Volume 82, Number 3, IN PRESS

Review
Sofia Toniolo, Marta Scarioni, Francesco Di Lorenzo, Jakub Hort, Jean Georges, Svetlana Tomic, Flavio Nobili, Kristian Steen Frederiksen, the Management Group of the EAN Dementia and Cognitive Disorders Scientific Panel (Handling Associate Editor: Laura Bonanni)
Dementia and COVID-19, a Bidirectional Liaison: Risk Factors, Biomarkers, and Optimal Health Care
Abstract: Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.

Short Communication
Marie-Laure Ancelin, Joanna Norton, Jacqueline Scali, Karen Ritchie, Isabelle Chaudieu, Joanne Ryan
A Prospective Study of Diurnal Cortisol and Incident Dementia in Community-Dwelling Older Adults
Abstract: Diurnal salivary cortisol was measured in 334 older adults without dementia, at four times on two separate days, under quiet and stressful conditions. In multivariate Cox proportional hazard models, higher global diurnal cortisol secretion was associated with incident dementia (HR=1.09 [1.02-1.15] per one-unit increase in cortisol measure, p=0.007) and Alzheimer’s disease (HR=1.12 [1.04-1.21], p=0.003) over a mean(SD) of 8.1(4.0) years, independent of potential confounders and stressful conditions. Individuals with incident dementia had a slower rate of cortisol elimination under non-stressful conditions, reflected by higher cortisol levels in the evening, and an abnormal response to stress (blunted evening stress response).

Short Communication
Bárbara Luzia Covatti Malcorra, Natália Bezerra Mota, Janaina Weissheimer, Lucas Porcello Schilling, Maximiliano Agustin Wilson, Lilian Cristine Hübner (Handling Associate Editor: Paulo Carameli)
Low Speech Connectedness in Alzheimer’s Disease Is Associated with Poorer Semantic Memory Performance
Abstract: Connected speech is an everyday activity. We aimed to investigate whether connected speech can differentiate oral narrative production between adults with Alzheimer’s disease (AD; n = 24) and cognitively healthy older adults (n = 48). We used graph attributes analysis to represent connected speech. Participants produced oral narratives and performed semantic, episodic, and working memory tasks. AD patients produced less connected narratives than cognitively healthy older adults. Connectedness was associated with semantic memory in AD and with episodic memory in controls. Word-graphs connectedness represents a practical tool to assess cognitive impairment in AD patients.

Short Communication
Andrea Pilotto*, Alberto Imarisio*, Claudia Carrarini, Mirella Russo, Stefano Masciocchi, Stefano Gipponi, Elisabetta Cottini, Dag Aarsland, Henrik Zetterberg, Nicholas J. Ashton, Abdul Hye, Laura Bonanni, Alessandro Padovani *These authors contributed equally to this work.
Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies
Abstract: Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

X. Richard Chen, Yongzhao Shao, Martin J. Sadowski for the Alzheimer’s Disease Neuroimaging Initiative
Segmented Linear Mixed Model Analysis Reveals Association of the APOE ε4 Allele with Faster Rate of Alzheimer’s Disease Dementia Progression
Abstract: Background: APOE ε4 allele carriers present with increased risk for late-onset Alzheimer’s disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ε4 allele controls the rate of disease progression. Objective: To determine effects of the ε4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. Methods: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ε3/ε3, 99 ε3/ε4, and 39 ε4/ε4 Alzheimer’s Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. Results: ε4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ε4 allele-dose effects after dementia transition but not during MCI. The ε4 effect was more prevalent in younger participants and in females. ε4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. Conclusion: Possession of the ε4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.

Gregorio González-Alcaide*, Mercedes Fernández-Ríos*, Rosa Redolat, Emilia Serra *These authors contributed equally to this work.
Research on Emotion Recognition and Dementias: Foundations and Prospects
Abstract: Background: The study of emotion recognition could be crucial for detecting alterations in certain cognitive areas or as an early sign of neurological disorders. Objective: The main objective of the study is to characterize research development on emotion recognition, identifying the intellectual structure that supports this area of knowledge, and the main lines of research attracting investigators’ interest. Methods: We identified publications on emotion recognition and dementia included in the Web of Science Core Collection, analyzing the scientific output and main disciplines involved in generating knowledge in the area. A co-citation analysis and an analysis of the bibliographic coupling between the retrieved documents elucidated the thematic orientations of the research and the reference works that constitute the foundation for development in the field. Results: A total of 345 documents, with 24,282 bibliographic references between them, were included. This is an emerging research area, attracting the interest of investigators in Neurosciences, Psychology, Clinical Neurology, and Psychiatry, among other disciplines. Four prominent topic areas were identified, linked to frontotemporal dementia, autism spectrum disorders, Alzheimer’s disease, and Parkinson’s and Huntington disease. Many recent papers focus on the detection of mild cognitive impairment. Conclusion: Impaired emotion recognition may be a key sign facilitating the diagnosis and early treatment of different neurodegenerative diseases as well as for triggering the necessary provision of social and family support, explaining the growing research interest in this area.

Nicolas Darmanthé, Hossein Tabatabaei-Jafari, Nicolas Cherbuin for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Khalid Iqbal)
Combination of Plasma Neurofilament Light Chain and Mini-Mental State Examination Score Predicts Progression from Mild Cognitive Impairment to Alzheimer’s Disease within 5 Years
Abstract: Background: Individuals with mild cognitive impairment (MCI) are at high risk of progression to Alzheimer’s disease (AD) dementia, but some remain stable. There is a need to identify those at higher risk of progression to improve patient management and outcomes. Objective: To evaluate the trajectory of plasma neurofilament light chain (pNFL) prior to progression from MCI to AD dementia, the performance of pNFL, in combination with the Mini-Mental State Examination (MMSE), as a predictor of progression from MCI to AD dementia and to inform clinicians on the use of pNFL as a predictive biomarker. Methods: Participants (n=440) with MCI and longitudinal follow-up (mean = 4.2 years) from the AD Neuroimaging Initiative dataset were included. pNFL as a marker for neurodegeneration and the MMSE as a cognitive measure were investigated as simple/practical predictors of progression. The risk of progressing from MCI to AD dementia associated with pNFL and MMSE scores was assessed using Cox and logistic regression models. Results: The current risk of progression to AD dementia was 37% higher in individuals with high pNFL (>56 ng/L) compared to those with average pNFL (≤40 ng/L). A combination of baseline pNFL and MMSE could differentiate those who progressed within 5 years (AUC = 0.75) from stable individuals. Including change in MMSE over 6-12 months further improved the model (AUC = 0.84). Conclusion: Our findings reveal that combining pNFL with a simple dementia screener (MMSE) can reliably predict whether a person with MCI is likely to progress to AD dementia within 5 years.

