/reinforce the permanence and coherence of the Self in AD. We studied the research of empirical evidence supporting the power of the sensorial cues associated with emotion, which could be capable of enhancing the SC in AD. We presented the studies about "Emotional stimulations" using odor, music, or taste cues in AD. All studies have shown to have a positive impact on SC in AD patients such as odor-evoked autobiographical memories, taste/odor-evoked autobiographical memories, emotional sensorial stimulation using musical cues, and multi-sensorial stimulations using healing gardens. We found research supporting the notion that emotional sensorial stimulations can even temporarily exalt memory, affective state, and personal identity, that is, the SC in AD. The emotional sensory stimulations could be used as a tool to activate the SC in AD and hence improve the quality of life of patients and caregivers.

Pages 523-537

Sahnah Lim, Sadia Mohaimin, Deborah Min, Timothy Roberts, Young-Jin Sohn, Jazmine Wong, Ragavan Sivanesathurai, Simona C. Kwon, Chau Trinh-Shevrin
Alzheimer’s Disease and its Related Dementias among Asian Americans, Native Hawaiians, and Pacific Islanders: A Scoping Review
Abstract: Background: The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) aging population is rapidly growing and the burden of Alzheimer’s disease and its related dementias (ADRD) will likely mirror this demographic growth. AANHPIs face significant barriers in obtaining timely ADRD diagnosis and services; yet little is known about ADRD in this population. Objective: The study objective is to conduct a systematic review on the published literature on ADRD among AANHPIs to identify gaps and priorities to inform future research and action plans. Methods: The systematic review was conducted following the PRISMA Protocol for Systematic Reviews. Co-author (TR), an experienced Medical Librarian, searched PubMed, EMBASE, PsycINFO, Cochrane Central of Clinical Trials, Ageline, and Web of Science for peer-reviewed articles describing ADRD among AANHPIs. The search was not limited by language or publication date. Each citation was reviewed by two trained independent reviewers. Conflicts were resolved through consensus. Results: The title/abstract and full texts of 1,447 unique articles were screened for inclusion, yielding 168 articles for analysis. Major research topics included prevalence, risk factors, comorbidities, interventions and outreach, knowledge and attitudes, caregiving, and detection tools. A limited number of studies reported on national data, on NHPI communities generally, and on efficacy of interventions targeting AANHPI communities. Conclusion: To our knowledge, this is the first systematic review on ADRD among AANHPI populations. Our review provides a first step in mapping the extant literature on ADRD among this underserved and under-researched population and will serve as a guide for future research, policy, and intervention.

Pages 539-541

Akito Tsugawa, Shu Sakurai, Yuta Inagawa, Daisuke Hirose, Yoshitsugu Kaneko, Yusuke Ogawa, Shuntaro Serisawa, Naoto Takenoshita, Hirofumi Sakurai, Hidekazu Kanetaka, Kentaro Hirao, Soichiro Shimizu
Awareness of the COVID-19 Outbreak and Resultant Depressive Tendencies in Patients with Severe Alzheimer’s Disease
Abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic has substantially affected patients with dementia and their caregivers. However, we found not all Alzheimer’s disease (AD) patients were afraid of COVID-19 infection. Therefore, we investigated the association between rate of awareness of COVID-19 and depressive tendency in AD. 126 consecutive outpatients with AD were enrolled in this study from May 25, on the day when the declaration of emergency was lifted in Japan, through June 30, 2020. In addition to routine psychological tests, the participants were asked the following two questions: “Do you know COVID-19?” and “Why are you wearing a face mask?”. Moderate to severe AD patients were found to have a low COVID-19 recognition rate and did not fully understand why they were wearing face masks. In addition, because they did not understand the seriousness of the COVID-19 outbreak, their Geriatric Depression Scale scores were also substantially lower. These results may appear to simply indicate that people with severe dementia are unaware of current events. However, these results provide insights into how to care for patients with dementia and how to allocate the time and support of our limited staff during the COVID-19 outbreak.

Pages 543-545

Joachim Denner, Rudolph Tanzi, Steve Jacobson
Animal Models of Alzheimer’s Disease Should Be Controlled for Roseolovirus
Abstract: Animal models to study Alzheimer’s disease (AD) pathogenesis are under development. Since herpesviruses have been postulated to be capable of triggering the pathogenic process, AD animal models (mouse, pig, and non-human primates) should be controlled for the presence of these viruses. Only virus-free models allow studying the genetic factors and the effect of adding viruses. Roseoloviruses such as human herpesvirus 6 and the related viruses in the animals are the main topic of this commentary.

Pages 547-550
Short Communication

Adam Heller Sheryl S. Coffman, Karalee Jarvis
Potentially Pathogenic Calcium Oxalate Dihydrate and Titanium Dioxide Crystals in the Alzheimer’s Disease Entorhinal Cortex
Abstract: Knowing that Alzheimer’s disease (AD) nucleates in the entorhinal cortex (EC), samples of 12 EC specimens were probed for crystals by a protocol detecting fewer than 1/5000th of those present. Of the 61 crystals found, 31 were expected and 30 were novel. Twenty-one crystals of iron oxides and 10 atherosclerosis-associated calcium pyrophosphate dihydrate crystals were expected and found. The 30 unexpected crystals were NLRP3-inflammasome activating calcium oxalate dihydrate (12) and titanium dioxide (18). Their unusual distribution raises the possibility that some were of AD origination sites.

