Volume 81, Number 3, IN PRESS

Review
Luisa Müller, Timo Kirschstein, Rüdiger Köhling, Angela Kuhla, Stefan Teipel
Neuronal Hyperexcitability in APPSWE/PS1dE9 Mouse Models of Alzheimer’s Disease
Abstract: Transgenic mouse models serve a better understanding of Alzheimer’s disease (AD) pathogenesis and its consequences on neuronal function. Well-known and broadly used AD models are APPswe/PS1dE9 mice, which are able to reproduce features of amyloid-β (Aβ) plaque formations as well as neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. The most prominent findings include abnormal synaptic function and synaptic reorganization as well as changes in membrane threshold and spontaneous neuronal firing activities leading to generalized excitation-inhibition imbalances in larger neuronal circuits and networks. Importantly, these findings in APPswe/PS1dE9 mice are at least partly consistent with results of electrophysiological studies in humans with sporadic AD. This underscores the potential to transfer mechanistic insights into amyloid related neuronal dysfunction from animal models to humans. This is of high relevance for targeted downstream interventions into neuronal hyperexcitability, for example based on repurposing of existing antiepileptic drugs, as well as the use of combinations of imaging and electrophysiological readouts to monitor effects of upstream interventions into amyloid build-up and processing on neuronal function in animal models and human studies. This article gives an overview on the pathogenic and methodological basis for recording of neuronal hyperexcitability in AD mouse models and on key findings in APPswe/PS1dE9 mice. We point at several instances to the translational perspective into clinical intervention and observation studies in humans. We particularly focus on bi-directional relations between hyperexcitability and cerebral amyloidosis, including build-up as well as clearance of amyloid, possibly related to sleep and so called glymphatic system function.

Review
Taylor J. Krivanek, Seth A. Gale, Brittany M. McFeeley, Casey M. Nicastri, Kirk R. Daffner
Promoting Successful Cognitive Aging: A Ten-Year Update
Abstract: A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.

Review
Leslie C. Norins
Repurposing Licensed Drugs for Use Against Alzheimer’s Disease
Abstract: Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics.

Review
Efraim Jaul, Oded Meiron
Advanced Dementia: Brain-State Characteristics and Clinical Indicators of Early Mortality
Abstract: There is an urgent need in advanced dementia for evidence-based clinical prognostic predictors that could positively influence ethical decisions allowing health provider and family preparation for early mortality. Accordingly, the authors review and discuss the prognostic utility of clinical assessments and objective measures of pathological brain states in advanced dementia patients associated with accelerated mortality. Overall, due to the paucity of brain-activity and clinical-comorbidity predictors of survival in advanced dementia, authors outline the potential prognostic value of brain-state electroencephalography (EEG) measures and reliable clinical indicators for forecasting early mortality in advanced dementia patients. In conclusion, two consistent risk-factors for predicting accelerated mortality in terminal-stage patients with advanced dementia were identified: pressure ulcers and paroxysmal slow-wave EEG parameters associated with cognitive impairment severity and organic disease progression. In parallel, immobility, malnutrition, and co-morbid systemic diseases are highly associated with the risk for early mortality in advanced dementia patients. Importantly, the authors' conclusions suggest utilizing reliable quantitative-parameters of disease progression for estimating accelerated mortality in dementia patients entering the terminal disease-stages characterized by severe intellectual deficits and functional disability.

Short Communication
Dianxu Ren, Oscar L. Lopez, Jennifer H. Lingler, Yvette Conley
Association Between the APOE ε2/ε4 Genotype and Alzheimer’s Disease and Mild Cognitive Impairment Among African Americans
Abstract: We examined the association between APOE ε2/ε4 with incident Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer’s Coordinating Center (NACC) from 2005 to September 2019. Compared to ε3/ε3 carriers, ε2/ε4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR]=0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR=0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOE ε2/ε4 genotype is not associated with the incidence of AD and MCI among African Americans.

Marcos Vasconcelos Pais, Júlia Cunha Loureiro, Vagner Santigado do Vale, Marcia Radanovic, Leda Leme Talib, Florindo Stella, Orestes Vicente Forlenza
Heterogeneity of Cerebrospinal Fluid Biomarkers Profiles in Individuals with Distinct Levels of Cognitive Decline: A Cross-Sectional Study
Abstract: Background: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer’s disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. Objective: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. Methods: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n=60, 29.4%); MCI (n=84, 41.2%); or normal cognition (NC, n=60, 29.4%). CSF concentrations of Aβ42, T-tau, and 181Thr-P-tau were determined, and Aβ42/P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. Results: The majority (73.7%) of patients in the AD group had the Aβ42/P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A+, 28 (46.7%) as T+, and 23 (38.3%) as N+. In the AD group, 66.7% of the cases were classified as A+, 78.3% as T+, and 80% as N+. Conclusion: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases.

Joon Yul Choi, Seunghyun Lee, Wanhyung Lee
The Impact of Hearing Loss on Clinical Dementia and Preclinical Cognitive Impairment in Later Life
Abstract: Background: Dementia and cognitive impairment were significantly associated with hearing loss. The impact of hearing loss on dementia and cognitive impairment is understudied, particularly for different effect on cognitive impairment according to types of hearing loss. Objective: The present study was conducted to elucidate the association between clinically diagnosed dementia and hearing loss with consideration of the type of hearing loss among an elderly population, and to explore the effects of different types of hearing loss on preclinical cognitive impairment. Methods: Data (n = 59,675) from the Korean National Health Insurance Service–Health Screening were used to calculate odds ratios (OR) for cognitive impairment according to type of hearing loss (conductive, sensorineural, mixed, and noise-induced hearing losses, and presbycusis). Cognitive impairment was assessed using the Korean Dementia Screening Questionnaire-Prescreening (KDSQ-P). Results: Cognitive impairment was significantly associated with conductive (OR: 1.45, 95% confidence interval (CI): 1.20–1.77), sensorineural (OR: 1.23, CI: 1.12–1.36), and noise-induced hearing loss (OR: 1.32, CI: 1.12–1.56), and presbycusis (OR: 1.53, CI: 1.25–1.87). Among participants scoring positive on the KDSQ-P (score ≥4), the KDSQ-P score was significantly elevated in the mixed and noise-induced hearing loss groups. Conclusion: This study revealed a significant correlation between different types of hearing loss and cognitive impairment. Noise-induced hearing loss is especially important because it occurs earlier than other types of hearing loss and has large effects on cognitive impairment.