Marte Kvello-Alme, Geir Bråthen, Linda R. White, Sigrid Botne Sando (Handling Associate Editor: David Knopman)
Time to Diagnosis in Young Onset Alzheimer’s Disease: A Population-Based Study from Central Norway
Abstract: Background: Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer’s disease is associated with a substantial diagnostic delay in patients < 65 years. Objective: To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer’s disease in central Norway. Methods: The main sources of patients were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone. Results: Time from first symptom to diagnosis in typical young onset Alzheimer’s disease was 5.5 years (n = 223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months ( SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9). Conclusion: Typical Alzheimer’s disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer’s disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process.

Yosuke Yamada, Hiroyuki Umegaki, Fumie Kinoshita, Chi Hsien Huang, Taiki Sugimoto, Chisato Fujisawa, Hitoshi Komiya, Kazuhisa Watanabe, Masaaki Nagae, Masafumi Kuzuya, Takashi Sakurai (Handling Associate Editor: Miguel Borda)
Cross-Sectional Examination of Homocysteine Levels with Sarcopenia and Its Components in Memory Clinic Outpatients
Abstract: Background: Homocysteine is a common risk factor for cognitive impairment and sarcopenia. However, very few studies have shown an association between sarcopenia and serum homocysteine levels after adjustment for cognitive function. Objective: The purpose of this study was to investigate the relationship between homocysteine and sarcopenia in memory clinic patients. Methods: This cross-sectional study investigated outpatients in a memory clinic. We enrolled 1,774 participants (≥65 years old) with measured skeletal muscle mass index (SMI), hand grip strength (HGS), and homocysteine. All participants had undergone cognitive assessments and were diagnosed with dementia, mild cognitive impairment, or normal cognition. Patient characteristics were compared according to sarcopenia presence, SMI level, or HGS. Multivariate logistic regression analysis was performed to determine the association of homocysteine with sarcopenia, low SMI, or low HGS. Next, linear regression analysis was performed using HGS as a continuous variable. Results: Logistic regression analysis showed that low HGS was significantly associated with homocysteine levels (p = 0.002), but sarcopenia and low SMI were not. In linear regression analysis, HGS was negatively associated with homocysteine levels after adjustment for Mini-Mental State Examination score (β = −2.790, p < 0.001) or clinical diagnosis of dementia (β = −3.145, p < 0.001). These results were similar for men and women. Conclusion: Our results showed a negative association between homocysteine and HGS after adjustment for cognitive function. Our findings strengthen the assumed association between homocysteine and HGS. Further research is needed to determine whether lower homocysteine levels lead to prevent muscle weakness.

Laura Serra, Marcello D’Amelio, Sharon Esposito, Carlotta Di Domenico, Giacomo Koch, Camillo Marra, Nicola Biagio Mercuri, Carlo Caltagirone, Carlo Alberto Artusi, Leonardo Lopiano, Mara Cercignani, Marco Bozzali
Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment
Abstract: Background: Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective: In this study, we longitudinally investigated by resting-state fMRI (RS-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods: a cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and RS-fMRI to assess VTA connectivity at baseline and at follow-up. Results: At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-converters compared to non-converters remained substantially unchanged at 24-month follow-up. Conclusion: This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression.

Elena Tsoy, Alissa Bernstein Sideman, Stefanie D. Piña Escudero, Maritza Pintado-Caipa, Suchanan Kanjanapong, Tala Al-Rousan, Lingani Mbakile-Mahlanza, Maira Okada de Oliveira, Myriam De la Cruz Puebla, Stelios Zygouris, Aya Ashour Mohamed, Hany Ibrahim, Collette A. Goode, Bruce L. Miller, Victor Valcour, Katherine L. Possin
Global Perspectives on Brief Cognitive Assessments for Dementia Diagnosis
Abstract:Background: Timely diagnosis of dementia is a global healthcare priority, particularly in low to middle income countries where rapid increases in older adult populations are expected. Objective: To investigate global perspectives on the role of brief cognitive assessments (BCAs) in dementia diagnosis, strengths and limitations of existing measures, and future directions and needs. Methods: This is a qualitative study of 18 dementia experts from different areas of the world. Participants were selected using purposeful sampling based on the following criteria: 1) practicing in countries with projected growth of older adult population of over 100% by 2050; 2) expertise in dementia diagnosis and treatment; 3) involvement in clinical practice and training; and 4) recognition as a national dementia expert based on leadership positions within healthcare system, research, and/or policy work. Participants were individually interviewed in their language of choice over secure videoconference sessions. Interviews were analyzed by a multidisciplinary team using theme identification approach. Results: Four domains with subthemes emerged illustrating participants’ perspectives: 1) strengths of BCAs; 2) limitations of BCAs; 3) needs related to the use of BCAs; and 4) characteristics of an ideal BCA. While most experts agreed that BCAs were important and useful for dementia diagnosis, the themes emphasized the need for development and validation of novel measures that are sensitive, psychometrically sound, and culturally appropriate. Conclusion: BCAs are important for guiding diagnosis and care for dementia patients. Findings provide a roadmap for novel BCA development to assist in diagnostic decision making for clinicians serving a rapidly growing and diverse dementia population.