Pages 551-568
Thomas Vogels, Gréta Vargová, Veronika Brezováková, Wim Hendricus Quint, Tomáš Hromádka
Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice
Abstract: Background: Neuronal accumulation of hyperphosphorylated and truncated tau aggregates is one of the major defining factors and key drivers of neurodegeneration in Alzheimer’s disease and other tauopathies. Objective: We developed an AAV-induced model of tauopathy mediated by human truncated tau protein without familial frontotemporal dementia-related mutations to study tau propagation and the functional consequences of tau pathology. Methods: We performed targeted transductions of the hippocampus or entorhinal cortex in adult mice followed by histological analysis to study the progression of hippocampal tau pathology and tau spreading. We performed behavioral analysis of mice with AAV-induced hippocampal tau pathology. Results: AAV-induced hippocampal tau pathology was characterized by tau hyperphosphorylation (AT8 positivity), sarkosyl insolubility, and the presence of neurofibrillary tangles. AAV-induced tau pathology was associated with microgliosis and hypertrophic astrocytes in the absence of cognitive deficits. Additionally, the co-expression of mCherry fluorescent protein and human truncated tau enabled us to detect both local spreading of human tau and spreading from the entorhinal cortex to the synaptically connected dentate gyrus. Conclusion: Targeted delivery of AAV with truncated tau protein into subcortical and cortical structures of mammalian brains represents an efficient approach for creating temporally and spatially well-defined tau pathology suitable for in vivo studies of tau propagation and neuronal circuit deficits in Alzheimer’s disease.

Pages 568-579
Jesus D. Melgarejo, Daniel C. Aguirre-Acevedo, Ciro Gaona, Carlos A. Chavez, Gustavo E. Calmón, Eglé R. Silva, Gabriel A. de Erausquin, Mario Gil, Luis J. Mena, Joseph D. Terwilliger, Humberto Arboleda, Nikolaos Scarmeas, Joseph H. Lee, Gladys E. Maestre
Nighttime Blood Pressure Interacts with APOE Genotype to Increase the Risk of Incident Dementia of the Alzheimer’s Type in Hispanics
Abstract: Background: Dementia of the Alzheimer’s type (DAT) impacts Hispanics disproportionately, with almost a twofold elevated risk of developing DAT, as well as earlier onset of the disease, than in non-Hispanic Whites. However, the role of main risk factors for DAT, such as APOE ԑ4 and blood pressure (BP) levels, remains uncertain among Hispanics. Objective: To investigate the association of APOE ԑ4 and BP levels, measures with 24-h ambulatory BP monitoring, with incidence of DAT in an elderly cohort of Hispanics. Methods: 1,320 participants from the Maracaibo Aging Study, free of dementia at the baseline, and with ambulatory BP measurements and APOE genotype available were included. Adjusted Cox proportional models were performed to examine 1) the incidence of DAT and 2) the relationship between BP levels and DAT according to APOE genotypes. Models were adjusted by competing risk of death before the onset of DAT. Model performance was assessed by likelihood test. Results: The average follow-up time was 5.3 years. DAT incidence was 5.8 per 1000 person-year. APOE ε4 carriers had a higher risk of DAT. In unadjusted analyses, conventional, 24-h, and nighttime systolic BP levels were significantly higher in participants who developed DAT and of APOE ԑ4 carriers (p<0.05). After adjustment for competing for risks, only higher nighttime systolic BP was associated with DAT incidence, but only among subjects carrying APOE ε4. Conclusion: In this Hispanic population, both APOE ε4 genotype and assessment of nocturnal systolic BP (rather than diurnal or office BP) were necessary to estimate DAT risk.

Pages 581-590
Vanessa Stypa, Peter Häussermann, Tim Fleiner, Sandra Neumann (Handling Associate Editor: Josep Lluís Conde-Sala)
Validity and Reliability of the German Quality of Life–Alzheimer’s Disease (QoL-AD) Self-Report Scale
Abstract: Background: The Quality of Life–Alzheimer’s Disease (QoL-AD) scale is a widely used measure of quality of life (QoL) in dementia. Although the instrument has been validated in several languages, the psychometric properties of the German self-report version have not yet been analyzed. Objective: This study examines the internal consistency, test-retest reliability, and construct validity of the German QoL-AD self-report scale. Methods: The sample included 30 patients suffering from mild to moderate Alzheimer’s disease or vascular dementia (19 females; mean age 77.3 years; mean Mini-Mental State Examination (MMSE) score 19.7 points). To determine test-retest reliability, the QoL-AD self-report scale was re-administered four to seven days apart. For construct validity analysis, the Dementia Quality of Life instrument (DQoL), Geriatric Depression Scale (GDS), MMSE, and an adapted short form of the Neuropsychiatric Inventory (NPI) were used. Results: The German QoL-AD self-report scale shows an internal consistency of α = 0.79 and a test-retest reliability of r = 0.75 (p < 0.01). Regarding construct validity, there was a significant positive correlation between the total scores of the QoL-AD and DQoL (r = 0.47, p < 0.05). The analysis revealed no significant correlations with the GDS or the adapted NPI. No association could be observed between the QoL-AD and the MMSE (r = 0.01), confirming divergent validity. Conclusion: The results indicate that the German QoL-AD self-report scale is a suitable instrument for assessing QoL in patients suffering from mild to moderate dementia, thus supporting its use in clinical practice and research.