Miguel E. Habeych, Tatiana Falcone, Anjali Dagar, Lisa Ford, Ruby Castilla-Puentes
Dementia, Subtype of Seizures, and the Risk of New Onset Seizures: A Cohort Study of a National U.S. Managed Care Database
Abstract: Background: Seizure disorders have been identified in patients suffering from different types of dementia. However, the risks associated with the seizure subtypes have not been characterized. Objective: To compare the occurrence and risk of various seizure subtypes (focal and generalized) between patients with and without a dementia diagnosis. Methods: Data from 40.7 million private insured patient individual electronic health records from the U.S., were utilized. Patients 60 years of age or more from the Optum Insight Clinformatics-data Mart database were included in this study. Using ICD-9 diagnoses, the occurrence of generalized or focal seizure disorders was identified. The risk of new-onset seizures and the types of seizures associated with a dementia diagnosis were estimated in a cohort of 2,885,336 patients followed from 2005 to 2014. Group differences were analyzed using continuity-adjusted chi-square and hazard ratios with 95% confidence intervals calculated after a logistic regression analysis Results: A total of 79,561 patient records had a dementia diagnosis, and 56.38% of them were females. Patients with dementia when compared to those without dementia had higher risk for seizure disorders [Hazard ratio (HR)=6.5 95% CI=4.4-9.5]; grand mal status (HR=6.5, 95% CI=5.7-7.3); focal seizures (HR =6.0, 95% CI=5.5-6.6); motor simple focal status (HR =5.6, 95% CI=3.5-9.0); epilepsy (HR =5.0, 95% CI=4.8-5.2); generalized convulsive epilepsy (HR =4.8, 95% CI=4.5-5.0); localization-related epilepsy (HR =4.5, 95% CI=4.1-4.9); focal status (HR =4.2, 95% CI=2.9-6.1); and fits convulsions (HR =3.5, 95% CI=3.4-3.6). Conclusion: The study confirms that patients with dementia have higher risks of generalized or focal seizure than patients without dementia.

Jin-wu Zhou*, Man Zhao, Wen-liang Rang*, Xiao-yan Zhang, Zhen-ming Liu, Liang-ren Zhang, Tong-xing Wang, Chu-Tse Wu, Xiao-rui Cheng, Wen-xia Zhou *These authors contributed equally to this work.
Proteome Profiling Identified Amyloid-β Protein Precursor as a Novel Binding Partner and Modulator of VGLUT1
Abstract: Background: The toxicity of excessive glutamate release has been implicated in various acute and chronic neurodegenerative conditions. Vesicular glutamate transporters (VGLUTs) are the major mediators for the uptake of glutamate into synaptic vesicles. However, the dynamics and mechanism of this process in glutamatergic neurons are still largely unknown. Objective: This study aimed to investigate the candidate protein partners of VGLUT1 and their regulatory roles in the vesicles in rat brain. Methods: Pull down assay, co-immunoprecipitation assay, or split-ubiquitin membrane yeast two‐hybrid screening coupled with nanoRPLC-MS/MS were used to identify the candidate protein partners of VGLUT1 in the vesicles in rat brain. The in vitro and in vivo models were used to test effects of AβPP, Atp6ap2, Gja1, and Synataxin on VGLUT1 expression. Results: A total of 255 and 225 proteins and 172 known genes were identified in the pull down assay, co-immunoprecipitation assay, or split-ubiquitin yeast two-hybrid screening respectively. The physiological interactions of SV2A, Syntaxin 12, Gja1, AβPP, and Atp6ap2 to VGLUT1 were further confirmed. Knockdown of Atp6ap2, Gja1, and Synataxin increased VGLUT1 mRNA expression and only knockdown of AβPP increased both mRNA and protein levels of VGLUT1 in PC12 cells. The regulatory function of AβPP on VGLUT1 expression was further confirmed in the in vitro and in vivo models. Conclusion: These results elucidate that the AβPP and VGLUT1 interacts at vesicular level and AβPP plays a role in the regulation of VGLUT1 expression which is essential for maintaining vesicular activities.

Samantha L. Gardener, Michael Weinborn, Hamid R. Sohrabi, James D. Doecke, Pierrick Bourgeat, Stephanie R. Rainey-Smith, Kai-kai Shen, Jurgen Fripp, Kevin Taddei, Paul Maruff, Olivier Salvado, Greg Savage, David Ames, Colin L. Masters, Christopher C. Rowe, Ralph N. Martins, for the AIBL Research Group (Handling Associate Editor: Sid O'Bryant)
Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults
Abstract: Background: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. Objective: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. Methods: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70+ at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30–44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. Results: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. Conclusion: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