Junyeon Won, Daniel D. Callow, Gabriel S. Pena, Leslie S. Jordan, Naomi A. Arnold-Nedimala, Kristy A. Nielson, J. Carson Smith
Hippocampal Functional Connectivity and Memory Performance After Exercise Intervention in Older Adults with Mild Cognitive Impairment
Abstract: Background: Exercise training (ET) has neuroprotective effects in the hippocampus, a key brain region for memory that is vulnerable to age-related dysfunction. Objective: We investigated the effects of ET on functional connectivity (FC) of the hippocampus in older adults with mild cognitive impairment (MCI) and a cognitively normal (CN) control group. We also assessed whether the ET-induced changes in hippocampal FC (Δhippocampal-FC) are associated with changes in memory task performance (Δmemory performance). Methods: 32 older adults (77.0±7.6 years; 16 MCI and 16 CN) participated in the present study. Cardiorespiratory fitness tests, memory tasks (Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory Test (LM)), and resting-state fMRI were administered before and after a 12-week walking ET intervention. We utilized a seed-based correlation analysis using the bilateral anterior and posterior hippocampi as priori seed regions of interest. The associations of residualized ET-induced Δhippocampal-FC and Δmemory performance were assessed using linear regression. Results: There were significant improvements in RAVLT Trial 1 and LM test performance after ET across participants. At baseline, MCI, compared to CN, demonstrated significantly lower posterior hippocampal FC. ET was associated with increased hippocampal FC across groups. Greater ET-related anterior and posterior hippocampal FC with right posterior cingulate were associated with improved LM recognition performance in MCI participants. Conclusion: Our findings indicate that hippocampal FC is significantly increased following 12-weeks of ET in older adults and, moreover, suggest that increased hippocampal FC may reflect neural network plasticity associated with ET-related improvements in memory performance in individuals diagnosed with MCI.

Gerardo Fernández, Mario A. Parra
Oculomotor Behaviors and Integrative Memory Functions in the Alzheimer’s Clinical Syndrome
Abstract: Background: Biological information drawn from eye-tracking metrics is providing evidence regarding drivers of cognitive decline in Alzheimer’s disease. In particular, pupil size has proved useful to investigate cognitive performance during online activities. Objective: To investigate the oculomotor correlates of impaired performance of patients with mild Alzheimer’s Clinical Syndrome (ACS) on a recently developed memory paradigm, namely the Short-Term Memory Binding Test (STMBT). Methods: We assessed a sample of eighteen healthy controls (HC) and eighteen patients with a diagnosis of mild ACS with the STMBT while we recorded their oculomotor behaviors using pupillometry and eye-tracking. Results: As expected, a group (healthy controls versus ACS) by condition (Unbound Colours versus Bound Colours) interaction was found whereby behavioral group differences were paramount in the Bound Colours condition. Healthy controls’ pupils dilated significantly more in the Bound Colours than in the Unbound Colours condition, a discrepancy not observed in ACS patients. Furthermore, ROC analysis revealed the abnormal pupil behaviors distinguished ACS patients from healthy controls with values of sensitivity and specify of 100%, thus outperforming both recognition scores and gaze duration. Conclusion: The biological correlates of Short-Term Memory Binding impairments appear to involve a network much wider than we have thought to date, which expands across cortical and subcortical structures. We discuss these findings focusing on their implications for our understanding of neurocognitive phenotypes in the preclinical stages of Alzheimer’s disease and potential development of cognitive biomarkers that can support ongoing initiatives to prevent dementia.

Zuo-Teng Wang*, Kun-Yan Li*, Chen-Chen Tan, Wei Xu, Xue-Ning Shen, Xi-Peng Cao, Ping Wang, Yan-Lin Bi, Qiang Dong, Lan Tan, Jin-Tai Yu *These authors contributed equally to this work.
Associations of Alcohol Consumption with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE Study
Abstract: Background: The relationship between alcohol consumption and Alzheimer's disease (AD) pathology is unclear. Amyloid-β (Aβ) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD. Objective: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects. Methods: A total of 806 cognitively intact participants who had measurements of CSF Aβ, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE) ε4 status on the relationships between the frequency of drinking and CSF biomarkers. Results: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (65 years) participants. Conclusion: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage.

Mingyue Qu, Hanxu Shi, Kai Wang, Xinggang Wang, Nan Yu, Baoshi Guo
The Associations of Plasma/Serum Carotenoids with Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD. Objective: Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots and Egger’s test. Results: Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = -0.86, 95% CI: -1.67 to -0.05, p=0.04) and zeaxanthin (SMD = -0.59; 95% CI: -1.12 to -0.06, p=0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95% CI: -0.68 to 0.26, p=0.39), β-carotene (SMD = 0.04, 95% CI: -0.57 to 0.65, p=0.9), lycopene (SMD = -0.12, 95% CI: -0.96 to 0.72, p=0.78), and β-cryptoxanthin (SMD = -0.09, 95% CI: -0.83 to 0.65, p=0.81) did not achieve significant differences. Conclusion: Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings.

