Volume 80, Number 4, IN PRESS

Review
Baiwen Zhang, Lan Lin, Shuicai Wu
A Review of Brain Atrophy Subtypes Definition and Analysis for Alzheimer’s Disease Heterogeneity Studies
Abstract:Alzheimer's disease (AD) is a heterogeneous disease with different subtypes. Studying AD subtypes from brain structure, neuropathology, and cognition are of great importance for AD heterogeneity research. Starting from the study of constructing AD subtypes based on the features of T1-weighted structural magnetic resonance imaging, this paper introduces the major connections between the subtype definition and analysis strategies, including brain region-based subtype definition, and their demographic, neuropathological, and neuropsychological characteristics. The advantages and existing problems are analyzed, and reasonable improvement schemes are prospected. Overall, this review offers a more comprehensive view in the field of atrophy subtype in AD, along with their advantages, challenges, and future prospects, and provide a basis for improving individualized AD diagnosis.

Review
Xu-long Ding*, Qing-zhang Tuo*, Peng Lei *These authors have contributed equally to this work.
An Introduction to Ultrasensitive Assays for Plasma Tau Detection
Abstract: The detection of plasma tau and its phosphorylation is technically challenging due to the relatively low sensitivity. However, in Alzheimer’s disease and other tauopathies, it is hypothesized that tau in the biofluid may serve as a biomarker. In recent years, several ultrasensitive assays have been developed, which can successfully detect tau and its phosphorylation in various biofluids, and collectively demonstrated the prognostic and diagnostic value of plasma tau/phosphorylated tau. Here we have summarized the principle of four ultrasensitive assays newly developed suitable for plasma tau detection, namely single-molecule array, immunomagnetic reduction assay, enhanced immunoassay using multi-arrayed fiber optics, and meso scale discovery assay, with their advantages and applications. We have also compared these assays with traditional enzyme-linked-immunosorbent serologic assay, hoping to facilitate future tau-based biomarker discovery for Alzheimer’s disease and other neurodegenerative diseases.

Review
Eduardo Perez-Valero, Miguel A. Lopez-Gordo, Christian Morillas, Francisco Pelayo, Miguel A. Vaquero-Blasco
A Review of Automated Techniques for Assisting the Early Detection of Alzheimer’s Disease with a Focus on EEG
Abstract: In this paper, we review state-of-the-art approaches that apply signal processing (SP) and machine learning (ML) to automate the detection of Alzheimer’s disease (AD) and its prodromal stages. In the first part of the document, we describe the economic and social implications of the disease, traditional diagnosis techniques, and the fundaments of automated AD detection. Then, we present electroencephalography (EEG) as an appropriate alternative for the early detection of AD, owing to its reduced cost, portability, and non-invasiveness. We also describe the main time and frequency domain EEG features that are employed in AD detection. Subsequently, we examine some of the main studies of the last decade that aim to provide an automatic detection of AD and its previous stages by means of SP and ML. In these studies, brain data was acquired using multiple medical techniques such as magnetic resonance imaging, positron emission tomography, and EEG. The main aspects of each approach, namely feature extraction, classification model, validation approach, and performance metrics, are compiled and discussed. Lastly, a set of conclusions and recommendations for future research on AD automatic detection are drawn in the final section of the paper.

Short Communication
Félix Viñuela, Angeles Barro
Assessment of a Potential Synergistic Effect of Souvenaid® in Mild Alzheimer’s Disease Patients on Treatment with Acetylcholinesterase Inhibitors: An Observational, Non-Interventional Study
Abstract: We evaluated the efficacy and safety of Souvenaid (a multinutrient supplement) in patients with mild Alzheimer’s disease (AD) in real clinical practice and assessed a potential synergistic effect of acetylcholinesterase (AChE) inhibitors. Clinical Dementia Rating (CDR) scale was evaluated after six months follow-up. Patients were divided into 4 groups according to the treatment they received: Souvenaid + AChE inhibitors (n=23); only Souvenaid (n=8); only AChE inhibitors (n=7); no treatment (n=16). The Souvenaid + AChE inhibitors and Souvenaid alone groups were associated with significantly lower increases in CDR per month than the AChE inhibitors or no treatment ones. The efficacy of Souvenaid +AChE inhibitors tended to be higher than Souvenaid alone.

Short Communication
Bartholomew White, Constantine G. Lyketsos, Paul B. Rosenberg, Esther S. Oh, Liam Chen
Multiple Neurodegenerative Pathologies in an Alzheimer’s Disease Patient Treated with Fornical Deep Brain Stimulation
Abstract: As an established treatment for movement disorders, deep brain stimulation (DBS) has been adapted for the treatment of Alzheimer’s disease (AD) by modulating fornix activity. Although it is generally regarded as a safe intervention in patients over 65 years of age, the complex neurophysiology and interconnection within circuits connected to the fornix warrants a careful ongoing evaluation of the true benefit and risk potential of DBS on slowing cognitive decline in AD patients. Here we report on a patient who died long after being implanted with a DBS device who donated her brain for neuropathologic study. The autopsy confirmed multiple proteinopathies including AD-related change, diffuse neocortical Lewy body disease, TDP-43 proteinopathy, and a nonspecific tauopathy. We discuss the possible mechanisms of these overlapping neurodegenerative disorders and caution that future studies of DBS for AD will need to take these findings into consideration.

Short Communication
Amory Jardel, Lucie Hopes, Catherine Malaplate, Véronique Roch, Chloé Manca, Thérèse Rivasseau Jonveaux, Antoine Verger
Prognostic Impact of 18-F-Florbetaben Amyloid PET Imaging in Patients with Isolated Increases in Cerebrospinal Fluid Phospho-Tau Biomarkers: A Longitudinal Study
Abstract: This longitudinal study evaluates the prognostic impact of amyloid PET in patients suspected of Alzheimer’s disease and presenting with isolated cerebrospinal fluid (CSF) increases in P-Tau proteins (NCT02556502). The rate of conversion, based on the DSM-5 criteria and all collected data (average follow-up of 39.2±13.2 months), was determined by a panel of experts blinded to the PET results and was 75% (6/8) for positive and 35% (6/17) for negative baseline amyloid PET. In this population with isolated CSF increases in P-Tau, a positive baseline amyloid PET was associated with greater than twice the proportion of dementia conversions within the following three years.