John P.K. Bernstein, Katherine E. Dorociak, Nora Mattek, Mira Leese, Zachary T. Beattie, Jeffrey A. Kaye, Adriana Hughes
Passively-Measured Routine Home Computer Activity and Application Use Can Detect Mild Cognitive Impairment and Correlate with Important Cognitive Functions in Older Adulthood
Abstract: Background: Computer use is a cognitively complex instrumental activity of daily living (IADL) that has been linked to cognitive functioning in older adulthood, yet little work has explored its capacity to detect incident mild cognitive impairment (MCI). Objective: To examine whether routine home computer use (general computer use as well as use of specific applications) could effectively discriminate between older adults with and without MCI, as well as explore associations between use of common computer applications and cognitive domains known to be important for IADL performance. Methods: A total of 60 community-dwelling older adults (39 cognitively healthy, 21 with MCI) completed a neuropsychological evaluation at study baseline and subsequently had their routine home computer use behaviors passively recorded for three months. Results: Compared to those with MCI, cognitively healthy participants spent more time using the computer, had a greater number of computer sessions, and had an earlier mean time of first daily computer session. They also spent more time using email and word processing applications, and used email, search, and word processing applications on a greater number of days. Better performance in several cognitive domains, but in particular memory and language, was associated with greater frequency of browser, word processing, search, and game application use. Conclusion: Computer and application use are useful in identifying older adults with MCI. Longitudinal studies are needed to determine whether decreases in overall computer use and specific computer application use are predictors of incident cognitive decline.

Akiko Mizuno, Helmet T. Karim, Maria J. Ly, Ann D. Cohen, Brian J. Lopresti, Chester A. Mathis, William E. Klunk, Howard J. Aizenstein, Beth E. Snitz (Handling Associate Editor: Maddelena Boccia)
An Effect of Education on Memory-Encoding Activation in Subjective Cognitive Decline
Abstract: Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer’s disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. Methods: We measured brain activation during the “face-name” memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n=63, mean age 73.1±7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education. Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve.

Johannes C. Michaelian, Shantel L. Duffy, Loren Mowszowski, Adam J. Guastella, Donna McCade, Andrew C. McKinnon*, Sharon L. Naismith* (Handling Associate Editor: Michael Hornberger) *Joint last authors
Poorer Theory of Mind in Amnestic Mild Cognitive Impairment Is Associated with Decreased Functional Connectivity in the Default Mode Network
Abstract: Background: Older adults living with amnestic mild cognitive impairment (aMCI) not only demonstrate impairments in Theory of Mind (ToM), relative to adults with non-amnestic MCI (naMCI), but are also at a higher risk of developing dementia. Objective: Our primary objective was to ascertain whether default mode network (DMN) functional connectivity was differentially associated with ToM abilities between MCI subgroups. Methods: Using functional magnetic resonance imaging, we investigated alterations in resting-state functional connectivity within the brain’s DMN in a sample of 43 older adults with aMCI (n=19) and naMCI (n=24), previously reported to demonstrate poorer ToM abilities. Results: Compared to naMCI, the aMCI subgroup revealed a significant association between poorer ToM performance and reduced functional connectivity between the bilateral temporal pole (TempP) and the left lateral temporal cortex (LTC) (LTC_L-TempP_L: b=-0.06, t(33)=-3.53, p=0.02; LTC_L-TempP_R: b=-0.07,t(33)=-3.20, p=0.03); between the right TempP and the dorsal medial prefrontal cortex (dMPFC) (b =-0.04, t(33)=-3.02, p=0.03) and between the left and right TempP (b=-0.05, t(33)=-3.26, p=0.03). In the naMCI subgroup, the opposite relationship was present between the bilateral TempP and the left LTC (Combined correlation: r=-0.47, p=0.02), however, not between the right TempP and the dMPFC (r=-0.14, p=0.51) or the left and right TempP (r=-0.31, p=0.14). Conclusion: Our findings suggest that alterations in functional connectivity within the DMN involving temporal and frontal lobe regions are associated with ToM deficits in aMCI.

Keita Sakurai, Daita Kaneda, Shohei Inui, Yuto Uchida, Satoru Morimoto, Takashi Nihashi, Takashi Kato, Kengo Ito, Yoshio Hashizume (Handling Associate Editor: Anette Hall)
Simple Quantitative Indices for the Differentiation of Advanced-Stage Alzheimer’s Disease and Other Limbic Tauopathies
Abstract: Background: The differentiation of Alzheimer’s disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. Objective: The purpose of this study is to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Methods: Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Results: Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Conclusion: Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice.

Olli Halminen, Aino Vesikansa, Juha Mehtälä, Iiris Hörhammer, Teija Mikkola, Lauri J. Virta, Tero Ylisaukko-oja, Miika Linna (Handling Associate Editor: Sophie Vandepitte)
Early Start of Anti-Dementia Medication Delays Transition to 24-Hour Care in Alzheimer’s Disease Patients: A Finnish Nationwide Cohort Study
Abstract: Background: Dementia is one of the strongest predictors of admission to a 24-hour care facility among older people, and 24-hour care is the major cost of Alzheimer’s disease (AD). Objective: The aim of this study was to evaluate the association of early start of anti-dementia medication and other predisposing factors with 2-year risk of transition to 24-hour care in the nationwide cohort of Finnish AD patients. Methods: This was a retrospective, non-interventional study based on individual-level data from Finnish national health and social care registers. The incident cohort included 7,454 AD patients (ICD-10, G30) comprised of two subgroups: those living unassisted at home (n=5,002), and those receiving professional home care (n=2,452). The primary outcome was admission to a 24-hour care facility. Exploratory variables were early versus late anti-dementia medication start, sociodemographic variables, care intensity level, and comorbidities. Results: Early anti-dementia medication reduced the risk of admission to 24-hour care both in patients living unassisted at home, with a hazard ratio (HR) of 0.58 (p<0.001), and those receiving professional home care (HR, 0.84; p=0.039). Being unmarried (HR, 1.69; p<0.001), having an informal caregiver (HR, 1.69; p=0.003), or having a diagnosis of additional neurological disorder (HR, 1.68; p=0.006) or hip fracture (HR, 1.61; p=0.004) were associated with higher risk of admission to 24-hour care in patients living unassisted at home. Conclusion: To support living at home, early start of anti-dementia medication should be a high priority in newly diagnosed AD patients.