Mychael V. Lourenco, Felipe C. Ribeiro, Luis E. Santos, Danielle Beckman, Helen M. Melo, Felipe K. Sudo, Cláudia Drummond, Naima Assunção, Bart Vanderborght, Fernanda Tovar-Moll, Fernanda G. De Felice, Paulo Mattos, Sergio T. Ferreira (Handling Associate Editor: Ricardo Maccioni)
Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer’s and Lewy Body Diseases
Abstract: Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusion: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Myrto Samara, Stephen Z. Levine, Kazufumi Yoshida, Yair Goldberg, Andrea Cipriani, Orestis Efthimiou, Takeshi Iwatsubo, Stefan Leucht, Toshiaki A. Furakawa
Linking the Clinical Dementia Rating Scale-Sum of Boxes, the Clinician’s Interview-Based Impression Plus Caregiver Input, and the Clinical Global Impression Scale: Evidence based on Individual Participant Data from Five Randomized Clinical Trials of Donepezil
Abstract: Background: In patients with Alzheimer’s disease, global assessment scales, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Clinician’s Interview-Based Impression Plus Caregiver Input (CIBI plus), and the Clinical Global Impression (CGI) are commonly used. Objective: To clinically understand and interpret the associations between these scales, we examined the linkages for the total and change scores of CDR-SB, CIBI plus, and CGI. Methods: Individual participant data (N= 2,198) from five pivotal randomized placebo-controlled trials of donepezil were included. Data were collected at baseline and scheduled visits for up to 6 months. Spearman’s correlation coefficients ρ were examined between corresponding total and change scores of simultaneous CDR-SB, CIBI plus, and CGI ratings. To link between the simultaneous ratings, equipercentile linking was used. Results: We found strong evidence that the Spearman’s correlation coefficients between the CDR-SB and CGI, and CDR-SB and CIBI plus total scores were at least adequately correlated (ρ=0.50 to 0.71, with p<0.01). The correlation coefficients between the change scores of CDR-SB and CGI were deemed adequate for weeks 6 to 24 (ρ=0.44 to 0.65); the remaining correlations were smaller in magnitude (ρ=0.09 to 0.35). Overall, the linkages were in-line with expectations, e.g., CDR-SB range score of 3-4 (=very mild dementia) was linked to a CGI score of 3 (=mildly ill), and an increase of CDR-SB of 1 was linked to a change of 5 (=minimal worsening) in both CGI and CIBI plus. Conclusion: The study findings can be useful for clinicians wishing to compare scores of different scales across patients. They can also help researchers understand results of studies using different scales and can facilitate meta-analyses, to increase statistical power.

Claudio Babiloni, Raffaele Ferri, Giuseppe Noce, Roberta Lizio, Susanna Lopez, Ivan Lorenzo, Federico Tucci, Andrea Soricelli, Flavio Nobili, Dario Arnaldi, Francesco Famà, Francesco Orzi, Carla Buttinelli, Franco Giubilei, Virginia Cipollini, Moira Marizzoni, Bahar Güntekin, Tuba Aktürk, Lutfu Hanoğlu, Görsev Yener, Yağmur Özbek, Fabrizio Stocchi, Laura Vacca, Giovanni B. Frisoni, Claudio Del Percio
Resting State Alpha Electroencephalographic Rhythms Are Differently Related to Aging in Cognitively Unimpaired Seniors and Patients with Alzheimer’s Disease and Amnesic Mild Cognitive Impairment
Abstract: Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8-13 Hz). Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8-12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI). Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands, as well as fixed beta (14-30 Hz) and gamma (30-40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles). Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores. Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD.

Kazuhisa Watanabe, Hiroyuki Umegaki, Taiki Sugimoto, Chisato Fujisawa, Hitoshi Komiya, Masaaki Nagae, Yosuke Yamada, Masafumi Kuzuya, Takashi Sakurai (Handling Associate Editor: Lucy Stirland)
Associations Between Polypharmacy and Gait Speed According to Cognitive Impairment Status: Cross-Sectional Study in a Japanese Memory Clinic
Abstract: Background: Polypharmacy, usually defined as the use of 5 or more drugs, is associated with reduced quality of life, adverse events, and frailty. Slow gait speed is a component of physical frailty, and some studies have suggested an association between polypharmacy and slow gait speed. Objective: We aimed to determine the effects of polypharmacy on the gait difference according to stages of cognitive decline in a cross-sectional study of memory clinic patients. Methods: Participants were 431 outpatients aged 65 year or older who were cognitively normal (CN) or had mild cognitive impairment (MCI) or Alzheimer's disease. Participants were divided into a polypharmacy group and a non-polypharmacy group in each group. Multiple regression analysis and logistic analysis were used for data analysis. Results: There were 182 patients in the polypharmacy group and 249 patients in the non-polypharmacy group. Multiple regression analysis revealed that gait speed had significant negative associations with number of medications and polypharmacy status in the CN group (β: -0.026 [-0.041 to -0.0018] and -0.128 [-0.022 to -0.0033], respectively) and MCI group (-0.018 [-0.028 to -0.0009] and -0.100 [-0.166 to -0.0034]). Logistic regression analysis also showed that number of medications was associated with slow gait status (

Nathaniel Klooster, Stacey Humphries, Eileen Cardillo, Franziska Hartung, Long Xie, Sandhitsu Das, Paul Yushkevich, Arun Pilania, Jieqiong Wang, David A. Wolk, Anjan Chatterjee (Handling Associate Editor: David Loewenstein)
Sensitive Measures of Cognition in Mild Cognitive Impairment
Abstract: Background: Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer’s disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. Objective: We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. Methods: Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. Results: On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. Conclusion: These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention.

Lianghui Ni, Mingyan Zhao, Zhishan Hu, Kun Yang, Xing Zhao, Haijing Niu, Hua Lin
Neural Mechanism of Shentai Tea Polyphenols on Cognitive Improvements for Individuals with Subjective Cognitive Decline: A Functional Near-Infrared Spectroscopy Study
Abstract: Background: A growing awareness about non-pharmacological intervention for cognitively impaired individuals may represent an alternative therapeutic approach that is actively accepted by patients with very early stage of Alzheimer's disease. Understanding the neural basis of non-pharmacological intervention is a crucial step toward wide use for patients with cognitive disorders. Objective: To investigate the underlying neural mechanism of shentai tea polyphenols in subjects with subjective cognitive decline (SCD) using functional near-infrared spectroscopy (fNIRS). Methods: A total number of 36 patients with SCD participated in the study and received supplementation with shentai tea polyphenols for three months. All participants underwent a series of tests on neuropsychological function and fNIRS assessment during n-back tasks at baseline and follow-up. Results: After intervention with shentai tea polyphenols in SCD, increased cerebral activity was observed in left dorsolateral prefrontal cortex (DLPFC), left premotor cortex (PMC), left primary somatosensory cortex (PSC), right inferior frontal gyrus (IFG), and premotor cortex (PMC). Moreover, shentai tea polyphenols intervention of three months significantly improved SCD subjects' cognitive functions (memory, language, and subjective cognitive ability) and depression condition. We further found that the improvement of HAMD and AVLT-R scores had positive correlations with increased brain activity in right IFG and left DLPFC, respectively. Conclusion: This study provides new evidence that the frontal cortex was found to be specifically activated after non-pharmacological intervention of shentai tea polyphenols in SCD, which may be associated with cognitive enhancement and mental wellbeing. These findings provide important implications for the selection of shentai tea polyphenols interventions for SCD.