Commentary
Pia Kontos, Mary L. Radnofsky, Phyllis Fehr, Mike R. Belleville, Frances Bottenberg, Mary Fridley, Susan Massad, Alisa Grigorovich, Jennifer Carson, Kari Rogenski, Kyrié S. Carpenter, Sherry Dupuis, Jill Battalen, David McDonagh, Kathryne Fassbender, Peter Whitehouse
Separate and Unequal: A Time to Reimagine Dementia
Abstract: The rapid emergence of COVID-19 has had far-reaching effects across all sectors of health and social care, but none more so than for residential long-term care homes. Mortality rates of older people with dementia in residential long-term care homes have been exponentially higher than the general public. Morbidity rates are also higher in these homes with the effects of government-imposed COVID-19 public health directives (e.g., strict social distancing), which have led most residential long-term care homes to adopt strict “no visitor” and lockdown policies out of concern for their residents’ physical safety. This tragic toll of the COVID-19 pandemic highlights profound stigma-related inequities. Societal assumptions that people living with dementia have no purpose or meaning and perpetuate a deep and pernicious fear of, and disregard for, persons with dementia. This has enabled discriminatory practices such as segregation and confinement to residential long-term care settings that are sorely understaffed and lack a supportive, relational, and enriching environment. With a sense of moral urgency to address this crisis, we forged alliances across the globe to form “Reimagining Dementia: A Creative Coalition for Justice.” We are committed to shifting the culture of dementia care from centralized control, safety, isolation, and punitive interventions to a culture of inclusion, creativity, justice, and respect. Drawing on the emancipatory power of the imagination with the arts (e.g., theatre, improvisation, music), and grounded in authentic partnerships with persons living with dementia, we aim to advance this culture shift through education, advocacy, and innovation at every level of society.

Alessandra Dodich, Chiara Crespi, Gaia Chiara Santi, Simona Luzzi, Valentina Ranaldi, Sandro Iannaccone, Alessandra Marcone, Michele Zamboni, Stefano F. Cappa, Chiara Cerami (Handling Associate Editor: Jordi A. Matias-Guiu)
Diagnostic Accuracy of Affective Social Tasks in the Clinical Classification Between the Behavioral Variant of Frontotemporal Dementia and Other Neurodegenerative Disease
Abstract: Background: Severe socio-emotional impairments characterize the behavioral variant of frontotemporal dementia (bvFTD). However, literature reports social cognition disorders in other dementias. Objective: In this study, we investigated the accuracy of social cognition performances in the early and differential diagnosis of bvFTD. Methods: We included 131 subjects: 32 bvFTD, 26 Alzheimer’s disease (AD), 16 primary progressive aphasia (PPA), 17 corticobasal syndrome (CBS), and 40 healthy control (HC). Each subject completed the Ekman 60 faces (Ek-60F) test assessing basic emotion recognition and the Story-based Empathy Task (SET) assessing attribution of intentions/emotions. A combined social measure (i.e., Emotion Recognition and Attribution (ERA) Index) was calculated. One-way ANOVA has been used to compare performances among groups, while receiver operating characteristic (ROC) curve tested measures ability to distinguish subjects with and without bvFTD. Results: Ek-60F and ERA Index scores were significantly lower in bvFTD versus HC, AD, and PPA groups. ROC analyses significantly distinguished bvFTD from HC (AUC 0.82-0.92), with the Ek-60F test showing the highest performance, followed by the ERA index. These two social measures showed the best accuracy in detecting bvFTD from AD (AUC 0.78-0.74) and PPA (AUC 0.80-0.76). Investigated measures failed in detecting bvFTD from CBS. Conclusion: Accuracy analyses support the advantage of using social cognition tests for bvFTD diagnosis. Short social battery may reduce uncertainties and improve disease identification in clinical settings. We recommend a revision of current clinical criteria considering neuropsychological deficits in emotion recognition and processing tasks as key cognitive markers of this neurodegenerative syndrome.

Kathleen H. Elverman, Elizabeth R. Paitel, Christina M. Figueroa, Ryan J. McKindles, Kristy A. Nielson
Event-Related Potentials, Inhibition, and Risk for Alzheimer’s Disease Among Cognitively Intact Elders
Abstract: Background: Despite advances in understanding Alzheimer’s disease (AD), prediction of AD prior to symptom onset remains severely limited, even when primary risk factors such as the apolipoprotein E (APOE) ε4 allele are known. Objective: Although executive dysfunction is highly prevalent and is a primary contributor to loss of independence in those with AD, few studies have examined neural differences underlying executive functioning as indicators of risk for AD prior to symptom onset, when intervention might be effective. Methods: This study examined event-related potential (ERP) differences during inhibitory control in 44 cognitively intact older adults (20 ε4+, 24 ε4-), relative to 41 young adults. All participants completed go/no-go and stop-signal tasks. Results: Overall, both older adult groups exhibited slower reaction times and longer ERP latencies compared to young adults. Older adults also had generally smaller N200 and P300 amplitudes, except at frontal electrodes and for N200 stop-signal amplitudes, which were larger in older adults. Considered with intact task accuracy, these findings suggest age-related neural compensation. Although ε4 did not distinguish elders during go or no-go tasks, this study uniquely showed that the more demanding stop-signal task was sensitive to ε4 differences, despite comparable task and neuropsychological performance with non-carriers. Specifically, ε4+ elders had slower frontal N200 latency and larger N200 amplitude, which was most robust at frontal sites, compared with ε4-. Conclusion: N200 during a stop-signal task is sensitive to AD risk, prior to any evidence of cognitive dysfunction, suggesting that stop-signal ERPs may be an important protocol addition to neuropsychological testing.

