Volume 82, Number 1, IN PRESS

Mini-Forum: Digital Neuropsychological Assessment: New Technology for Measuring Subtle Neuropsychological Behavior (Guest Editors: David J. Libon, Ganesh Baliga, Rod Swenson, Rhoda Au)

Introduction
David J. Libon, Ganesh Baliga, Rod Swenson, Rhoda Au
Digital Neuropsychological Assessment: New Technology for Measuring Subtle Neuropsychological Behavior

Sheina Emrani, Melissa Lamar, Catherine Price, Satya Baliga, Victor Wasserman, Emily F. Matusz, Johnathan Saunders, Vaughn Gietka, James Strate, Rod Swenson, Ganesh Baliga, David J. Libon (Handling Associate Editor: Mark Bondi)
Neurocognitive Constructs Underlying Executive Control in Statistically-Determined Mild Cognitive Impairment
Abstract: Background: The model of executive attention proposes that temporal organization, i.e., the time necessary to bring novel tasks to fruition is an important construct that modulates executive control. Subordinate to temporal organization are the constructs of working memory, preparatory set, and inhibitory control. Objective: The current research operationally-defined the constructs underlying the theory of executive attention using intra-component latencies (i.e., reaction times) from a 5-span backward digit test from patients with suspected mild cognitive impairment (MCI). Methods: An iPad-version of the Backward Digit Span Test (BDT) was administered to memory clinic patients. Patients with (n= 22) and without (n= 36) MCI were classified. Outcome variables included intra-component latencies for all correct 5-span serial order responses. Results: Average total time did not differ. A significant 2-group by 5-serial order latency interaction revealed the existence of distinct time epochs. Non-MCI patients produced slower latencies on initial (position 2- working memory/ preparatory set) and latter (position 4- inhibitory control) correct serial order responses. By contrast, patients with MCI produced a slower latency for middle serial order responses (i.e., position 3-preparatory set). No group differences were obtained for incorrect 5-span test trials. Conclusion: The analysis of 5-span BDT serial order latencies found distinct epochs regarding how time was allocated in the context of successful test performance. Intra-component latencies obtained from tests assessing mental re-ordering may constitute useful neurocognitive biomarkers for emergent neurodegenerative illness.

Stacy L. Andersen, Benjamin Sweigart, Nancy W. Glynn, Mary K. Wojczynski, Bharat Thyagarajan, Jonas Mengel-From, Stephen Thielke, Thomas T. Perls, David J. Libon, Rhoda Au, Stephanie Cosentino, Paola Sebastiani on behalf of the Long Life Family Study (Handling Associate Editor: Mark Bondi)
Digital Technology Differentiates Graphomotor and Information Processing Speed Patterns of Behavior
Abstract: Background: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition. Objective: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST). Methods: A subset of Long Life Family Study participants (n=1,594) completed the DSST. Total time to draw each symbol was divided into ‘writing’ and non-writing or ‘thinking’ time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90-s test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores. Results: Clustering revealed four ‘thinking’ time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of ‘writing’ time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores. Conclusion: Digital data identified previously unrecognized patterns of ‘writing’ and ‘thinking’ time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions.

Natalia Parjane, Sunghye Cho, Sharon Ash, Katheryn A.Q. Cousins, Sanjana Shellikeri, Mark Liberman, Leslie M. Shaw, David J. Irwin, Murray Grossman, Naomi Nevler (Handling Associate Editor: Mark Bondi)
Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes
Abstract: Background: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. Objective: Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA. Methods: Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n=87), naPPA (n=25), and healthy controls (HC, n=41). We related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes. Results: Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA. Conclusion: Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels.

Anis Davoudi, Catherine Dion, Shawna Amini, Patrick J. Tighe, Catherine C. Price, David J. Libon*, Parisa Rashidi* (Handling Associate Editor: Mark Bondi) *These authors contributed equally to this work.
Classifying Non-Dementia and Alzheimer’s Disease/Vascular Dementia Patients Using Kinematic, Time-Based, and Visuospatial Parameters: The Digital Clock Drawing Test
Abstract: Background: Advantages of digital clock drawing metrics for dementia subtype classification needs examination. Objective: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer’s disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer’s disease (AD) versus vascular dementia (VaD). Methods: Healthy, community-dwelling control participants (n=175), patients diagnosed clinically with Alzheimer’s disease (n=29), and vascular dementia (n=27) completed the dCDT to command and copy with hands to 10 after 11”. Thirty-seven dCDT command and 37 copy dCDT features were extracted and subjected to Random Forest machine learning analysis. Results: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC=91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, again, achieved with models that combined both command and copy features (AUC=76.94%). Subsequent follow-up analyzes of a corpus of 10 variables of interest complied using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features. Conclusion: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide much needed neurocognitive biomarkers that may be able to identify and tract dementia syndromes.

Anis Davoudi*, Catherine Dion*, Erin Formanski, Brandon E. Frank, Shawna Amini, Emily F. Matusz, Victor Wasserman, Dana Penney, Randall Davis, Parisa Rashidi, Patrick Tighe, Kenneth M. Heilman, Rhoda Au, David J. Libon, Catherine C. Price *These authors contributed equally to this work.
Normative References for Graphomotor and Latency Digital Clock Drawing Metrics for Adults Age 55 and Older: Operationalizing the Production of a Normal Appearing Clock
Abstract: Background: Relative to the abundance of publications on dementia and clock drawing, there is limited literature operationalizing ‘normal’ clock production. Objective: To operationalize subtle behavioral patterns seen in normal digital clock drawing to command and copy conditions. Methods: From two research cohorts of cognitively-well participants aged 55+ who completed digital clock drawing to command and copy conditions (n=430), we examined variables operationalizing clock face construction, digit placement, clock hand construction, and a variety of time-based, latency measures. Data are stratified by age, education, handedness, and number anchoring. Results: Normative data are provided in supplementary tables. Typical errors reported in clock research with dementia were largely absent. Adults age 55+ produce symmetric clock faces with one stroke, with minimal overshoot and digit misplacement, and hands with expected short to long ratio. Data suggest digitally acquired graphomotor and latency differences based on handedness, age, education, and anchoring. Conclusion: Data provide useful benchmarks from which to assess digital clock drawing performance in Alzheimer’s disease and related dementias.