Pages 591-605
Atef Badji, Adrián Noriega de la Colina, Tommy Boshkovski, Dalia Sabra, Agah Karakuzu, Marie-Christine Robitaille-Grou, Charley Gros, Sven Joubert, Louis Bherer, Maxime Lamarre-cliche, Nikola Stikov, Claudine J. Gauthier, Julien Cohen-Adad*, Hélène Girouard* * These authors jointly supervised this work.
A Cross-Sectional Study on the Impact of Arterial Stiffness on the Corpus Callosum, a Key White Matter Tract Implicated in Alzheimer’s Disease
Abstract Background: Vascular risk factors such as arterial stiffness play an important role in the etiology of Alzheimer’s disease (AD), presumably due to the emergence of white matter lesions. However, the impact of arterial stiffness to white matter structure involved in the etiology of AD, including the corpus callosum remains poorly understood. Objective: The aims of the study are to better understand the relationship between arterial stiffness, white matter microstructure, and perfusion of the corpus callosum in older adults. Methods: Arterial stiffness was estimated using the gold standard measure of carotid-femoral pulse wave velocity (cfPWV). Cognitive performance was evaluated with the Trail Making Test part B-A. Neurite orientation dispersion and density imaging was used to obtain microstructural information such as neurite density and extracellular water diffusion. The cerebral blood flow was estimated using arterial spin labelling. Results: cfPWV better predicts the microstructural integrity of the corpus callosum when compared with other index of vascular aging (the augmentation index, the systolic blood pressure, and the pulse pressure). In particular, significant associations were found between the cfPWV, an alteration of the extracellular water diffusion, and a neuronal density increase in the body of the corpus callosum which was also correlated with the performance in cognitive flexibility. Conclusion: Our results suggest that arterial stiffness is associated with an alteration of brain integrity which impacts cognitive function in older adults.

Pages 607-618
Sander Lamballais, Jendé L. Zijlmans, Meike W. Vernooij, M. Kamran Ikram, Annemarie I. Luik, M. Arfan Ikram
The Risk of Dementia in Relation to Cognitive and Brain Reserve
Abstract: Background: Individual differences in the risk to develop dementia remain poorly understood. These differences may partly be explained through reserve, which is the ability to buffer cognitive decline due to neuropathology and age. Objective: To determine how much early and late life cognitive reserve (CR) and brain reserve (BR) contribute to the risk of dementia. Methods: 4,112 dementia-free participants (mean age = 66.3 years) from the Rotterdam Study were followed up for on average 6.0 years. Early-life CR and BR were defined as attained education and intracranial volume, respectively. Late-life CR was derived through variance decomposition based on cognition. Late-life BR was set as the total non-lesioned brain volume divided by intracranial volume. Results: Higher early-life CR (hazard ratio = 0.48, 95% CI = [0.21; 1.06]) but not early-life BR associated with a lower risk of incident dementia. Higher late-life CR (hazard ratio = 0.57, 95% CI = [0.48; 0.68]) and late-life BR (hazard ratio = 0.54, 95% CI = [0.43; 0.68]) also showed lower levels of dementia. Combining all proxies into one model attenuated the association between early-life CR and dementia (hazard ratio = 0.56, 95% CI = [0.25; 1.25]) whereas the other associations were unaffected. These findings were stable upon stratification for sex, age, and APOE ɛ4. Finally, high levels of late-life CR and BR provided additive protection against dementia. Conclusion: The findings illustrate the importance of late-life over early-life reserve in understanding the risk of dementia, and show the need to study CR and BR conjointly.

Pages 619-627
Francisca A. de Leeuw, William G. Honer, Julie A. Schneider, Martha Clare Morris
Brain γ-Tocopherol Levels Are Associated with Presynaptic Protein Levels in Elderly Human Midfrontal Cortex
Abstract: Background: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation. Objective: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans. Methods: We examined associations of α- and γ-tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels. Results: Higher brain γ-tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE)=0.272 to 0.412 (0.084 to 0.091), p < 0.001 to 0.003). When additionally adjusted for global Alzheimer’s disease pathology, cerebral infarcts, and Lewy body disease pathology, these associations remained largely similar. No associations were found between α-tocopherol and presynaptic protein levels. Conclusion: In this cross-sectional study, we found higher brain γ-tocopherol levels were associated with presynaptic protein levels in the midfrontal cortex. These results are consistent with a proposed role of vitamin E to maintain presynaptic protein levels.