Yuanjing Li, Lin Cong, Tingting Hou, Liguo Chang, Chuanchen Zhang, Shi Tang, Xiaolei Han, Yongxiang Wang, Xiang Wang, Grégoria Kalpouzos, Yifeng Du, Chengxuan Qiu
Characterizing Global and Regional Brain Structures in Amnestic Mild Cognitive Impairment Among Rural Residents: A Population-Based Study
Abstract: Background: Structural brain magnetic resonance imaging (MRI) scans may provide reliable neuroimaging markers for defining amnestic mild cognitive impairment (aMCI). Objective: We sought to characterize global and regional brain structures of aMCI among rural-dwelling older adults with limited education in China. Methods: This population-based study included 180 participants (aged ≥65 years, 42 with aMCI and 138 normal controls) in the Shandong Yanggu Study of Aging and Dementia during 2014-2016. We defined aMCI following the Petersen’s criteria. Global and regional brain volumes were automatically segmented on MRI scans and compared using a region-of-interest approach. Data were analyzed using general linear regression models. Results: Multi-adjusted β-coefficient (95% confidence interval) of brain volumes (cm3) associated with aMCI was -12.07 (-21.49, -2.64) for global grey matter (GM), -18.31 (-28.45, -8.17) for global white matter (WM), 28.17 (12.83, 44.07) for cerebrospinal fluid (CSF), and 2.20 (0.24, 4.16) for white matter hyperintensities (WMH). Furthermore, aMCI was significantly associated with lower GM volumes in bilateral superior temporal gyri, thalamus and right cuneus, and lower WM volumes in lateral areas extending from the frontal to the parietal, temporal, and occipital lobes, as well as right hippocampus (p<0.05). Conclusion: Brain structure of older adults with aMCI is characterized by reduced global GM and WM volumes, enlarged CSF volume, increased WMH burden, reduced GM volumes in bilateral superior temporal gyri, thalamus, and right cuneus, and widespread reductions of lateral WM volumes.

Najla Jouini, Zakaria Saied, Samia Ben Sassi, Fatma Nebli, Taieb Messaoud, Faycel Hentati, Samir Belal
Impacts of Iron Metabolism Dysregulation on Alzheimer’s Disease
Abstract: Background: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function. Objective: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer’s disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1–42 (Aβ1–42), which is a major species of Aβ, and the most toxic. Methods: We evaluated the concentrations of iron, calcium, magnesium, and Aβ1–42 in the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ1–42, immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium. Results: We found that the AD group had lower CSF concentrations of Aβ1–42 (p < 0.001) and calcium (p < 0.001), but a higher CSF concentration of iron (p < 0.001). Significantly lower plasma concentrations of ceruloplasmin (p = 0.003), transferrin (mean, p < 0.001), and iron (p < 0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components. Conclusion: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD.

Alexandra L. Clark, Alexandra J. Weigand, Kelsey R. Thomas, Seraphina K. Solders, Lisa Delano-Wood, Mark W. Bondi, Rachel A. Bernier, Erin E. Sundermann, Sarah J. Banks, Katherine J. Bangen for the Alzheimer’s Disease Neuroimaging Initiative
Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment
Abstract: Background: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer’s disease (AD), although their interactive effects have yet to be fully examined. Objective: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). Methods: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. Results: Multiple regression analyses controlling for age, education, and APOE ε4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (ps < 0.05). Conclusion: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

Olivier Beauchet, Harmehr Sekhon, Cyrille P. Launay, Pierrette Gaudreau, José A. Morais, Gilles Allali
Pre-Dementia Stages and Incident Dementia in the NuAge Study
Abstract: Background: Motoric cognitive risk syndrome (MCR) and mild cognitive impairment (MCI) are two pre-dementia stages with an overlap, which may influence the risk for dementia. Objective: The study aims to examine the association of MCR, MCI, and their combination with incident dementia in Quebec community-dwelling older adults. Methods: 1,063 older adults (i.e., ≥65) were selected from a population-based observational cohort study known as the “Nutrition as a determinant of successful aging: The Quebec longitudinal study” (NuAge). Participants were separated into four groups at the baseline assessment: those without MCR and MCI, those with MCR alone, those with MCI alone, and those with MCR plus MCI. Incident dementia was recorded at each annual visit during a 3-year follow-up. Results: The prevalence of CHI was 87.2%, MCR 3.0%, MCI 8.8%, and MCR plus MCI 0.9%. The overall incidence of dementia was 2.3% and was significantly associated with MCR alone (Odd Ratio (OR)=5.00 with 95% Confidence interval (CI)=[1.01;24.59] and p=0.049), MCI alone (OR=6.04 with 95%CI=[2.36;15.47] and p≤0.001), and the combination of MCR and MCI (OR=25.75 with 95%CI=[5.32;124.66] and p≤0.001). Conclusion: Combining MCR and MCI increased the risk for incident dementia. These results also demonstrated that this combination is a better predictor of dementia than MCI and MCR alone.

Rebecca Zingel, Jens Bohlken, Karel Kostev
Association Between Inflammatory Bowel Disease and Dementia: A Retrospective Cohort Study
Abstract: Background: The critical role of inflammatory processes in the pathogenesis of dementia has recently been established. Objective: The aim of this study was to investigate the association between inflammatory bowel disease (IBD) and dementia risk in patients followed in general practices in Germany. Methods: This study included patients aged over 60 with an initial diagnosis of IBD (Crohn’s Disease (CD), ulcerative colitis (UC)) who were followed in 1,159 German general practices between January 1995 and December 2014. IBD patients were matched to healthy patients using propensity scores based on age, gender, index year, insurance type and comorbidities. Kaplan-Meier curves were used to study the development of dementia in patients with or without IBD within up to 15 years of the index date. Cox proportional hazard regression models were used to estimate the relationship between IBD and dementia. Results: The study included 3,850 patients with and 3,850 patients without IBD and revealed a higher cumulative incidence of dementia in IBD patients than in non-IBD patients after the follow-up period. The cumulative incidence of dementia differed within IBD subtypes; it was significantly higher in UC patients than in CD patients. Cox proportional hazard models showed that IBD is associated with a 1.22-fold increase in the risk (95% CI: 1,07-1,39) of developing dementia. UC patients had a 1.25-fold higher risk of developing dementia (95% CI: 1.07-1.46). CD is not significantly associated with an increased risk of dementia (HR: 1.17, 95% CI: 0.93-1.47). Conclusion: A positive association between IBD and dementia was found in patients followed in general practices in Germany.