Ossi Nerg*, Antti Junkkari*, Ilona Hallikainen*, Tuomas Rauramaa, Antti Luikku, Mikko Hiltunen, Juha E. Jääskeläinen, Ville Leinonen, Tuomo Hänninen*, Anne Koivisto* *These authors contributed equally to this work.
The CERAD Neuropsychological Battery in Patients with Idiopathic Normal Pressure Hydrocephalus Compared with Normal Population and Patients with Mild Alzheimer’s Disease
Abstract: Background: The usefulness of CERAD Neuropsychological Battery for describing the cognitive impairment in idiopathic normal pressure hydrocephalus (iNPH) is unknown. Objective: To compare the cognitive profile of patients with iNPH to patients with mild Alzheimer’s disease (AD) and age-matched cognitively healthy individuals by using the CERAD-NB. Methods: We studied CERAD-NB subtest results, including the Mini-Mental State Examination (MMSE), between 199 patients with probable iNPH, 236 patients with mild AD, and 309 people with normal cognition, using age, education, and gender adjusted multivariate linear regression model. In addition, the effects of AD-related brain pathology detected in frontal cortical brain biopsies in iNPH patients’ cognitive profiles were examined. Results: The iNPH patients performed worse than cognitively healthy people in all CERAD-NB subtests. Despite similar performances in the MMSE, AD patients outperformed iNPH patients in Verbal Fluency (p=0.016) and Clock Drawing (p<0.001) tests. However, iNPH patients outperformed AD patients in the Boston Naming Test and Word List Recall and Recognition (p<0.001). AD-related pathology in brain biopsies did not correlate with the CERAD-NB results. Conclusion: At the time of the iNPH diagnosis, cognitive performances differed from cognitively healthy people in all CERAD-NB subtests. When the iNPH and AD patients’ results were compared, the iNPH patients performed worse in Verbal Fluency and Clock Drawing tests while the AD group had more pronounced episodic memory dysfunctions. This study demonstrates significant differences in the CERAD-NB subtests between cognitive profiles of iNPH and AD patients. These differences are not captured by the MMSE alone.

Reena T. Gottesman, Anton Kociolek, Kayri Fernandez, Stephanie Cosentino, D.P. Devanand, Yaakov Stern, Yian Gu (Handling Associate Editor: Gad Marshall)
Association Between Early Psychotic Symptoms and Alzheimer’s Disease Prognosis in a Community-Based Cohort
Abstract: Background: Psychotic symptoms are an important and increasingly recognized aspect of Alzheimer’s disease (AD). They have been shown to contribute to faster disease progression in clinic-based, demographically homogenous samples with high educational attainment. Objective: We studied the association between baseline psychotic symptoms and disease progression among individuals with incident AD or ‘at risk’ of developing AD, from a demographically heterogenous, community-based cohort with minimal educational attainment. Methods: 212 participants received the Columbia University Scale of Psychopathology in Alzheimer’s Disease scale. Participants had psychotic symptoms with any of: visual illusions, delusions, hallucinations, or agitation/aggression. Disease progression was measured yearly and defined by meeting cognitive (≤10 on the Folstein MMSE) or functional endpoints (≥10 on the Blessed Dementia Rating Scale or ≥4 on the Dependence Scale). Results: The mean age was 85 years old. The cohort was 78.3% female, 75.9% Hispanic, and had a mean 6.96 years of education. Within the follow-up period (mean: 3.69 years), 24 met the cognitive endpoint, 59 met the functional endpoint, and 132 met the cutoff for dependence. The presence of at least one psychotic symptom was initially associated with an increased risk of reaching the functional endpoint (HR 3.12, 95% CI 1.67-5.86, p<0.001) and the endpoint of dependence (HR = 1.498, 95% CI 1.05-2.13, p=0.03). However, these associations were attenuated and non-significant when adjusted for baseline functional status. Psychotic symptoms were not associated with the cognitive endpoint. Conclusion: Psychotic symptoms may predict functional decline in patients of non-Caucasian ethnicity and with lower educational attainment.

Lujie Xu, Tao Li, Lingchuan Xiong, Xiao Wang, Zahinoor Ismail, Masami Fukuda, Zhiyu Sun, Jing Wang, Serge Gauthier, Xin Yu, Huali Wang
Reliability and Validity of the Chinese Version of Mild Behavioral Impairment Checklist in Mild Cognitive Impairment and Mild Alzheimer’s Disease
Abstract: Background: Mild behavioral impairment (MBI) has been proposed as an early manifestation of dementia. The Mild Behavioral Impairment Checklist (MBI-C) may help identify MBI in prodromal and preclinical dementia. Objective: The study aimed to evaluate the reliability and validity of the Chinese version of MBI-C in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD), and to explore the structure of the five factors of the MBI-C in Chinese culture. Methods: Sixty dyads of MCI and mild AD (MCI, n=33; mild AD, n=35) were recruited. The informants completed the MBI-C and Neuropsychiatric Inventory Questionnaire (NPI-Q) and were interviewed for clinician rating of the NPI. The Cronbach’s coefficient was used to measure the structural reliability of the MBI-C. The criterion-validity was evaluated with the correlation coefficient between the MBI-C and the total scores of NPI-Q and NPI. Exploratory factor analysis was conducted to investigate the structure of the MBI-C. Results: The Cronbach’s α coefficient was 0.895. The MBI-C total score was positively correlated with all five domains (r=0.577~0.840). The total score of MBI-C was significantly correlated with the total scores of NPI-Q (r=0.714) and NPI (r=0.749). Similarly, the five domain scores of MBI-C were significantly correlated with the factor and total scores of NPI-Q (r=0.312~0.673) and NPI (r=0.389~0.673). The components of each factor in Chinese version of MBI-C were slightly different from those of the a priori defined domains (χ2 = 1818.202, df=496, p < 0.001). Conclusion: The Chinese version of MBI-C has good reliability and validity, and can be used to evaluate the psychological and behavioral changes in MCI and mild AD.