Pages 629-640
Li Hu*, Shaoping Zhu*, Xiaoping Peng*, Kanglan Li, Wanjuan Peng, Yu Zhong, Chenyao Kangc, Xingxing Cao, Zhou Liu, Bin Zhao *These authors contributed equally to this work.
High Salt Elicits Brain Inflammation and Cognitive Dysfunction, Accompanied by Alternations in the Gut Microbiota and Decreased SCFA Production
Abstract: Background: Excessive salt intake is considered an important risk factor for cognitive impairment, which might be the consequence of imbalanced intestinal homeostasis. Objective: To investigate the effects of dietary salt on the gut microbiota and cognitive performance and the underlying mechanisms. Methods: Adult female C57BL6 mice were maintained on either normal chow (control group, CON) or sodium-rich chow containing 8% NaCl (high-salt diet, HSD) for 8 weeks. Spatial learning and memory ability, short-chain fatty acids (SCFAs) concentrations, gut bacterial flora composition, blood-brain barrier permeability, and proinflammatory cytokine levels and apoptosis in the brain were evaluated. Results: The mice fed an HSD for 8 weeks displayed impaired learning and memory abilities. HSD significantly reduced the proportions of Bacteroidetes (S24-7 and Alloprevotella) and Proteobacteria and increased that of Firmicutes (Lachnospiraceae and Ruminococcaceae). SCFA concentrations decreased in the absolute concentrations of acetate, propionate, and butyrate in the fecal samples from the HSD-fed mice. The HSD induced both BBB dysfunction and microglial activation in the mouse brain, and increased the IL-1β, IL-6, and TNF-α expression levels in the cortex. More importantly, the degree of apoptosis was higher in the cortex and hippocampus region of mice fed the HSD, and this effect was accompanied by significantly higher expression of cleaved caspase-3, caspase-3, and caspase-1. Conclusion: The HSD directly causes cognitive dysfunction in mice by eliciting an inflammatory environment and triggering apoptosis in the brain, and these effects are accompanied by gut dysbiosis, particularly reduced SCFA production.

Pages 641-653
Almudena Junquera Fernández, Estefanía García-Zamora, Javier Olazarán Rodríguez, Mario A. Parra Rodríguez, Sara Fernández-Guinea
Role of Executive Functions in the Conversion from Mild Cognitive Impairment to Dementia
Abstract: Background: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI)–dementia in Alzheimer’s clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). Objective: The present study analyzes the contributions of executive functions to predict MCI–dementia progression in ACS. Methods: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at 1-year follow-up, together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. Results: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI–dementia conversion, even after controlling for the severity of MCI at baseline (F(1, 68)=116.25, p=0.000, R2=0.63). Classical memory-based MCI classification failed to predict such a conversion (F(1, 68)=5.09, p=0.955, R2=0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. Conclusion: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia.

Pages 655-666
Giulia Caruso, Roberta Perri, Lucia Fadda, Carlo Caltagirone, Giovanni Augusto Carlesimo
Recall and Recognition in Alzheimer’s Disease and Frontotemporal Dementia
Abstract: Background: It has long been debated whether performance on recall and recognition tests depends on the same or different memory systems and whether performance on these two tasks is dissociated in clinical populations. According to Dual process theories of recall, performance on recall and recognition tests dissociates in the relative reliance on frontal lobe related activities; in fact, the recall test requires more strategic retrieval of memoranda than the recognition task. By contrast, Dual process theories of recognition posit that performance on these tests differs in the relative contribution of recollection and familiarity memory processes in the two tasks: both recollection and familiarity contribute to recognition judgments, but only recollection supports recall performance. Objective: The aim of this study was to clarify the cognitive processes involved in recall and recognition in patients with dementia. Methods: We administered a 15-word recall task followed by a yes/no recognition paradigm to 28 patients with Alzheimer’s disease (AD), 22 patients with the behavioral variant of frontotemporal dementia (bvFTD), and 45 normal controls (NCs). Results: Results showed that on the delayed recall task, bvFTD patients performed much better than AD patients but the two groups did not differ on any index of recognition performance. Conclusion: The present data support the hypothesis that the performance of the two groups is expression of the different reliance on recollection (more impaired in the AD than in the bvFTD group) and familiarity (similarly impaired in the two groups) in performance on recall and recognition tasks.

Pages 667-674
Ji-ping Tan*, Xiaoxiao Wang*, Xiaoyang Lan*, Nan Li, Shimin Zhang, Yiming Zhao, Lu-ning Wang *These authors contributed equally to this work.
The Epoch Effect on Cognitive Function Requires Regular Updating of Cognitive Screening Tests
Abstract: Background: Over time, improved cognitive abilities in elderly individuals lead to an overall increase in performance on widely used cognitive screening tests (e.g., Mini-Mental State Examination, MMSE) and impact screening efficacy. Objective: We aimed to examine the epoch effect on cognitive function measured using MMSE, in addition to the influence of demographic characteristics on MMSE. We also evaluated the ability of the MMSE in detecting dementia and examined the discrimination ability and measurement precision of the MMSE. Methods: In a cross-sectional survey, Chinese veterans aged ≥60 years were interviewed. Multiple linear regression analysis was applied to explore the factors affecting the MMSE. The expected MMSE score was calculated to examine the epoch effect. The diagnostic accuracy of the MMSE was determined via receiver operating characteristic curve analyses. Item response theory methods were implemented using Stata 16.0. Results: The MMSE score increased with higher education and decreased with advancing age. The observed MMSE score in this study (26.9) was higher than the expected MMSE score (24.9). It demonstrated 78.3%/84.1%/89.9% sensitivity and 85.8%/79.5%/66.8% specificity in detecting dementia using the cut-off score 25/26/27. The MMSE showed reduced discrimination and provided little information for ability level of -1 and above. Conclusion: Improved cognitive ability over time may increase the performance on cognitive screening tests (e.g., MMSE). This impact of epoch in cognitive function emphasizes the importance of regularly updating cognitive screening tests.