Seyyed Hani Moussavi Nik*, Tenielle Porter*, Morgan Newman, Benjamin Bartlett, Imran Khan , Miheer Sabale, Melissa Eccles, Amy Woodfield, David Groth, Vincent Dore, Victor L. Villemagne, Colin L. Masters, Ralph N. Martins, Simon M. Laws, Michael Lardelli, Giuseppe Verdile (Handling Associate Editor: D. Allan Butterfield) *These authors contributed equally to this work.
Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer’s Disease and Neurodegeneration
Abstract: Background: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer’s disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. Objective: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. Method: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n= 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. Results: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p=0.024) and AD (p=0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n=62, β=-0.269, p=0.03). Conclusion: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

Laura Zamarian, Elfriede Karner, Thomas Bodner, Atbin Djamshidian, Margarete Delazer
Differential Impact of Education on Cognitive Performance in Neurological Patients with Progressive Cognitive Decline
Abstract: Background: Education has a protective effect toward cognitive decline in advanced age and is an important factor contributing to cognitive reserve. Objective: To elucidate the interaction effect of education and global mental status on cognitive performance of older patients with progressive cognitive decline. Methods: This retrospective study included 1,392 patients. We performed moderation regressions to examine the interaction between education and global mental status (Mini-Mental State Examination (MMSE) score) on performance in episodic memory, executive functions (EF), language, and constructional praxis tests. Significant interaction effects were further explored through separate linear regressions by MMSE level (inferior: ≤ 24; intermediate: 25-27; superior: 28-30). Results: There was an interaction between MMSE and education for some but not all variables. At intermediate and superior MMSE levels, high-educated people had a clear advantage relative to low-educated people in verbal memory and EF tests. This advantage was not significant at an inferior MMSE level. In object naming, constructional praxis recall, and constructional praxis, high-educated people performed better than low-educated people, independently of MMSE level. Conclusion: Education has a differential effect on cognitive performance in patients with cognitive decline. While high education is not helpful for episodic memory and EF at low cognitive levels, it is still beneficial for retrieving words or other semantic knowledge. These findings suggest an interaction between global mental status and education on different cognitive domains and have strong clinical implications. Diagnostic judgments should be based on the knowledge of such interaction. This study highlights the beneficial but selective effects of high education.

Yongjie Chen*, Yue Du*, Zhuoyu Sun*, Qian Liu, Changqing Sun, Hongyan Lin, Mengdi Jin, Jingzhu Fu, Fei Ma, Wen Li, Huan Liu, Xumei Zhang, Guangshun Wang, Guowei Huang (Handling Associate Editor: Anne Ording) *These authors contributed equally to this work.
Interactions Between Handgrip Strength and Serum Folate and Homocysteine Levels on Cognitive Function in the Elderly Chinese Population
Abstract: Background: Handgrip strength (HGS) and serum folate and homocysteine (Hcy) levels were associated with cognitive function. However, little was known whether there were interactions between HGS and serum folate and Hcy levels on cognitive function. Objective: To examine the interactions between HGS and serum folate and Hcy levels on cognitive function. Methods: This study analyzed the baseline data of the Tianjin Elderly Nutrition and Cognition Cohort study. All participants aged ≥60 years were potential eligible. HGS was measured using a grip strength dynamometer. Serum folate and Hcy levels were assayed using standard laboratory protocol. A Mini-Mental State Examination was used to assess cognitive function. Linear regressions were employed to examine the interactions between HGS and serum folate and Hcy levels on cognitive function. Results: 4,484 participants were included in this study. There were interactions between HGS and serum folate and Hcy levels on cognitive function. Furthermore, subjects with strong HGS and sufficient folate level had the best cognitive function (β=2.018), sequentially followed by those with strong HGS and insufficient folate level (β=1.698) and with poor HGS and sufficient folate level (β=0.873). Similarly, cognitive function was ranked in the descending order of subjects with strong HGS and normal Hcy level (β=1.971), strong HGS and high Hcy level (β=1.467), and poor HGS and normal Hcy level (β=0.657). Conclusion: There were interactions between HGS and serum folate and Hcy levels on cognitive function. However, the temporal associations cannot be examined in a cross-sectional study. Further cohort study should be conducted to confirm these associations in the future.

Frederic Gervais, Virginie Dauphinot, Christelle Mouchoux, Pierre Krolak-Salmon
Exposure to Anticholinergic and Sedative Drugs and Healthcare Costs in Older Patients with Neurocognitive Disorders
Abstract: Background: Literature supports an increasing number of older patients living with neurocognitive disorders alongside with their annual worldwide costs. Therapeutic management of behavioral and psychological symptoms includes the use of anticholinergic and sedative drugs for which significant exposure is negatively associated with clinical outcomes. Objective: The aim of this study was to assess the healthcare costs differences related to an increase in the exposure to anticholinergic and sedative drugs in older patients with neurocognitive disorder. Methods: A longitudinal study was conducted during 3 years on 1,604 participants of the MEMORA cohort linked with both regional public health insurance and hospital discharge databases between 2012 and 2017. Direct medical and non-medical costs were included. Exposure to anticholinergic and sedative drugs was measured by the drug burden index (DBI). Results: Costs difference associated with a DBI ≥ 0.5 were +338€ (p<0.001). After adjustment on comorbidities, NCD stage, cognitive impairment, functional limitation, polypharmacy, and sociodemographic characteristics, a DBI ≥ 0.5 was found to be an independent predictor of an increase of total healthcare costs by 22% (p<0.001). Conclusion: Anticholinergic and sedative drugs have a substantial economic burden among older patients with neurocognitive disorder. More studies are required to assess the clinical and economic impact of an efficient strategy based on the reduction of the exposure to anticholinergic and sedative drugs and the promotion of non-pharmacological interventions.