Carsten T. Beuckmann, Hiroyuki Suzuki, Erik S. Musiek, Takashi Ueno, Toshitaka Sato, Masahiro Bando, Yoshihide Osada, Margaret Moline
Evaluation of SAMP8 Mice as a Model for Sleep-Wake and Rhythm Disturbances Associated with Alzheimer’s Disease: Impact of Treatment with the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant
Abstract: Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances.

Robin Feldman
Physicians Treating Alzheimer’s Disease Patients Should Be Aware that Televised Direct-to-Consumer Advertising Links More Strongly to Drug Utilization in Older Patients
Abstract: Background: US direct-to-consumer advertising spending for medicine has soared in recent decades. Advertising has been shown to impact drug utilization. Most Alzheimer’s disease patients are above age 65 and may take a range of prescription medications for various disease states. Objective: To investigate how direct-to-consumer advertising is associated with the drug utilization of patients ≥ 65 years old. Methods: Using advertising expenditure data and Medicare Part D drug purchase claims, we performed regression analyses for each of the highest-spending drugs and age group, with cumulative monthly spending as the predictor variable and drug utilization as the response variable. For each drug, we ran a second set of regression analyses to determine if the spending-utilization correlation showed a significant difference between the two patient age groups (older than 65, younger than 65). Results: For all 14 drugs in our study, advertising spending is positively correlated with utilization (p < 0.01) in both age groups. For seven of the 14 drugs studied, the difference in the utilization of patients older than 65 and the utilization of patients younger than 65 is statistically significant at a p < 0.01 level. The 65-and-older age bracket exhibits significantly greater utilization for all seven of these drugs. Conclusion: We find televised advertising for certain drugs to be associated with significantly stronger drug utilization among seniors, as compared to younger patients. Alzheimer’s disease physicians should be aware of this result, in light of the medications that patients may take for other disease states, particularly mood and mental health medications.

Wei-hao Li, Lin-hua Gan, Fang-fang Ma, Rui-li Feng, Jiao Wang, Yan-hui Li, Yang-yang Sun, Ya-jiang Wang, Xin Diao, Fei-yang Qian, Tie-qiao Wen
Deletion of Dcf1 Reduces Amyloid-β Aggregation and Mitigates Memory Deficits
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-β (Aβ) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aβ aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. Objective: Our goal is to investigate the effect of Dcf1 on Aβ aggregation and memory deficits in AD development. Methods: The mouse and Drosophila AD model were used to test the expression and aggregation of Aβ, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. Results: Deletion of Dcf1 resulted in decreased Aβ42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aβ42 AD Drosophila, the expression of Dcf1 in Aβ42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aβ aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. Conclusion: Dcf1 causes Aβ-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues.

Vince Szegeczki*, Helga Perényi*, Gabriella Horváth, Barbara Hinnah, Andrea Tamás, Zsolt Radák, Dóra Ábrahám, Róza Zákány, Dora Reglodi*, Tamás Juhász* *These authors contributed equally to this work.
Physical Training Inhibits the Fibrosis Formation in Alzheimer’s Disease Kidney Influencing the TGFβ Signaling Pathways
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-β (Aβ) plaques in the kidney. Alterations of transforming growth factor β (TGFβ) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aβ. Objective: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFβ signalization is involved in this effect. Methods: The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing wild type and AD organs. Alterations of canonical and non-canonical TGFβ signaling pathways were followed with PCR, western blot, and immunohistochemistry. Results: Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFβ pathways in non-trained mice, while expression levels of signal molecules of both TGFβ pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AβPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. Conclusion: Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFβ signaling plays a role in this phenomenon.

Joanna Perła-Kaján, Olga Włoczkowska, Anetta Zioła-Frankowska, Marcin Frankowski, A. David Smith, Celeste A. de Jager, Helga Refsum, Hieronim Jakubowski
Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment
Abstract: Background: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer’s disease. Objective: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI). Methods: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates. Results: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition. Conclusion: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

Leonardo Guzman-Martinez, Gonzalo A. Farías, José P. Tapia, María P. Sánchez, Patricio Fuentes, Sergio Gloger, Ricardo B. Maccioni
Interventional Study to Evaluate the Clinical Effects and Safety of the Nutraceutical Compound BrainUp-10® in a Cohort of Patients with Alzheimer’s Disease: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Trial
Abstract: Background: Clinically-evaluated nutraceuticals are candidates for Alzheimer’s disease (AD) prevention and treatment. Phase I studies showed biological safety of the nutraceutical BrainUp-10®, while a pilot trial demonstrated efficacy for treatment. Cell studies demonstrated neuroprotection. BrainUp-10® blocks tau self-assembly. Apathy is the most common of behavioral alterations. Objective: The aim was to explore efficacy of BrainUp-10® in mitigating cognitive and behavioral symptoms and in providing life quality, in a cohort of Chilean patients with mild to moderate AD. Methods: The was a multicenter, randomized, double blind, placebo-controlled phase II clinical study in mild to moderate AD patients treated with BrainUp-10® daily, while controls received a placebo. Primary endpoint was Apathy (AES scale), while secondary endpoints included Mini-Mental State Examination (MMSE), Trail Making Test (TMT A and TMT B), and Neuropsychiatry Index (NPI). AD blood biomarkers were analyzed. Laboratory tests were applied to all subjects. Results: 82 patients were enrolled. The MMSE score improved significantly at week 24 compared to baseline with tendency to increase, which met the pre-defined superiority criteria. NPI scores improved, the same for caregiver distress at 12th week (p=0.0557), and the alimentary response (p=0.0333). Apathy tests showed a statistically significant decrease in group treated with BrainUp-10®, with p=0.0321 at week 4 and p=0.0480 at week 12 treatment. A marked decrease in homocysteine was shown with BrainUp-10® (p=0.0222). Conclusion: Data show that BrainUp-10® produces a statistically significant improvement in apathy, ameliorating neuropsychiatric distress of patients. There were no compound-related adverse events. BrainUp-10® technology may enable patients to receive the benefits for their cognitive and behavioral problems.