Pages 675-688
Susan Fung*, Carole L. Smith*, Katherine E. Prater, Amanda Case, Kevin Green, Leah Osnis, Chloe Winston, Yoshito Kinoshita, Bryce Sopher, Richard S. Morrison, Gwenn A. Garden, Suman Jayadev (Handling Associate Editor: Steven Estus) *These authors contributed equally to this work.
Early-Onset Familial Alzheimer’s Disease Variant PSEN2 N141I Heterozygosity Is Associated with Altered Microglia Phenotype
Abstract: Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. Objective: Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ-secretase activity as well as exaggerated inflammatory cytokine release, NFκB activity, and Aβ internalization. In vivo, PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mice brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production.

Pages 689-699
Maurizio Gallucci, Anna Paola Mazzarolo, Lucia Focella, Cinzia Piovesan, Manuela Mazzetto, Mauro Ramigni, Emanuele Marzetti (Handling Associate Editor: Patrizia Meccoci)
“Camminando e Leggendo… Ricordo” (Walking and Reading… I Remember): Prevention of Frailty Through the Promotion of Physical Activity and Reading in People with Mild Cognitive Impairment. Results from the TREDEM Registry
Abstract: Background: Frailty is a condition of increased vulnerability to exogenous and endogenous stressors, which is correlated with aging, functional decline, institutionalization, hospitalization, and mortality. Given the multifaceted nature of frailty, programs aimed at its prevention are recommended to act on multiple domains. Objective: The present intervention program aimed at assessing the effects of combined physical and cognitive training in older people with mild cognitive impairment (MCI) and at investigating how their frailty status changed over one year of follow-up. Methods: Two-hundred and seven participants were recruited among outpatients of the Cognitive Impairment Center who agreed to receive a comprehensive assessment. Forty-six participants, who joined a structured program of physical activity and group readings for a period of one year, were defined as active. The remaining 161, who decided not to engage in those activities, were considered controls. In both groups, frailty status was assessed at baseline and over one year of follow-up. Results: Control participants showed twice the risk of becoming frail at 12 months compared with those in the active group. Participants in the active group had more than three times the probability of improving their frailty status compared with the control group from T0 to T12. Age and NPI scores were significantly associated with worsening frailty status. When analyses were restricted to participants who were robust at baseline, the frailty status varied significantly between groups over time. Conclusion: Findings of the present study confirm the beneficial effects of physical activity and reading to prevent frailty in older people with MCI.

Pages 701-714
Pengfei Fu, Ken Kin Lam Yung
Air Pollution and Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: Ambient air pollution has been associated with Alzheimer’s disease (AD) in the elderly. However, its effects on AD have not been meta-analyzed comprehensively. Objective: We conducted a systematic review and meta-analysis to assess the associations between air pollution and AD incidence. Methods: We searched PubMed and Web of Science for indexed publications up to March 2020. Odds risk (OR) and confidence intervals (CI) were estimated for particulate matter (PM)10 (PM10), PM2.5, ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO). The subgroup analysis was conducted based on the pollution levels. Results: Nine studies were included in the meta-analysis and review. The OR per 10 μg/m3 increase of PM2.5 was 1.95 (95% CI: 0.88-4.30). The corresponding values per 10 μg/m3 increment of other pollutants were 1.03 (95% CI: 0.68-1.57) for O3, 1.00 (95% CI: 0.89-1.13) for NO2, and 0.95 (95% CI: 0.91-0.99) for PM10 (only one study), respectively. Overall OR of the five air pollutants above with AD was 1.32 (95% CI: 1.09-1.61), suggesting a positive association between ambient air pollution and AD incidence. The sub-analysis indicated that the OR (2.20) in heavily polluted regions was notably higher than that in lightly polluted regions (1.06). Although AD risk rate data related to SO2 or CO exposure are still limited, the epidemiologic and toxicological evidence indicated that higher concentration of SO2 or CO exposure increased risks of dementia, implying that SO2 or CO might have a potential impact on AD. Conclusion: Air pollution exposure may exacerbate AD development.