Lisanne F. ten Brinke, Chun Liang Hsu, Kirk I. Erickson, Todd C. Handy, Teresa Liu-Ambrose
Functional Connectivity and Response Inhibition: A Secondary Analysis of an 8-Week Randomized Controlled Trial of Computerized Cognitive Training
Abstract: Background: Evidence suggests that computerized cognitive training (CCT) can improve cognitive function in older adults, particularly executive functions. However, the underlying mechanisms by which CCT may improve executive functions are not well established. Objective: To determine: 1) inter-network functional connectivity correlates of changes in executive functions; and 2) the effect of CCT on these functional connectivity correlates. Methods: This secondary analysis included a subset of 124 adults aged 65-85 years enrolled in an 8-week randomized controlled trial of CCT. Participants were randomized to either: 1) group-based CCT 3x/week for 1 hour plus 3x/week home-based training; 2) group-based CCT preceded by brisk walking (Ex-CCT) 3x/week for 1 hour plus 3x/week home-based training (exercise+CCT); or 3) group-based balanced and toned (BAT) classes 3x/week for 1 hour (control). At baseline and trial completion, 65 of the 124 participants completed resting-state functional magnetic resonance imaging and neuropsychological tests of executive functions, specifically the Stroop Colour-Word Test and Flanker Test. Results: Improved performance on the Stroop Colour-Word Test and Flanker Test were associated with decreased correlation between the default mode network (DMN) and the fronto-parietal network (FPN) (p<0.05). Compared with BAT, CCT alone significantly decreased correlation between the left dorsolateral prefrontal cortex and both the left and right medial temporal gyrus (-0.143, 95% CI[-0.256,-0.030], p=0.014, and -0.123, 95% CI[-0.242,-0.004], p=0.043, respectively). Conclusion: Decreased correlation between DMN and FPN, indicating less connection between these networks, may be an underlying mechanism by which CCT improves executive functions. Future studies are needed to replicate this finding.

Jared J. Tanner, Shivani Hanchate, Catherine C. Price, Cynthia Garvan, Song Lai, Roland Staud, Hrishikesh Deshpande, Georg Deutsch, Burel R. Goodin, Roger B. Fillingim, Kimberly T. Sibille
Relationships Between Chronic Pain Stage, Cognition, Temporal Lobe Cortex, and Sociodemographic Variables
Abstract: Background: Non-Hispanic black (NHB) individuals have increased risk of Alzheimer’s disease (AD) relative to non-Hispanic whites (NHW). Ethnicity/race can serve as a proxy sociodemographic variable for a complex representation of sociocultural and environmental factors. Chronic pain is a form of stress with high prevalence and sociodemographic disparities. Chronic pain is linked to lower cognition and accelerated biological aging. Objective: The purpose of this study is to seek understanding of potential cognitive and temporal lobe structural brain AD vulnerabilities based on chronic pain stage and ethnicity/race. Methods: Participants included 147 community dwelling NHB and NHW adults without dementia between 45-85 years old who had or were at risk of knee osteoarthritis. All participants received an MRI (3T Philips), the Montreal Cognitive Assessment (MoCA), and assessment of clinical knee pain stage. Results: There were ethnic/race group differences in MoCA scores but no relationships with chronic knee pain stage. Ethnicity/race moderated the relationship between AD-related temporal lobe thickness and chronic pain stage with quadratic patterns suggesting thinner cortex in high chronic pain stage NHB adults. Conclusion: There appear to be complex relationships between chronic knee pain stage, temporal lobe cortex, and sociodemographic variables. Specifically, NHB participants without dementia but with high chronic knee pain stage appeared to have thinner temporal cortex in areas associated with AD. Understanding the effects of sociocultural and socioeconomic factors on health outcomes is the first step to challenging the disparities in healthcare that now appear to link disease conditions to neurodegenerative processes.

Jonathan D. Drake, Alison B. Chambers, Brian R. Ott, Lori A. Daiello, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ruth Peters)
Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer’s Disease
Abstract: Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n=112 AD, n=396 mild cognitive impairment (MCI), n=58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n=351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p=0.0026) and ICAM-1 (p=0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p=0.0157), and APOE ε4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ42 (all < p=0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

Lucy C. Beishon, Ronney B. Panerai, Charley Budgeon, Hari Subramaniam, Elizabeta Mukaetova-Ladinska, Thompson G. Robinson, Victoria J. Haunton
The Cognition and Flow Study: A Feasibility Randomized Controlled Trial of the Effects of Cognitive Training on Cerebral Blood Flow
Abstract: Background: Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown. Objective: This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv). Methods: Twenty HG, 24 with Alzheimer’s disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke’s Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) and 95% confidence interval (CI). Results: 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: -4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial. Conclusion: A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial.

Salma M.S. El Said, Nermien N. Adly, Samia A Abdul-RahmanExecutive Function and Physical Function Among Community-Dwelling Egyptian Older Adults
Abstract: Background: The ongoing scientific debate regarding the association between physical function and cognitive impairment has focused mainly on global cognitive performance rather than specific cognitive functions tests and the importance of recognition of its associations and any factors that could play a role later in the prevention of such decline. Objective: This study examined the association between physical function, using handgrip strength (HGS) and Timed Up-and-Go test (TUGT), and executive function (EF), using Clock Drawing Test (CDT), among community-dwelling Egyptian elderly. Methods: A cross-sectional study was conducted in 5 social clubs in Cairo, Egypt and included a sample of 136 elderly males and females aged ≥55 years old. All participants had their physical function assessed using TUGT, and measurement of HGS using a pneumatic hand-held dynamometer. Assessment of EF using CDT was also done. Results: Higher CDT scores were significantly associated with both better HGS, and lower TUGT (OR= 3.77, and 0.65 respectively). This persisted even after adjustment for age and gender (OR=2.56, and 0.71 respectively) and after further adjustment for weight, systolic blood pressure, education, smoking, hyperlipidemia, hypothyroidism, and physical activity (O.R.= 4.79, and 0.76 respectively). Adjustment for both male and female genders showed an association between physical (HGS and TUGT) and EF was stronger among men. Conclusion: A strong association between CDT score and both of HGS and TUGT was found among the studied sample. Higher HGS and lower TUGT was significantly associated with better performance in the CDT. This association is stronger in males than in females for both HGS and TUGT.