Jessica Plácido, José Vinicius Ferreira, Juliana Araújo, Felipe de Oliveira Silva, Renan Baltar Ferreira, Carla Guimarães, Andréa Nunes de Carvalho, Jerson Laks, Andrea Camaz Deslandes
Beyond the Mini-Mental State Examination: The Use of Physical and Spatial Navigation Tests to Help to Screen for Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: Spatial navigation and dual-task (DT) performance may represent a low-cost approach to the identification of the cognitive decline in older adults and may support the clinical diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: To assess the accuracy of different types of motor tasks in differentiating older persons with MCI and AD from healthy peers. Methods: Older adults aged 60 years or over (n=105; healthy = 39; MCI = 23; AD = 43) were evaluated by the floor maze test (FMT), the senior fitness test, and DT performance. Receiver operating characteristic curve (ROC) analysis was used to evaluate the accuracy of the tests. We also performed principal component analysis (PCA) and logistic regression analysis to explore the variance and possible associations of the variables within the sample. Results: FMT (AUC = 0.84, sensitivity = 75.7%, specificity = 76.1%, p < 0.001) and DT (AUC = 0.87, sensitivity = 80.4%, specificity = 86.9%, p < 0.001) showed the highest performance for distinguishing MCI from AD individuals. Moreover, FMT presented better sensitivity in distinguishing AD patients from their healthy peers (AUC = 0.93, sensitivity = 94%, specificity = 85.6%, p < 0.001) when compared to the Mini-Mental State Examination. PCA revealed that the motor test performance explains a total of 73.9% of the variance of the sample. Additionally, the results of the motor tests were not influenced by age and education. Conclusion: Spatial navigation tests showed better accuracy than usual cognitive screening tests in distinguishing patients with neurocognitive disorders.

Eva Zupanic, Mia von Euler, Bengt Winblad, Hong Xu, Juraj Secnik, Milica Gregoric Kramberger, Dorota Religa, Bo Norrving, Sara Garcia-Ptacek
Mortality After Ischemic Stroke in Patients with Alzheimer’s Disease Dementia and Other Dementia Disorders
Abstract: Background: Stroke and dementia are interrelated diseases and risk for both increases with age. Even though stroke incidence and age-standardized death rates have decreased due to prevention of stroke risk factors, increased utilization of reperfusion therapies, and other changes in healthcare, the absolute numbers are increasing due to population growth and aging. Objective: To analyze predictors of death after stroke in patients with dementia and investigate possible time and treatment trends. Methods: A national longitudinal cohort study 2007–2017 using Swedish national registries. We compared 12,629 ischemic stroke events in patients with dementia with matched 57,954 stroke events in non-dementia controls in different aspects of patient care and mortality. Relationship between dementia status and dementia type (Alzheimer’s disease and mixed dementia, vascular dementia, other dementias) and death was analyzed using Cox regressions. Results: Differences in receiving intravenous thrombolysis between patients with and without dementia disappeared after the year 2015 (administered to 11.1% dementia versus 12.3% non-dementia patients, p=0.117). One year after stroke, nearly 50% dementia and 30% non-dementia patients had died. After adjustment for demographics, mobility, nursing home placement, and comorbidity index, dementia was an independent predictor of death compared with non-dementia patients (HR 1.26 [1.23–1.29]). Conclusion: Dementia before ischemic stroke is an independent predictor of death. Over time, early and delayed mortality in patients with dementia remained increased, regardless of dementia type. Patients with ≤80 years with prior Alzheimer’s disease or mixed dementia had higher mortality rates after stroke compared to patients with prior vascular dementia.

Won Jun Kim, Jung Hyun Noh, Kyungdo Han, Cheol-Young Park
The Association Between Second-Line Oral Antihyperglycemic Medication on Types of Dementia in Type 2 Diabetes: A Nationwide Real-World Longitudinal Study
Abstract: Background: There are few reports that evaluated the association between various types of dementia and dual oral therapy with antihyperglycemic medication. Objective: The goal of this study was to investigate the association between treatment of dual antihyperglycemic medication and dementia subclass in type 2 diabetes mellitus using the Korean National Health Insurance System. Methods: This study included 701,193 individuals with diabetes prescribed dual oral therapy between 2009 and 2012 from the Korean National Health Insurance Service Database, which were tracked until 2017. All-cause, Alzheimer’s (AD) and vascular dementia (VaD) were investigated by dual oral therapy. Adjustments were made for age, sex, income, diabetes duration, hypertension, dyslipidemia, smoking, drinking, exercise, body mass index, glucose level, and estimated glomerular filtration rate. Results: Dual therapy with metformin (Met) + dipeptidyl peptidase-4 inhibitor (DPP-4i), Met + thiazolidinedione (TZD), and sulfonylurea (SU) + thiazolidinediones (TZD) were significantly associated with all-cause dementia (HR = 0.904, 0.804, and 0.962, respectively) and VaD (HR = 0.865, 0.725, and 0.911, respectively), compared with Met + SU. Met + DPP-4i and Met + TZD were associated with significantly lower risk of AD (HR = 0.922 and 0.812), compared with Met + SU. Dual therapy with TZD was associated with a significantly lower risk of all-cause dementia, AD, and VaD than nonusers of TZD (HR = 0.918, 0.925 and 0.859, respectively). Conclusion: Adding TZD or DPP-4i instead of SU as second-line anti-diabetic treatment may be considered for delaying or preventing dementia. Also, TZD users relative to TZD non-users on dual oral therapy were significantly associated with lower risk of various types of dementia.