Pages 715-732
Eleni Poptsi, Despina Moraitou, Emmanouil Tsardoulias, Andreas L. Symeonidis, Magda Tsolaki
Is the Discrimination of Subjective Cognitive Decline from Cognitively Healthy Adulthood and Mild Cognitive Impairment Possible? A Pilot Study Utilizing the R4Alz Battery
Abstract: Background: The early diagnosis of neurocognitive disorders before the symptoms’ onset is the ultimate goal of the scientific community. REMEDES for Alzheimer (R4Alz) is a battery, designed for assessing cognitive control abilities in people with minor and major neurocognitive disorders. Objective: To investigate whether the R4Alz battery’s tasks differentiate subjective cognitive decline (SCD) from cognitively healthy adults (CHA) and mild cognitive impairment (MCI). Methods: The R4Alz battery was administered to 175 Greek adults, categorized in five groups a) healthy young adults (n = 42), b) healthy middle-aged adults (n = 33), c) healthy older adults (HOA; n = 14), d) community-dwelling older adults with SCD (n = 34), and e) people with MCI (n = 52). Results: Between the seven R4Alz subtasks, four showcased the best results for differentiating HOA from SCD: the working memory updating (WMCUT-S3), the inhibition and switching subtask (ICT/RST-S1&S2), the failure sets (FS) of the ICT/RST-S1&S2, and the cognitive flexibility subtask (ICT/RST-S3). The total score of the four R4Alz subtasks (R4AlzTot4) leads to an excellent discrimination among SCD and healthy adulthood, and to fare discrimination among SCD and MCI. Conclusion: The R4Alz battery is a novel approach regarding the neuropsychological assessment of people with SCD, since it can very well assist toward discriminating SCD from HOA. The R4Alz is able to measure decline of specific cognitive control abilities—namely of working memory updating, and complex executive functions—which seem to be the neuropsychological substrate of cognitive complaints in community dwelling adults of advancing age.

Pages 733-744
Steve Pedrini, Eugene Hone, Veer B. Gupta, Ian James, Elham Teimouri, Ashley I. Bush, Christopher C. Rowe, Victor L. Villemagne, David Ames, Colin L. Masters, Stephanie Rainey-Smith, Giuseppe Verdile, Hamid R. Sohrabi, Manfred R. Raida, Markus R. Wenk, Kevin Taddei, Pratishtha Chatterjee, Ian Martins, Simon M. Laws, Ralph N. Martins and the AIBL Research Group (Handling Associate Editor: Giulio Pasinetti)
Plasma High Density Lipoprotein Small Subclass Is Reduced in Alzheimer’s Disease Patients and Correlates with Cognitive Performance
Abstract: Background: The link between cholesterol and Alzheimer’s disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a “good” lipid complex due to its ability to enable clearance of excess cholesterol via ‘cholesterol reverse transport’, although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL. Objective: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition. Methods: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. Results: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. Conclusion: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.

Pages 745-752
Audrey Keleman, Julie K. Wisch, Rebecca M. Bollinger, Elizabeth A. Grant, Tammie L. Benzinger, John C. Morris, Beau M. Ances, Susan L. Stark (Handling Associate Editor: Michael Rafii) *These authors contributed equally to this work.
Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer’s Disease
Abstract: Background: Behavioral markers for Alzheimer’s disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

Pages 753-771
Shalini S. Rao, Stuart. D. Portbury, Larissa Lago, Ashley I. Bush, Paul A. Adlard
The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy
Abstract: Background: Abnormally hyperphosphorylated tau is a defining pathological feature of tauopathies, such as Alzheimer’s disease (AD), and accumulating evidence suggests a role for iron in mediating tau pathology that may lead to cognitive decline in these conditions. The metal chelator deferiprone (DFP), which has a high affinity for iron, is currently in clinical trials for AD and Parkinson’s disease. However, the effect of DFP on tau pathology remains underexplored. Objective: We aimed to investigate the impact of chronic DFP treatment on tau pathology using a well-characterized mouse model of tauopathy (rTg(tauP301L)4510). Methods: Animals were treated daily with DFP (100 mg/kg) via oral gavage for 16 weeks. After 14 weeks, mice were tested in the Y-maze, open field, Morris water maze, and rotorod. At the end of the study, brain tissue was collected to examine metal levels (using inductively coupled plasma-mass spectrometry) and for western blot analysis of DFP on tau and iron associated pathways. Results: DFP significantly reduced anxiety-like behavior, and revealed a trend toward improved cognitive function. This was accompanied by a decrease in brain iron levels and sarkosyl-insoluble tau. Our data also showed downregulation of the tau kinases glycogen synthase kinase 3β and cyclin dependent kinase-5 in DFP treated mice and an increase in the methylation of the catalytic subunit of protein phosphatase 2A. Conclusion: These data support the hypothesis that suggests that iron plays a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders.

Pages 773-780
Tohru Hasegawa, Yoshinori Kosoku, Yuka Sano, Hiroshi Yoshida, Chiaki Kudoh, Takeshi Tabira
Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study
Abstract: Background: In the treatment of Alzheimer’s disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD. Objective: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. Methods: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients’ plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. Results: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116 μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. Conclusion: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.

Pages 781-794
Chenbo Zhang, Jianfeng Luo, Changzheng Yuan, Ding Ding
Vitamin B12, B6, or Folate and Cognitive Function in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis
Abstract: Background: Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults. Objective: To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis. Methods: Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity. Results: Twenty-one observational studies with sample sizes ranging from 155-7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61-0.97) and folate concentration (OR = 0.68, 95% CI = 0.51-0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship. Conclusion: The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals.