Rui Zhou*, Hua-Min Liu*, Fu-Rong Li, Hai-Lian Yang, Jia-Zhen Zheng, Meng-Chen Zou, Lian-Wu Zou, Xiao-Xiang Wu, Xian-Bo Wu *These authors contributed equally to this work.
Depression as a Mediator of the Association Between Wealth Status and Risk of Cognitive Impairment and Dementia: A Longitudinal Population-Based Cohort Study
Abstract: Background: Wealth and income are potential modifiable risk factors for dementia, but whether wealth status, which is composed of a combination of debt and poverty, and assessed by wealth and income, is associated with cognitive impairment among elderly adults remains unknown. Objective: To examine the associations of different combinations of debt and poverty with the incidence of dementia and cognitive impairment without dementia (CIND) and to evaluate the mediating role of depression in these relationships. Methods: We included 15,565 participants aged 51 years or older from the Health and Retirement Study (1992-2012) who were free of CIND and dementia at baseline. Dementia and CIND were assessed using either the modified Telephone Interview for Cognitive Status (mTICS) or a proxy assessment. Cox models with time-dependent covariates and mediation analysis were used. Results: During a median of 14.4 years of follow-up, 4,484 participants experienced CIND and 1,774 were diagnosed with dementia. Both debt and poverty were independently associated with increased dementia and CIND risks, and the risks were augmented when both debt and poverty were present together (the hazard ratios [95% confidence intervals] were 1.35 [1.08-1.70] and 1.96 [1.48-2.60] for CIND and dementia, respectively). The associations between different wealth statuses and cognition were partially (mediation ratio range: 11.8-29.7%) mediated by depression. Conclusion: Debt and poverty were associated with an increased risk of dementia and CIND, and these associations were partially mediated by depression. Alleviating poverty and debt may be effective for improving mental health and therefore curbing the risk of cognitive impairment and dementia.

Harsh V. Gupta, Thomas G. Beach, Shyamal H. Mehta, Holly A. Shill, Erika Driver-Dunckley, Marwan N. Sabbagh, Christine M. Belden, Carolyn Liebsack, Brittany N. Dugger, Geidy E. Serrano, Lucia I. Sue, Andrew Siderowf, Michael J. Pontecorvo, Mark A. Mintun, Abhinay D. Joshi, Charles H. Adler
Clinicopathological Correlation: Dopamine and Amyloid PET Imaging with Neuropathology in Three Subjects Clinically Diagnosed with Alzheimer’s Disease or Dementia with Lewy Bodies
Abstract: Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid) is selective for the neuritic plaque amyloid of Alzheimer’s disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Methods: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

Eleni Poptsi, Magda Tsolaki, Sverre Bergh, Bruno Mario Cesana, Alfonso Ciccone, Andrea Fabbo, Giovanni B. Frisoni, Lutz Frölich, Sara Lavolpe, Anna Giulia Guazzarini, Jacques Hugon, Sara Fascendini, Patrizia Mecocci, Carlo Alberto Defanti
Rationale, Design, and Methodology of a Prospective Cohort Study for Coping with Behavioral and Psychological Symptoms of Dementia: The RECage Project
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are quite challenging problems during the dementia course. Special Care Units for people with dementia (PwD) and BPSD (SCU-B) are residential medical structures, where BPSD patients are temporarily admitted, in case of unmanageable behavioral disturbances at home. Objective: RECage (REspectful Caring for AGitated Elderly) aspires to assess the short and long-term effectiveness of SCU-Bs toward alleviating BPSD and improving the quality of life (QoL) of PwD and their caregivers. Methods: RECage is a three-year, prospective study enrolling 500 PwDs. Particularly, 250 community-dwelling PwDs presenting with severe BPSD will be recruited by five clinical centers across Europe, endowed with a SCU-B, for a short period of time; a second similar group of 250 PwD will be followed by six other no-SCU-B centers solely via outpatient visits. RECage’s endpoints include short and long-term SCU-B clinical efficacy, QoL of patients and caregivers, cost-effectiveness of the SCU-B, psychotropic drug consumption, caregivers’ attitude toward dementia, and time to nursing home placement. Results: PwDs admitted in SCU-Bs are expected to have diminished rates of BPSD and better QoL and their caregivers are also expected to have better QoL and improved attitude towards dementia, compared to those followed in no-SCU-Bs. Also, the cost of care and the psychotropic drug consumption are expected to be lower. Finally, PwDs followed in no-SCU-Bs are expected to have earlier admission to nursing homes. Conclusion: The cohort study results will refine the SCU-B model, issuing recommendations for implementation of SCU-Bs in the countries where they are scarce or non-existent.

Heikki Lukkarinen, Ina Tesseur, Darrel Pemberton, Peter Van Der Ark, Maarten Timmers, Randy Slemmon, Luc Janssens, Johannes Streffer, Luc Van Nueten, Astrid Bottelbergs, Tuomas Rauramaa, Anne M. Koivisto, Sanna-Kaisa Herukka, Ville E. Korhonen, Antti Junkkari, Mikko Hiltunen, Sebastiaan Engelborghs, Kaj Blennow, Henrik Zetterberg, Hartmuth C. Kolb, Ville Leinonen
Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus Abstract: Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R=0.87, T-tau R=0.83, P-tau R=0.92, NFL R=0.94, NRGN R=0.9; all p<0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ε4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