Jose M. Farfel, Lisa L. Barnes, Ana Capuano, Maria Carolina de Moraes Sampaio, Robert S. Wilson, David A. Bennett
Informant-Reported Discrimination, Dementia, and Cognitive Impairment in Older Brazilians
Abstract: Background: Self-reported discrimination is a source of psychosocial stress that has been previously associated with poor cognitive function in older African Americans without dementia. Objective: Here, we examine the association of discrimination with dementia and cognitive impairment in racially diverse older Brazilians. Methods: We included 899 participants 65 years or older (34.3% Black) from the Pathology, Alzheimer’s and Related Dementias Study (PARDoS), a community-based study of aging and dementia. A structured interview with informants of the deceased was conducted. The interview included the Clinical Dementia Rating (CDR) Scale for the diagnosis of dementia and cognitive impairment proximate to death and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) as a second measure of cognitive impairment. Informant-reported discrimination was assessed using modified items from the Major and Everyday Discrimination Scales. Results: Discrimination was reported by informants of 182 (20.2%) decedents and was more likely reported by informants of Blacks than Whites (25.3% versus 17.6%, p=0.006). Using the CDR, a higher level of informant-reported discrimination was associated with higher odds of dementia (OR: 1.24, 95%CI 1.08 – 1.42, p=0.002) and cognitive impairment (OR: 1.21, 95%CI: 1.06 – 1.39, p=0.004). Similar results were observed using the IQCODE (estimate: 0.07, SE: 0.02, p=0.003). The effects were independent of race, sex, education, socioeconomic status, major depression, neuroticism, or comorbidities. Conclusion: Higher level of informant-reported discrimination was associated with higher odds of dementia and cognitive impairment in racially diverse older Brazilians.

Daniela Smirni, Massimiliano Oliveri, Eliana Misuraca, Angela Catania, Laura Vernuccio, Valentina Picciolo, Flora Inzerillo, Mario Barbagallo, Lisa Cipolotti, Patrizia Turriziani
Verbal Fluency in Mild Alzheimer’s Disease: Transcranial Direct Current Stimulation over the Dorsolateral Prefrontal Cortex
Abstract: Background: Recent studies showed that in healthy controls and in aphasic patients, inhibitory trains of repetitive transcranial magnetic stimulation (rTMS) over the right prefrontal cortex can improve phonemic fluency performance, while anodal transcranial direct current stimulation (tDCS) over the left prefrontal cortex can improve performance in naming and semantic fluency tasks. Objective: This study aimed at investigating the effects of cathodal tDCS over the left or the right dorsolateral prefrontal cortex (DLPFC) on verbal fluency tasks (VFT) in patients with mild Alzheimer’s disease (AD). Methods: Forty mild AD patients participated in the study (mean age 73.17 ± 5.61 years). All participants underwent cognitive baseline tasks and a VFT twice. Twenty patients randomly received cathodal tDCS to the left or the right DLPFC, and twenty patients were assigned to a control group in which only the two measures of VFT were taken, without the administration of the tDCS. Results: A significant improvement of performance on the VFT in AD patients was present after tDCS over the right DLPFC (p=0.001). Instead, no difference was detected between the two VFTs sessions after tDCS over the left DLPFC (p=0.42). Furthermore, these results cannot be related to task learning effects, since no significant difference was found between the two VFT sessions in the control group (p=0.73). Conclusion: These data suggest that tDCS over DLPFC can improve VFT performance in AD patients. A hypothesis is that tDCS enhances adaptive patterns of brain activity between functionally connected areas.

Yajie Lin*, Qingze Zeng*, MengJie Hu, Guoping Peng, Benyan Luo, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Temporal Dynamic Changes of Intrinsic Brain Activity Associated with Cognitive Reserve in Prodromal Alzheimer’s Disease
Abstract: Background: Cognitive reserve (CR) is an important protective factor for Alzheimer’s disease (AD), yet its mechanism has not been fully elucidated. Objective: To explore the effect of CR on resting and dynamic brain intrinsic activity in patients with mild cognitive impairment (MCI). Methods: 65 amyloid-β PET-negative (Aβ-) normal controls (NC) and 30 amyloid-β PET-positive (Aβ+) MCI patients underwent resting-state functional magnetic resonance imaging were included from Alzheimer's Disease Neuroimaging Initiative. According to the years of education, the subjects were divided into high education group and low education group. A two-way analysis of variance was employed for the fractional amplitude of low-frequency fluctuation (fALFF) and dynamic fALFF (dfALFF) comparisons among the four groups. Moreover, the interaction effect of neuroimaging × pathology on clinical cognitive function was tested with linear regression analysis. Results: The value of fALFF in the left prefrontal lobe was increased in Aβ+ MCI patients compared to Aβ- NC. The significant interactive effect between disease state and education (binary factor) was observed in the right parahippocampal gyrus (PHG) for fALFF, the right PHG and the right inferior parietal lobule for dfALFF. While no significant results between education (continuous factor) and brain activity was found in voxel-by-voxel analysis. For MCI patients, a significant fluorodeoxyglucose hypometabolic convergence index × right PHG dfALFF interaction was found, indicating the maintenance of executive function at higher levels of dfALFF in the right PHG. Conclusion: High CR can alleviate the impairment of hypometabolism on executive function in MCI patients, which is partially achieved by regulating the dynamic brain activity in the right PHG.