Pages 795-806
André Furtado, Rosario Astaburuaga, Ana Costa, Ana C. Duarte, Isabel Gonçalves, José Cipolla-Neto, Manuel C. Lemos, Eva Carro, Angela Relógio, Cecília R.A. Santos*, Telma Quintela* *These authors share senior authorship.
The Rhythmicity of Clock Genes Is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. Besides, a significant circadian pattern of Bmal1 occurs in the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

Pages 807-819
Yan-Juan Wang, Wei-Gang Gong, Qing-Guo Ren, Zhi-Jun Zhang
Escitalopram Alleviates Alzheimer’s Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice
Abstract: Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway.

Pages 821-830
Hannah E. Silverman, Yunglin Gazes, Megan S. Barker, Masood Manoochehri, Jill S. Goldman, Eric M. Wassermann, Michael C. Tierney, Stephanie Cosentino, Jordan Grafman, Edward D. Huey (Handling Associate Editor: Cristian Leyton)
Frontal Pole Hypometabolism Linked to Reduced Prosocial Sexual Behaviors in Frontotemporal Dementia and Corticobasal Syndrome
Abstract: Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p=0.009] and NC [p<0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p=0.026] and NC [p<0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors [p<0.01]. Hypometabolism in Brodmann’s Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p(FWE-corr)<0.05, k=44]. No anatomical associations were found with other sexual changes. Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction.

Pages 831-842
Mari Aksnes, Ebba Gløersen Müller, Ann Tiiman, Trine Holt Edwin, Lars Terenius, Mona-Elisabeth Revheim, Vladana Vukojević, Nenad Bogdanović, Anne-Brita Knapskog
Amyloidogenic Nanoplaques in Cerebrospinal Fluid: Relationship to Amyloid Brain Uptake and Clinical Alzheimer’s Disease in a Memory Clinic Cohort
Abstract: Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

Pages 843-853
Antoine R. Trammell, Darius J. McDaniel, Malik Obideen, Maureen Okafor, Tiffany L. Thomas, Felicia C. Goldstein, Leslie M. Shaw, Ihab M. Hajjar (Handling Associate Editor: Robert Rissman)
Perceived Stress is Associated with Alzheimer's Disease Cerebrospinal Fluid Biomarkers in African Americans with Mild Cognitive Impairment
Abstract: Background: African Americans (AA) have a higher Alzheimer's disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort. Objective: Establish biomarker evidence for the observed association between stress and AD, especially in AA. Methods: A cross-sectional study (n = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n = 309) provided cerebrospinal fluid for measurement of Αβ42, Tau, Ptau, Tau/Aβ42 (TAR), and Ptau/Aβ42 (PTAR). Multivariate linear regression, including factors that confound racial differences in AD, was performed. Results: Higher PSS scores were associated with higher Ptau (β = 0.43, p = 0.01) and PTAR (β = 0.005, p = 0.03) in AA with impaired cognition (mild cognitive impairment). Conclusion: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity.

Pages 855-864
Javier Mar, Ania Gorostiza, Oliver Ibarrondo, Carlos Cernuda, Arantzazu Arrospide, Álvaro Iruin, Igor Larrañaga, Mikel Tainta, Enaitz Ezpeleta, Ane Alberdi
Validation of Random Forest Machine Learning Models to Predict Dementia-Related Neuropsychiatric Symptoms in Real-World Data
Abstract: Background: Neuropsychiatric symptoms (NPS) are the leading cause of the social burden of dementia but their role is underestimated. Objective: The objective of the study was to validate predictive models to separately identify psychotic and depressive symptoms in patients diagnosed with dementia using clinical databases representing the whole population to inform decision-makers. Methods: First, we searched the electronic health records of 4,003 patients with dementia to identify NPS. Second, machine learning (random forest) algorithms were applied to build separate predictive models for psychotic and depressive symptom clusters in the training set (N=3,003). Third, calibration and discrimination were assessed in the test set (N= 1,000) to assess the performance of the models. Results: Neuropsychiatric symptoms were noted in the electronic health record of 58% of patients. The area under the receiver operating curve reached 0.80 for the psychotic cluster model and 0.74 for the depressive cluster model. The Kappa index and accuracy also showed better discrimination in the psychotic model. Calibration plots indicated that both types of model had less predictive accuracy when the probability of neuropsychiatric symptoms was <25%. The most important variables in the psychotic cluster model were use of risperidone, level of sedation, use of quetiapine and haloperidol and the number of antipsychotics prescribed. In the depressive cluster model, the most important variables were number of antidepressants prescribed, escitalopram use, level of sedation, and age. Conclusion: Given their relatively good performance, the predictive models can be used to estimate prevalence of NPS in population databases.

Pages 865-875
Jessica Monsees, Tim Schmachtenberg, Wolfgang Hoffmann, Amy Kind, Andrea Gilmore-Bykovskyi, Alice J. Kim, Jochen René Thyrian
Dementia in People with a Turkish Migration Background: Experiences and Utilization of Healthcare Services
Abstract: Background: As the proportion of older people with migration background (PwM) increases, the proportion of older PwM with dementia might also increase. Dementia is underdiagnosed in this group and a large proportion of PwM with dementia and family caregivers are not properly supported. Healthcare utilization is lower among older migrant populations. Thus, a better understanding of how PwM and family caregivers perceive their situation and how they experience healthcare services is needed to improve utilization of the healthcare system. Objective: Analyze how family caregivers of PwM with dementia experience their situation, why healthcare services are utilized less often, and what can be done to reverse this. Methods: Eight semi-structured interviews were conducted with people with Turkish migration background caring for PwM with dementia. Qualitative content analysis was used for data analysis. Results: Daily care was performed by one family member with the support of others. Healthcare services were used by most participants. Participants identified a need for better access to relevant information and incorporation of Turkish culture into healthcare services. Conclusion: PwM face similar challenges in taking care of persons with dementia as those without migration background. There is a willingness to use services, and services embracing Turkish culture would help to reduce hesitance and make affected people feel more comfortable, thereby increasing utilization and satisfaction. A limitation of this study is that participants were already connected to health services, which may not reflect the help-seeking behavior of those in the Turkish community who are not involved in healthcare.