Elisabeth Maria van Zutphen, Judith Johanna Maria Rijnhart, Didericke Rhebergen, Majon Muller, Martijn Huisman, Aartjan Beekman, Almar Kok*, Yolande Appelman* (Handling Associate Editor: Jessica Kirkland Caldwell) *These authors share last authorship.
Do Cardiovascular Risk Factors and Cardiovascular Disease Explain Sex Differences in Cognitive Functioning in Old Age?
Abstract: Background: Sex differences in cognitive functioning in old age are known to exist yet are still poorly understood. Objective: This study examines to what extent differences in cardiovascular risk factors and cardiovascular disease between men and women explain sex differences in cognitive functioning. Methods: Data from 2,724 older adults from the Longitudinal Aging Study Amsterdam were used. Information processing speed and episodic memory, measured three times during six years of follow-up, served as outcomes. The mediating role of cardiovascular risk factors and cardiovascular disease was examined in single and multiple mediator models. Determinant-mediator effects were estimated using linear or logistic regression, and determinant-outcome and mediator-outcome effects were estimated using linear mixed models. Indirect effects were estimated using the product-of-coefficients estimator. Results: Women scored 1.58 points higher on information processing speed and 1.53 points higher on episodic memory. Several cardiovascular risk factors had small mediating effects. The sex difference in information processing speed was mediated by smoking, depressive symptoms, obesity, and systolic blood pressure. The sex difference in episodic memory was mediated by smoking, physical activity, and depressive symptoms. Effects of smoking, LDL cholesterol, and diabetes mellitus on information processing speed differed between men and women. Conclusion: Differences in cardiovascular risk factors between women and men partially explained why women had better cognitive functioning. A healthy cardiovascular lifestyle seems beneficial for cognition and sex-specific strategies may be important to preserve cognitive functioning at older age.

Varvara Valotassiou, Nikolaos Sifakis, Chara Tzavara, Evi Lykou, Niki Tsinia, Vasiliki Kamtsadeli, Dimitra Sali, George Angelidis, Dimitrios Psimadas, Ioannis Tsougos, Sokratis G. Papageorgiou, Panagiotis Georgoulias, John Papatriantafyllou
Eating Disorders in Frontotemporal Dementia and Alzheimer’s Disease: Evaluation of Brain Perfusion Correlates Using 99mTc-HMPAO SPECT with Brodmann Areas Analysis
Abstract: Background: Eating disorders (ED) in dementia represent a significant impairment affecting patients’ and caregivers’ lives. In frontotemporal dementia (FTD), ED include overeating, sweet food preference hyperorality, stereotypical eating, and hyperorality, while in Alzheimer’s disease (AD), anorexia and appetite loss are the most common ED. Objective: The aim of our study was to highlight Brodmann areas (BAs) implicated specifically in the appearance of ED in FTD and AD. Methods: We studied 141 patients, 75 with FTD and 66 with AD. We used the NeuroGamTM software on the reconstructed single photon emission computed tomography-SPECT data for the automated comparison of BAs perfusion on the left (L) and right (R) hemisphere with perfusion in corresponding BAs of a normal database. Results: The FTD group included 27 men and 48 women, age (mean±SD) 65.8±8.5 years, duration of disease 3.4±3.3 years, Mini-Mental State Examination (MMSE) 17.9±8.6, ED score on Neuropsychiatric Inventory (NPI) 4.7±8.5. ED in FTD were correlated with hypoperfusion in right anterior and dorsolateral prefrontal cortices (BAs 10R, 46R), left orbitofrontal cortex (BA 12L), orbital part of the right inferior frontal gyrus (BA 47R), and left parahippocampal gyrus (BA 36L). The AD group included 21 men and 45 women, age (mean±SD) 70.2±8.0 years, duration of disease 3.3±2.4 years, MMSE 20.2±6, ED-NPI score 2.7±3.9. ED in AD were correlated with hypoperfusion in left inferior temporal cortex (BA 20L). Conclusion: SPECT imaging with automated mapping of brain cortex could contribute to the understanding of the neural networks involved in the manifestation of ED in dementia.

Antonina Luca*, Alessandra Nicoletti*, Giulia Donzuso, Claudio Terravecchia, Calogero Edoardo Cicero, Concetta D’Agate, Cristina Rascunà, Roberta Manna, Giovanni Mostile, Mario Zappia *These authors contributed equally to this work.
Phonemic Verbal Fluency and Midbrain Atrophy in Progressive Supranuclear Palsy
Abstract: Background: The neuropsychological profile of progressive supranuclear palsy (PSP) patients is mainly characterized by executive dysfunction, but the relationship between the latter and midbrain atrophy is still unclear. Objective: The aims of the study were to investigate which test evaluating executive functioning is more frequently impaired in PSP patients and to evaluate the relationship between midbrain-based MRI morphometric measures and executive dysfunction. Methods: PSP patients who had undergone a neuropsychological battery assessing executive functioning with the Frontal Assessment Battery (FAB), the phonemic verbal fluency F-A-S, the Raven’s Progressive Colored Matrix, and the Stroop word colors test (time and errors) were enrolled in the study. A group of Parkinson’s disease (PD) patients matched by age, sex, education, and global cognitive status was selected. All the enrolled patients also underwent a volumetric T1-3D brain MRI. Results: Thirty-five PSP patients and 35 PD patients were enrolled. Patients with PSP as compared to patients with PD showed a significant greater impairment in verbal fluency (16.0±7.9 and 23.4±8.7 words/180 s; p<0.001) and a significant lower score at the FAB total score (11.5±3.8 and 13.7±3.4; p=0.013). Midbrain area was significantly smaller in PSP patients than in PD patients (83.9±20.1 and 134.5±19.9 mm2; p<0.001). In PSP patients, a significant positive correlation between verbal fluency and the midbrain area (r=0.421; p=0.028) was observed. Conclusion: Our findings suggest that the phonemic verbal fluency is among the most frequently impaired executive functions in PSP patients and is strongly correlated to midbrain atrophy.

Linda H.G. Pagen, Tom Smeets, Lisa Schmiedek, Michael A. Yassa, Frans R.J. Verhey, Heidi I.L. Jacobs
Elevated Activity of the Sympathetic Nervous System Is Related to Diminished Practice Effects in Memory: A Pilot Study
Abstract: Background: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load. Objective: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects. Methods: Thirty cognitively healthy individuals aged 40-70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance. Results: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners. Conclusion: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline.

Ferdous Taslima, Cha-Gyun Jung, Chunyu Zhou, Mona Abdelhamid, Mohammad Abdullah, Tetsuya Goto, Takashi Saito, Takaomi C Saido, Makoto Michikawa
Tooth Loss Induces Memory Impairment and Gliosis in App Knock-In Mouse Models of Alzheimer’s Disease
Abstract: Background: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. Objective: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. Methods: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-β (Aβ) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aβ ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. Results: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. Conclusion: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.