Yu-Ling Chang, Yi-Yuan Zhuo, Di-Hua Luo
Education Moderates the Negative Effect of Apolipoprotein E ε4 on Response Inhibition in Older Adults
Abstract: Background: Studies have reported that apolipoprotein E epsilon 4 (APOE ε4) has adverse effects on executive functions (EFs) in late adulthood. However, the results have been inconsistent. Insufficient measurements of executive functioning, uncontrolled clinical and demographic confounders, and moderation effects from other environmental factors are suspected to account for the inconsistency. Objective: This study used aggregate measures to examine the effects of APOE ε4 on four components of EFs, namely switching, working memory, inhibition, and reasoning. We further investigated whether high educational attainment, a proxy measure for cognitive reserve, moderates the adverse effects of ε4 on EFs. Methods: Cognitively unimpaired older participants were divided into groups based on APOE genotype and into subgroups based on educational attainment level. The demographic and clinical variables were matched between the groups. Four core components of the EFs were measured using a relatively comprehensive battery. Results: The results revealed that although no main effect of the APOE genotype was observed across the four EF components, the potentially adverse effects of ε4 on inhibition were alleviated by high educational attainment. A main effect of education on the reasoning component was also observed. The moderation analysis revealed that for older adults with 12 years of education or fewer, the relationship between the APOE ε4 genotype and inhibition performance became increasingly negative. Conclusion: This study highlights the distinctive role of response inhibition in the gene–environment interaction and underlines the importance of considering factors of both nature and nurture to understand the complex process of cognitive aging.

Mingxu Xia*, Ya Su*, Jiayu Fu, Jiajie Xu, Qiong Wang, Feng Gao, Yong Shen, Qiang Dong, Xin Cheng *These authors have contributed equally to this work.
The Use of Serum Matrix Metalloproteinases in Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage and Cognitive Impairment
Abstract: Background: Neuroimaging has played a primary role in predicting intracerebral hemorrhage (ICH) recurrence of cerebral amyloid angiopathy (CAA); however, the utilities of biomarkers in CAA-related ICH and cognitive impairment remain unexplored. Objective: To investigate the correlations of serum levels of matrix metalloproteinase-2 (MMP-2), MMP-3, and MMP-9 with CAA-related MRI markers, ICH recurrence, and cognitive status. Methods: 68 cases with first probable CAA-ICH and 69 controls were recruited. Clinical and imaging data were obtained at baseline and serum MMPs in the acute phase were measured by Luminex multiplex assays. Cognitive status was assessed with the Chinese version of Mini-Mental State Examination within 10-14 days after ICH onset. Results: Serum MMP-2 level was significantly lower in CAA-ICH patients than controls while MMP-9 was significantly higher. In CAA-ICH patients, MMP-3 level was significantly associated with lobar cerebral microbleeds count after adjusting age, sex, and hypertension (adjusted coefficient 0.368, 95% CI 0.099-0.637, p=0.008). During a median follow-up of 2.4 years, higher level of MMP-2 predicted lower CAA-ICH recurrence after adjusting age (adjusted HR 0.326, 95% CI 0.122-0.871, p=0.025), ICH volume (adjusted HR 0.259, 95% CI 0.094-0.715, p=0.009), total MRI burden of SVD score (adjusted HR 0.350, 95% CI 0.131-0.936, p=0.037) respectively. Besides, higher level of MMP-2 was significantly associated with decreased risk of cognitive impairment independent of age and ICH volume (adjusted OR 0.054, 95% CI 0.005-0.570, p=0.015). Conclusion: Serum MMP-2 in acute phase might be a promising biomarker to predict CAA-ICH recurrence and to evaluate the risk of cognitive impairment.

Pamela Herd, Kamil Sicinski, Sanjay Asthana
Does Rural Living in Early Life Increase the Risk for Reduced Cognitive Functioning in Later Life?
Abstract: Background: There is a robust consensus, most recently articulated in the 2020 Lancet Commission, that the roots of dementia can be traced to early life, and that the path to prevention may start there as well. Indeed, a growing body of research demonstrates that early life disadvantage may influence the risk for later life dementia and cognitive decline. A still understudied risk, however, is early life rural residence, a plausible pathway given related economic and educational disadvantages, as well as associations between later life rural living and lower levels of cognitive functioning. Objective: We aim to examine whether living in rural environments during early life has long term implications for cognitive health in later life. Methods: We employed the Wisconsin Longitudinal Study, which tracked 1 in every 3 high school graduates from the class of 1957, from infancy to ~age 72. The data include a rich array of prospectively collected early life data, unique among existing studies, as well as later life measures of cognitive functioning. Results: We found a robust relationship between early life rural residence, especially living on a farm, and long-term risk for reduced cognitive performance on recall and fluency tasks. Controls for adolescent cognitive functioning, APOE ε2 and APOE ε4, as well as childhood and adult factors, ranging from early life socioeconomic conditions to later life health and rural and farm residency, did not alter the findings. Conclusion: Rural living in early life is an independent risk for lower levels of cognitive functioning in later life.

Sara L. Paulo, Leonor Ribeiro-Rodrigues, Rui S. Rodrigues, Joana M. Mateus, João Fonseca-Gomes, Rita Soares, Maria J. Diógenes, Susana Solá, Ana M. Sebastião, Filipa F. Ribeiro, Sara Xapelli
Sustained Hippocampal Neural Plasticity Questions the Reproducibility of an Amyloid-β-Induced Alzheimer’s Disease Model
Abstract: Background: The use of Alzheimer’s disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges. Objective: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42). Methods: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration. Results: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points. Conclusion: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.