Pages 877-883
Andrea González, Leonardo Guzmán-Martínez, Ricardo B. Maccioni
Plasma Tau Variants Detected by a Novel Anti-Tau Monoclonal Antibody: A Potential Biomarker for Alzheimer’s Disease
Abstract: Background: A major drawback in Alzheimer’s disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau®, based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. Objective: To analyze a potential novel source of antigen for Alz-tau®, plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. Methods: We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by western blot with this novel monoclonal antibody. Results: The HMW/LMWtau ratio was statistically different between AD patients and controls. Conclusions: Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD.

Pages 885-901
Simon Lepper, Anika Rädke, Hannah Wehrmann, Bernhard Michalowsky, Wolfgang Hoffmann
Preferences of Cognitively Impaired Patients and Patients Living with Dementia: A Systematic Review of Quantitative Patient Preference Studies
Abstract: Background: Treatment decisions based on guidelines rather than patients’ preferences determine adherence to and compliance with treatment, which, in turn, could improve health-related outcomes. Objectives: To summarize the stated treatment and care preferences of people with dementia (PwD). Methods: A systematic review was conducted to assess the stated preferences of PwD. The inclusion criterion was the use of quantitative methods to elicit stated preferences, enabling a ranking of preferences. Results: Eleven studies revealed preferences for diagnostics, treatment decisions, patient-related outcomes, care services, end-of-life care, leisure activities, and digital life story work. PwDs prefer accurate, pain-free, and comfortable diagnostic procedures without radioactive markers as well as being accompanied by a caregiver. PwD’s quality of life (QoL), self-efficacy, and depression were equally most important for PwD and caregivers. However, PwD memory was only important for caregivers but not for PwD, and caregiver QoL was moderately important for PwD but least important for caregivers. Additionally, comfort and family involvement were most important for patients’ end-of-life care, whereas caregivers most preferred good communication and pain management. Also, preferences depend on the living situation: Patients living not alone prefer a regular care provider most, whereas those living alone only want to live nearby the caregiver. Preferences for leisure activities did not differ between past and present ratings, indicating that PwD prefer activities that have always been carried out. Conclusion: Only a few studies have applied quantitative methods to elicit the preferences of PwD. More research is needed to capture the stated preferences for the treatment, care, and support of PwD to improve health-related outcomes and the allocation of healthcare resources.

Pages 903-920
Can Sheng, Kun Yang, Xiaoni Wang, Hongyan Li, Taoran Li, Li Lin, Yi Liu, Qin Yang, Xiaoqi Wang, Xue Wang, Yu Sun, Ying Han (Handling Associate Editor: Ling-Qiang Zhu)
Advances in Non-Pharmacological Interventions for Subjective Cognitive Decline: A Systematic Review and Meta-Analysis
Abstract: Background: Subjective cognitive decline (SCD) is considered the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Currently, given the lack of effective and curable pharmacological treatments for AD, non-pharmacological interventions (NPIs) for individuals with SCD may provide a valuable opportunity for the secondary prevention of AD. Objective: This systematic review and meta-analysis, conducted in accordance with the PRISMA guidelines, aimed to investigate the benefits of current NPIs in the population with SCD. Methods: The online electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, PsycInfo, and CINAHL, were searched to identify randomized controlled trials of NPIs for SCD. Intervention strategies were psychological and health-related education interventions, mind-body therapy, lifestyle modification, cognitive training, and multidomain interventions. Outcomes included subjective memory, objective memory, global cognitive function, psychological well-being, and mood. Study quality was determined using the criteria of the Cochrane collaboration’s tool. The Hedges’ g of change was analyzed. Results: Eighteen studies were included in this review and meta-analysis. Overall, psychological and health-related education interventions exhibited a medium effect on objective memory function (Hedges’ g = 0.53, p = 0.01). Cognitive training led to a small effect on objective memory, which was marginal statistically (Hedges’ g = 0.19, p = 0.05). In addition, cognitive training also significantly improved subjective memory performance (Hedges’ g = 0.49, p = 0.0003) and psychological well-being (Hedges’ g = 0.27, p = 0.03). Conclusion: Overall, the psychological intervention and cognitive training may be beneficial to cognitive function and psychological well-being. NPIs may be effectively implemented in older adults with SCD.

Page 921
Book Review

The Neuroscience of Meditation by Yi-Yuan Tang and Rongxiang Tang, Academic Press, 2020, 234 pp. Reviewed by Dharma Singh Khalsa, MD