Wyllians Vendramini Borelli, Marina Coutinho Augustin, Paola Bell Felix de Oliveira, Lorenzo Casagrande Reggiani, Renato Gorga Bandeira-de-Mello, Artur Francisco Schumacher-Schuh, Marcia Lorena Fagundes Chaves, Raphael Machado Castilhos
Neuropsychiatric Symptoms in Patients with Dementia Associated with Increased Psychological Distress in Caregivers During the COVID-19 Pandemic
Abstract: Background: The social isolation imposed by COVID-19 pandemic can have a major impact on the mental health of dementia patients and their caregivers. Objective: We aim to evaluate the neurological decline of patients with dementia and the caregivers' burden during the pandemic. Methods: We performed a cross-sectional study. Caregivers of dementia patients following in the outpatient clinic were included. A structured telephone interview composed of the Neuropsychiatric Inventory Questionnaire (NPI-Q), Zarit Burden Interview (ZBI), Beck Depression (BDI) and Anxiety (BAI) Inventories to address cognitive, behavioral, and functional changes associated with social distancing during the Sars-Cov-2 outbreak. Patients were divided in two groups according to caregivers' report: with perceived Altered Cognition (AC) and Stable Cognition (SC). Results: A total of 58 patients (median age: 57 years [21-87], 58.6% females) and caregivers (median age: 76.5 years [55-89], 79.3% females) were included. Cognitive decline was shown by most patients (53.4%), as well as behavioral symptoms (48.3%), especially apathy/depression (24.1%), and functional decline (34.5%). The AC group (n=31) presented increased behavioral (67.7% versus 25.9%, p=0.002) and functional (61.3% versus 3.7%, p<0.001) changes when compared to the SC group. In the AC group, ZBI, BDI, NPI-Q caregiver distress, and NPI-Q patient's severity of symptoms scores were worse than the SC group (p<0.005 for all). Conclusion: Patients’ neuropsychiatric worsening and caregiver burden were frequent during the pandemic. Worsening of cognition was associated with increased caregivers’ psychological distress.

Elodie Pongan*, Jean-Michel Dorey*, Céline Borg, Jean Claude Getenet, Romain Bachelet, Charles Lourioux, Bernard Laurent, COVCARE Group, Romain Rey, Isabelle Rouch *These authors contributed equally to this work.
COVID-19: Association Between Increase of Behavioral and Psychological Symptoms of Dementia During Lockdown and Caregivers' Poor Mental Health
Abstract: Background: From March 2020, the support and care systems for caregivers and people with dementia (PWD) were suspended or dramatically changed due to the lockdown during the world pandemic of COVID-19. Thus, these changes in living conditions have had deleterious consequences on the behavior of PWD and subsequently on their caregivers’ mental health, the two being linked. Objective: Our study aimed to examine changes in behavior among PWD and to look for associations between the evolution of behavioral and psychological symptoms of dementia (BPSD) and caregivers’ mental health in the context of COVID-19. Methods: The study was conducted among caregivers of PWD living at home in France. Caregivers were interviewed via an anonymous cross-sectional online survey during the first lockdown between April 15 and June 15, 2020. Results: Three hundred and eighty-nine caregivers accompanying a relative living at home participated in the study; 43.3% of the PWD presented a worsening of BPSD during the lockdown. With multivariate logistic regressions, a significant association was observed between ”more BPSD” and burden, anxiety and depression, between “BPSD equivalent” and anxiety and depression, and between “emerging BPSD” and only depression. Conclusion: The lockdown seems to have an impact on behavioral disorders in PWD and these disorders are associated with poorer mental health of caregivers. Our findings suggest attention should be given to caregivers of PWD who have BPSD before lockdown and the need for continued consultations and professional help in case of new lockdowns.

Ruiqing Ni, Jennie Röjdner, Larysa Voytenko, Thomas Dyrks, Andrea Thiele, Amelia Marutle, Agneta Nordberg
In vitro Characterization of the Regional Binding Distribution of Amyloid PET Tracer Florbetaben and the Glia Tracers Deprenyl and PK1195 in Autopsy Alzheimer’s Brain Tissue
Abstract: Background: Emerging evidence indicates a central role of gliosis in Alzheimer’s disease (AD) pathophysiology. However, the regional distribution and interaction of astrogliosis and microgliosis in association with amyloid-β (Aβ) still remain uncertain. Objective: Here we studied the pathological profiles in autopsy AD brain by using specific imaging tracers. Methods: Autopsy brain tissues of AD (n=15, age 70.4±8.5 years) and control cases (n=12, age 76.6±10.9) were examined with homogenate binding assays, autoradiography for Aβ plaques (3H-florbetaben/3H-PIB), astrogliosis (3H-L-deprenyl), and microgliosis (3H-PK11195/3H-FEMPA), as well as immunoassays. Results: In vitro saturation analysis revealed high-affinity binding sites of 3H-florbetaben, 3H-L-deprenyl, and 3H-PK11195/3H-FEMPA in the frontal cortex of AD cases. In vitro 3H-florbetaben binding increased across cortical and subcortical regions of AD compared to control with the highest binding in the frontal and parietal cortices. The in vitro 3H-L-deprenyl binding showed highest binding in the hippocampus (dentate gyrus) followed cortical and subcortical regions of AD while the GFAP expression was upregulated only in the hippocampus compared to control. The in vitro 3H-PK11195 binding was solely increased in the parietal cortex and the hippocampus of AD compared to control. The 3H-florbetaben binding positively correlated with the 3H-L-deprenyl binding in the hippocampus and parietal cortex of AD and controls. Similarly, a positive correlation was observed between 3H-florbetaben binding and GFAP expression in hippocampal AD and control brain. Conclusion: The use of multi-modal imaging tracers revealed different regional pattern of changes in autopsy AD brain with respect to amyloid plaque pathology versus astrogliosis and microgliosis.