Ariana M. Stickel, Wassim Tarraf, Kevin A. Gonzalez, Carmen R. Isasi, Robert Kaplan, Linda C. Gallo, Donglin Zeng, Jianwen Cai, Amber Pirzada, Martha L. Daviglus, Zachary T. Goodman, Neil Schneiderman, Hector M. González (Handling Associate Editor: Lilian Calderón-Garcidueñas)
Central Obesity, Cardiometabolic Risk, and Cognitive Change in the Study of Latinos: Investigation of Neurocognitive Aging
Abstract: Background: The relationships between obesity and cognitive decline in aging are mixed and understudied among Hispanics/Latinos. Objective: To understand associations between central obesity, cognitive aging, and the role of concomitant cardiometabolic abnormalities among Hispanics/Latinos. Methods: Participants included 6,377 diverse Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation for Neurocognitive Aging (SOL-INCA). Participants were 45 years and older at the first cognitive testing session (Visit 1). Cognitive outcomes (z-score units) included global composite and domain specific (learning, memory, executive functioning, processing speed) measures at a second visit (SOL-INCA, on average, 7 years later), and 7-year change. We used survey linear regression to examine associations between central obesity (waist circumference ≥88 cm and ≥102 cm for women and men, respectively) and cognition. We also tested whether the relationships between obesity and cognition differed by cardiometabolic status (indication of/treatment for 2+ of the following: high triglycerides, hypertension, hyperglycemia, low high-density lipoprotein cholesterol). Results: Central obesity was largely unassociated with cognitive outcomes, adjusting for covariates. However, among individuals with central obesity, cardiometabolic abnormality was linked to poorer cognitive function at SOL-INCA (ΔGlobalCognition = -0.165, p<0.001) and to more pronounced cognitive declines over the average 7 years (ΔGlobalCognition = -0.109, p<0.05); this was consistent across cognitive domains. Conclusion: Central obesity alone was not associated with cognitive function. However, presence of both central obesity and cardiometabolic abnormalities was robustly predictive of cognition and 7-year cognitive declines, suggesting that in combination these factors may alter the cognitive trajectories of middle-aged and older Hispanics/Latinos.

Louise A Talbot, Margaret Thomas, Adrian Bauman, Karine E. Manera, Ben J. Smith
Impacts of the National Your Brain Matters Dementia Risk Reduction Campaign in Australia Over 2 Years
Abstract: Background: The number of people living with dementia is rising globally due to population aging. Mass media campaigns which aim to reduce the risk of people developing dementia have been conducted across many countries, but few have reported evaluation findings. Objective: The present study investigated the impact of the Your Brain Matters dementia risk reduction campaign in Australia. Methods: The campaign was evaluated by observational cross-sectional surveys of 1000 Australian adults aged 18-75 years before and 24 months after delivery. The national campaign utilized multiple media channels to promote messages about the importance of brain health and reducing the risk of dementia. Dementia risk reduction knowledge, confidence, intentions and actions were measured at baseline and follow-up, and analyzed 2019-2020. Results: Earned television and radio were the most common exposure channels. The proportion of people who understood that it is beneficial to take action to reduce dementia risk before middle age increased (54.1% to 59.4%, OR 1.20 95% CI: 1.01-1.44). There was also an increase (28.5% to 32.8%, OR 1.30, 95% CI: 1.07-1.59) in the proportion who reported taking action to improve brain health. There was no improvement in knowledge about vascular risk factors, or confidence to reduce personal dementia risk. Conclusion: The findings showed some receptivity and positive responses to messages about the benefits of taking action to reduce the risk of dementia. The campaign demonstrated the potential for generating news coverage about this issue, which should highlight the preventive benefits of vascular health behaviors.

Arturo Xosé Pereiro, Sonia Valladares‐Rodriguez, Alba Felpete, Cristina Lojo‐Seoane, María Campos-Magdaleno, Sabela Carme Mallo, David Facal, Luis Anido-Rifón, Sylvie Belleville, Onésimo Juncos‐Rabadán
Relevance of Complaint Severity in Predicting the Progression of Subjective Cognitive Decline and Mild Cognitive Impairment: A Machine Learning Approach
Abstract: Background: The presence of subjective cognitive complaints (SCCs) is a core criterion for diagnosis of subjective cognitive decline (SCD); however, no standard procedure for distinguishing normative and non-normative SCCs has yet been established. Objective: To determine whether differentiation of participants with SCD according to SCC severity improves the validity of the prediction of progression in SCD and MCI and to explore validity metrics for two extreme thresholds of the distribution in scores in a questionnaire on SCCs. Methods: Two hundred and fifty-three older adults with SCCs participating in the Compostela Aging Study (CompAS) were classified as MCI or SCD at baseline. The participants underwent two follow-up assessments and were classified as cognitively stable or worsened. Severity of SCCs (low and high) in SCD was established by using two different percentiles of the questionnaire score distribution as cut-off points. The validity of these cut-off points for predicting progression using socio-demographic, health, and neuropsychological variables was tested by machine learning (ML) analysis. Results: Severity of SCCs in SCD established considering the 5th percentile as a cut-off point proved to be the best metric for predicting progression. The variables with the main role in conforming the predictive algorithm were those related to memory, cognitive reserve, general health, and the stability of diagnosis over time. Conclusion: Moderate to high complainers showed an increased probability of progression in cognitive decline, suggesting the clinical relevance of standard procedures to determine SCC severity. Our findings highlight the important role of the multimodal ML approach in predicting progression.