Fabricio Ferreira de Oliveira, Marjorie Câmara Miraldo, Eduardo Ferreira de Castro-Neto, Sandro Soares de Almeida, Sandro Luiz de Andrade Matas, Paulo Henrique Ferreira Bertolucci, Maria da Graça Naffah-Mazzacoratti
Associations of Neuropsychiatric Features with Cerebrospinal Fluid Biomarkers of Amyloidogenesis and Neurodegeneration in Dementia with Lewy Bodies Compared with Alzheimer’s Disease and Cognitively Healthy People
Abstract: Background: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases. Objective: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer’s disease (AD) and cognitively healthy people. Methods: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-β (Aβ)42, Aβ40, Aβ38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOE ε4 carrier status. Results: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOE ε4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOE ε4 carriers) and 27 controls (78.48±8.7 years old, four APOE ε4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOE ε4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis. Conclusion: Biomarker ratios were superior to Aβ and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOE ε4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.

Martina Wiwie S. Nasrun, Profitasari Kusumaningrum, Petrin Redayani, Hasya Layalia Lahino, Fithriani Salma Mardhiyah, Amadeo D. Basfiansa, Nindya Nadila
Relationship Between Quality of Life of People with Dementia and Their Caregivers in Indonesia
Abstract: Background: Caregivers, as one of the most important roles in caring for a person with dementia, have a challenging task. Therefore, maintaining the quality of life (QoL) of caregivers is an integral part of dementia care. Objective: To explore the relationship between the QoL of people with dementia and their caregivers in Indonesia. Methods: This is a cross-sectional study using binary correlations to analyze the relationship between people with dementia and caregivers’ QoL. Conducted in Cipto Mangunkusumo Hospital in Jakarta, the subjects were 42 people diagnosed with dementia according to the PPDGJ-III (adapted from the ICD 10) and 42 primary caregivers with at least 6 hours duration of caregiving per day. The QoL of people with dementia was measured by EuroQol-5D and VAS EQ-5D, while severity of dementia was measured by MMSE. Caregivers underwent an interview using WHO Quality of Life Instrument (WHOQOL-BREF) and NPI. Results: Most caregivers were women, aged 40–70 years old. The study found caregivers’ QoL environmental domain strongly correlated with people with dementia’s QoL (r = 0.839). Severity of dementia had a strong correlation with caregivers’ QoL physical domain (r = 0.946). Age, duration of caregiving per day, period of care provided by caregivers, and caregiver’s distress had a strong correlation with caregiver QoL for specific domains. Conclusion: There was a strong correlation between people with dementia’s QoL and caregiver QoL, so in managing dementia, clinicians should consider caregivers’ wellbeing as an essential part significantly affecting the quality of elderly care improvement.

Elodie Bertrand, Eelco van Duinkerken, Jerson Laks, Marcia Cristina Nascimento Dourado, Gabriel Bernardes, Jesus Landeira-Fernandez, Daniel C. Mograbi
Structural Gray and White Matter Correlates of Awareness in Alzheimer’s Disease
Abstract: Background: Unawareness of disease is a common feature of Alzheimer’s disease (AD), but few studies explored its neural correlates. Additionally, neural correlates according to the object of awareness are unexplored. Objective: To investigate structural brain correlates in relation to different objects of awareness. Methods: 27 people with AD underwent MRI scanning on a 3T Siemens Prisma. T1-MPRAGE was used to investigate cortical thickness and white matter microstructure was defined by DTI as fractional anisotropy, mean, axial, and radial diffusivity. Preprocessing used FreeSurfer6.0, ExploreDTI, and FSL-TBSS. Awareness of disease, cognitive deficits, emotional state, relationships, and functional capacity were assessed with the short version of the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia. Voxel-wise correlations between brain structure and awareness were determined by FSL-PALM. Analyses were corrected for multiple comparisons using Threshold Free Cluster Enhancement and FWE. Results: Lower left hemisphere cortical thickness was related to poorer disease awareness uncorrected and corrected for age, sex, and MMSE. In the uncorrected model, mainly right-sided, but also left temporal lower cortical thickness was related to decreased awareness of cognitive deficits. Correcting for age, sex, and MMSE eliminated correlations for the right hemisphere, but extensive correlations in the left hemisphere remained. For white matter integrity, higher right hemisphere MD was related to lower cognitive awareness deficits, and lower FA was related to lower functional capacity awareness. Conclusion: Findings suggest that extensive regions of the brain are linked to self-awareness, with particular frontal and temporal alterations leading to unawareness, in agreement with theoretical models indicating executive and mnemonic forms of anosognosia in AD.

Ya-Yu Wang*, Yi-Jun Ge*, Chen-Chen Tan, Xi-Peng Cao, Lan Tan, Wei Xu *These authors contributed equally to this work.
The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers
Abstract: Background: The apolipoprotein E epsilon 4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Its carriage percentage in non-demented population varies across geographic regions and ethnic groups. Objective: To estimate the proportion of APOE4 (2/4, 3/4, or 4/4) carriers in non-demented community-dwellers. Methods: PubMed, EMBASE, and China National Knowledge Infrastructure were searched from inception to April 20, 2020. Community-based studies that reported APOE polymorphisms with a sample of ≥500 non-demented participants were included. Random-effects models were used to pool the results. Meta-regression and subgroup analyses were performed to test the source of heterogeneity and stratified effects. Age-standardized pooled proportion estimates (ASPPE) were calculated by direct standardization method. Results: A total of 121 studies were included, with a pooled sample of ~389,000 community-dwellers from 38 countries. The global average proportion of APOE4 carriers was 23.9% (age-standardized proportion: 26.3%; 2.1% for APOE4/4, 20.6% for APOE3/4 and 2.3% for APOE2/4), and varied significantly with geographical regions (from 19.3% to 30.0%) and ethnic groups (from 19.1% to 37.5%). The proportion was highest in Africa, followed by Europe, North America, Oceania, and lowest in South America and Asia (p < 0.0001). With respect to ethnicity, it was highest in Africans, followed by Caucasians, and was lowest in Hispanics/Latinos and Chinese (p < 0.0001). Conclusion: APOE4 carriers are common in communities, especially in Africans and Caucasians. Developing precision medicine strategies in this specific high-risk population is highly warranted in the future.