Steven D. Targum, Lisa Fosdick, Kristen E. Drake, Paul B. Rosenberg, Anna D. Burke, David A. Wolk, Kelly D. Foote, Wael F. Asaad, Marwan Sabbagh, Gwenn S. Smith, Andres M. Lozano, Constantine G. Lyketsos
Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer’s Disease
Abstract: Background: Age may affect treatment outcome in trials of mild probable Alzheimer’s disease (AD). Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation (“on”) or sham DBS-f (“off”) for 12 months. Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the “on” and “off” groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer’s Disease Assessment Scale; ADAS-cog-13 (p= 0.028). Six of the 12 enrolled participants <65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7% of the 30 participants ≥65 years old regardless of treatment assignment (p = 0.005). While not significant, post-hoc analyses favored DBS-f “off” versus “on” over 12 months in the < 65 age group but favored DBS-f “on” versus “off” in the ≥65 age group on all clinical metrics. On the integrated Alzheimer’s Disease rating scale (iADRS), the effect size contrasting DBS-f “on” versus “off” changed from +0.2 (favoring “off”) in the <65 group to -0.52 (favoring “on”) in the ≥65 age group. Conclusion: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.

Bojlul Bahar, Shalini Kanagasingam, Murtaza M. Tambuwala, Alaa A.A. Aljabali, Stephanie A. Dillon, Saeid Doaei, Richard Welbury, Sasanka S. Chukkapalli, Sim K. Singhrao
Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice
Abstract: Background: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health. Objective: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer's disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Methods: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis. Results: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.

Igor Akushevich, Arseniy P. Yashkin, Julia Kravchenko, Anatoliy I. Yashin
Analysis of Time Trends in Alzheimer’s Disease and Related Dementias Using Partitioning Approach
Abstract: Background: Understanding the dynamics of epidemiologic trends in Alzheimer’s disease (AD) and related dementias (ADRD) and their epidemiologic causes is vital to providing important insights into reducing the burden associated with these conditions. Objective: To model the time trends in age-adjusted AD/ADRD prevalence and incidence-based mortality (IBM), and identify the main causes of the changes in these measures over time in terms of interpretable epidemiologic quantities. Methods: Trend decomposition was applied to a 5% sample of Medicare beneficiaries between 1991 and 2017. Results: Prevalence of AD was increasing between 1992 and 2011 and declining thereafter, while IBM increased over the study period with a significant slowdown in its rate of growth from 2011 onwards. For ADRD, prevalence and IBM increased through 2014 prior to taking a downwards turn. The primary determinant responsible for declines in prevalence and IBM was the deceleration in the increase and eventual decrease in incidence rates though changes in relative survival began to affect the overall trends in prevalence/IBM in a noticeable manner after 2008. Other components showed only minor effects. Conclusion: The prevalence and IBM of ADRD is expected to continue to decrease. The directions of these trends for AD are not clear because AD incidence, the main contributing component, is decreasing but at a decreasing rate suggesting a possible reversal. Furthermore, emerging treatments may contribute through their effects on survival. Improving ascertainment of AD played an important role in trends of AD/ADRD over the 1991-2009/10 period but this effect has exhausted itself by 2017.

Hiroyuki Umegaki, Yusuke Suzuki, Hitoshi Komiya, Kazuhisa Watanabe, Yosuke Yamada, Masaaki Nagae, Masafumi Kuzuya (Handling Associate Editor: David Loewenstein)
Frequencies and Neuropsychological Characteristics of Errors in the Clock Drawing Test
Abstract: Background: Few studies have investigated associations between types of clock drawing test (CDT) errors and cognitive impairment. Objective: To explore associations of qualitative errors in the CDT with comprehensive neurocognitive assessment scores and clinical diagnosis. Methods: Outpatients at a memory clinic were enrolled. Frequencies of errors determined by Cahn’s method were explored according to cognitive status (cognitively normal [CN] (n=279), mild cognitive impairment [MCI] (n=321), and Alzheimer’s disease [AD]) (n=575). Neuropsychological assessment scores were compared between participants with and without errors. Results: Stimulus-bound response (SB) was relatively rare (6.8%) in the CN group but was markedly more common in the MCI (23.4%) and AD (33.2%) groups. Conceptual deficit (CD) was found in more than 20% of CN individuals, as well as about 50% of AD patients. Planning deficit (PD) frequencies were relatively similar among the groups. SB in both of CN and MCI individuals, and CD in both of CN and MCI individuals were associated with lower scores in several neuropsychological assessments. Meanwhile, PD was not associated with lower assessment scores in any of CN, MCI, or AD individuals. Conclusion: The frequencies of SB and CD increased from CN, MCI, to AD but showed somewhat different patterns. Both SB and CD were associated with lower cognition in all three cognitive stages.

Maxime François, Avinash Karpe, Jian-Wei Liu David Beale, Maryam Hor, Jane Hecker, Jeff Faunt, John Maddison, Sally Johns, James Doecke, Stephen Rose, Wayne R. Leifert
Salivaomics as a Potential Tool for Predicting Alzheimer’s Disease During the Early Stages of Neurodegeneration
Abstract: Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. Objective: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. Methods: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted utilizing mass spectrometry methods and data combined using pathway analysis. Results: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups. Conclusion: This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters.

Phansa Phitthayaphong*, Sirinart Kumfu*, Nipon Chattipakorn, Siriporn C. Chattipakorn *These authors contributed equally to this work.
Blockage of Fc Gamma Receptors Alleviates Neuronal and Microglial Toxicity Induced by Palmitic Acid
Abstract: Background: Palmitic acid (PA) promotes brain pathologies including Alzheimer’s disease (AD)-related proteins, neuroinflammation, and microglial activation. The activation of neurons and microglia via their Fc gamma receptors (FcγRs) results in producing inflammatory cytokines. Objective: To investigate the expression of FcγRs, FcγR signaling proteins, AD-related proteins, proinflammatory cytokines, and cell viability of neurons and microglia in association with PA exposure as well as the effects of FcγR blockade on these parameters in response to PA. Methods: 200 and 400 µM PA-conjugated BSA were applied to SH-SY5Y and HMC3 cells for 24 h. For FcγR blockage experiment, both cells were exposed to FcγR blocker before receiving of 200 and 400 µM of PA-conjugated BSA for 24 h. Results: PA significantly increased AD-related proteins, including Aβ and BACE1, as well as increasing TNFα, IL-1β, and IL-6 in SH-SY5Y and HMC3 cells. However, the p-Tau/Tau ratio was only increased in SH-SY5Y cells. These results were associated with an increase in FcγRs activation and a decrease in cell viability in both cell types. FcγRs blockage diminished the activation of FcγR in SH-SY5Y and HMC3 cells. Interestingly, blocking FcγRs before PA exposure reduced the increment of AD-related proteins, proinflammatory cytokines caused by PA. FcγRs blocking also inhibits cell death for 23% of SH-SY5Y cells and 64% of HMC3 cells, respectively. Conclusion: These findings suggest that PA is a risk factor for AD via the increased AD-related pathologies, inflammation, FcγRs activation, and brain cell death, while FcγR blockage can alleviate these effects.

Kenichiro Sato, Tatsuo Mano, Atsushi Iwata, Tatsushi Toda
Safety of Memantine in Combination with Potentially Interactive Drugs in the Real World: A Pharmacovigilance Study Using the Japanese Adverse Drug Event Report (JADER) Database
Abstract: Background: Memantine, an NMDA receptor antagonist, is used for the treatment of Alzheimer’s disease. There is a caution to refrain from administrating memantine in combination with some specific drugs such as amantadine or dextromethorphan due to potential interactions that might augment the adverse effects of memantine. Objective: This notification has not been validated in real-world data, which we aim to address using a large self-reporting database from Japan. Methods: We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database reported between April 2004 and March 2019 for detecting the neuropsychiatric adverse event (AE) signals associated with memantine and other potentially interactive drugs including amantadine, dextromethorphan, cimetidine, ranitidine, procainamide, quinidine, acetazolamide, citrate, and bicarbonate. Drug-drug interactions between memantine and these drugs were assessed using multiplicative and additive models. Results: There was no statistically robust evidence to support multiplicative or additive interactions between memantine and the aforementioned drugs to increase the reporting of any included neuropsychiatric AEs or AE categories. Conclusion: The real-world JADER data did not raise the concern about the interactive increase in the neuropsychiatric AEs in patients with dementia taking memantine in combination with amantadine or dextromethorphan, suggesting there may be no urgent need to prohibit the co-administration of these drugs presently.

Wenwen Zhu, Haoqiang Zhang, Sai Tian, Ke An, Wuyou Cao, Jijing Shi, Shaohua Wang
Elevated Plasma Free Fatty Acid Susceptible to Early Cognitive Impairment in Type 2 Diabetes Mellitus
Abstract: Background: Elevated free fatty acid (FFA) induces lipotoxicity, attributed to diabetes and cognitive decline. Sterol regulatory element-binding protein-1c (SREBP-1c) regulates lipid metabolism. Objective: We investigated the roles of FFA in mild cognitive impairment (MCI) of type 2 diabetes mellitus (T2DM) patients and determine its association with rs11868035 polymorphism. Methods: We recruited 191 Chinese T2DM patients into two groups through Montreal Cognitive Assessment. Demographic and clinical data were collected, multiple domain cognitive functions were tested, plasma FFA levels were measured through ELISA, and SREBP-1c rs11868035 genotype was detected using the Seqnome method. Results: In comparison with the healthy-cognition group (n=128), the MCI group (n=63) displayed lower glucose control (p=0.012) and higher plasma FFA level (p=0.021), which were independent risk factors of MCI in T2DM patients in multivariate regression analysis (OR=1.270, p=0.003; OR=1.005, p=0.036). Additionally, the plasma FFA levels of MCI patients were positively correlated with Stroop color word test-C time scores (r=0.303, p=0.021) and negatively related to apolipoprotein A1 levels (r=−0.311, p=0.017), which are associated positively with verbal fluency test scores (r=0.281, p=0.033). Both scores reflected attention ability and executive function. Moreover, the G allele carriers of rs11868035 showed higher digit span test scores than non-carriers in T2DM patients (p=0.019) but without correlation with plasma FFA levels. Conclusion: In T2DM, elevated plasma level of FFA, when combined with lower apolipoprotein A1 level portends abnormal cholesterol transport, were susceptible to early cognitive impairment, especially for attention and execution deficits. The G allele of SREBP-1c rs11868035 may be a protective factor for memory.

Ling-Zhi Xu*, Fang-Yu Li*, Bing-Qiu Li*, Shu-Man Cao, Yan Li, Jin Xuf Jian-Ping Jia *These authors contributed equally to this work.
Decreased Levels of Insulin-Like Growth Factor-1 Are Associated with Alzheimer’s Disease: A Meta-Analysis
Abstract: Background: Alterations in levels of peripheral insulin-like growth factor-1 (IGF-1) in Alzheimer’s disease (AD) have been reported in several studies, and results are inconsistent. Objective: We conducted a meta-analysis to investigate the relationship between peripheral and cerebrospinal fluid IGF-1 levels and AD or mild cognitive impairment (MCI). Methods: A systematic search in PubMed, Medline, Web of Science, Embase, and Cochrane Library was conducted and 18 studies were included. Results: Results of random-effects meta-analysis showed that there was no significant difference between AD patients and healthy control (17 studies; standard mean difference [SMD], -0.01; 95%CI, -0.35 to 0.32) and between MCI patients and healthy control (6 studies; SMD, -0.20; 95%CI, -0.52 to 0.13) in peripheral IGF-1 levels. Meta-regression analyses identified age difference might explain the heterogeneity (p = 0.017). However, peripheral IGF-1 levels were significantly decreased in AD subjects (9 studies; SMD, -0.44; 95%CI, -0.81 to -0.07) and MCI subjects exhibited a decreasing trend (4 studies; SMD, -0.31; 95%CI, -0.72 to 0.11) in studies with sample size ≥80. Cerebrospinal fluid IGF-1 levels also significantly decreased in AD subjects (3 studies; SMD, -2.40; 95%CI, -4.36 to -0.43). Conclusion: These findings suggest that decreased peripheral and cerebrospinal fluid IGF-1 levels might be a potential marker for the cognitive decline and progression of AD.