Regular Section

Review
Suélen Santos Alves, Rui Milton Patrício da Silva-Junior, Gabriel Servilha-Menezes, Jan Homolak, Melita Šalković-Petrišić, Norberto Garcia-Cairasco
Insulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses
Abstract: Almost 115 years ago, Alois Alzheimer described Alzheimer’s disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6% in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.

Review
Holly A. Massett, Alexandra K. Mitchell, Leah Alley, Elizabeth Simoneau, Panne Burke, Sae H. Han, Gerda Gallop-Goodman, Melissa McGowan (Handling Associate Editor: Carey Gleason)
Facilitators, Challenges, and Messaging Strategies for Hispanic/Latino Populations Participating in Alzheimer’s Disease and Related Dementias Clinical Research: A Literature Review
Abstract: Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) disproportionally affect Hispanic and Latino populations, yet Hispanics/Latinos are substantially underrepresented in AD/ADRD clinical research. Diverse inclusion in trials is an ethical and scientific imperative, as underrepresentation reduces the ability to generalize study findings and treatments across populations most affected by a disease. This paper presents findings from a narrative literature review (N=210) of the current landscape of Hispanic/Latino participation in clinical research, including the challenges, facilitators, and communication channels to conduct culturally appropriate outreach efforts to increase awareness and participation of Hispanics/Latinos in AD/ADRD clinical research studies. Many challenges identified were systemic in nature: lack of culturally relevant resources; staffing that do not represent participants’ cultures/language; eligibility criteria that disproportionately excludes Hispanics/Latinos; and too few studies available in Hispanic/Latino communities. The paper also details facilitators and messaging strategies to improve engagement and interest among Hispanics/Latinos in AD/ADRD research, starting with approaches that recognize and address the heterogeneity of the Hispanic/Latino ethnicity, and then, tailor outreach activities and programs to address their diverse needs and circumstances. The needs identified in this article represent longstanding failures to improve engagement and interest among Hispanics/Latinos in AD/ADRD research; we discuss how the field can move forward learning from the experiences of the COVID-19 pandemic.

Review
Davis C. Woodworth, Kiana A. Scambray, María M. Corrada, Claudia H. Kawas, S. Ahmad Sajjadi (Handling Associate Editor: Konstantinos Arfanakis)
Neuroimaging in the Oldest-Old: A Review of the Literature
Abstract: The oldest-old, those 85 years and older, are the fastest growing segment of the population and present with the highest prevalence of dementia. Given the importance of neuroimaging measures to understand aging and dementia, the objective of this study was to review neuroimaging studies performed in oldest-old participants. We used PubMed, Google Scholar, and Web of Science search engines to identify in vivo CT, MRI, and PET neuroimaging studies either performed in the oldest-old or that addressed the oldest-old as a distinct group in analyses. We identified 60 studies and summarized the main group characteristics and findings. Generally, oldest-old participants presented with greater atrophy compared to younger old participants, with most studies reporting a relatively stable constant decline in brain volumes over time. Oldest-old participants with greater global atrophy and atrophy in key brain structures such as the medial temporal lobe were more likely to have dementia or cognitive impairment. The oldest-old presented with a high burden of white matter lesions, which were associated with various lifestyle factors and some cognitive measures. Amyloid burden as assessed by PET, while high in the oldest-old compared to younger age groups, was still predictive of transition from normal to impaired cognition, especially when other adverse neuroimaging measures (atrophy and white matter lesions) were also present. While this review highlights past neuroimaging research in the oldest-old, it also highlights the dearth of studies in this important population. It is imperative to perform more neuroimaging studies in the oldest-old to better understand aging and dementia.

Review
Fan Ye, Anshi Wu
The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer’s Disease
Abstract: Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer's disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer's disease.

Kok Pin Ng, Grand H.-L. Cheng, Chathuri Yatawara, Pedro Rosa-Neto, Serge Gauthier, Nagaendran Kandiah for the Alzheimer’s Disease Neuroimaging Initiative
Baseline Neurodegeneration Influences the Longitudinal Effects of Tau on Cognition
Abstract: Background: Cerebrospinal fluid t-tau (CSF t-tau) is a measure of neurodegeneration in Alzheimer’s disease (AD) and has been increasingly demonstrated to be a non-specific biomarker within the AD continuum. Objective: We sought to test whether t-tau influences the longitudinal effects of amyloid-β (Aβ) and phospho-tau (p-tau) on memory and executive function (EF) in mild cognitive impairment (MCI). Methods: 319 MCI individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with baseline and 2-year CSF Aβ, p-tau, t-tau, and neuropsychological assessments were studied. Mediation and moderation analyses evaluated the role of t-tau in the effects of Aβ and p-tau on memory and EF over 2 years. Results: We found that high baseline p-tau but not Aβ was associated with higher t-tau and lower memory scores at 2 years follow-up. The association between p-tau and memory impairment was partially mediated by t-tau, whereby higher p-tau was indirectly associated with lower memory via higher t-tau. t-tau also moderated the association between p-tau and memory. When t-tau level was relatively lower, higher p-tau was associated with lower memory scores at 2 years. When t-tau level was higher, the memory scores were low regardless of the p-tau level. Conclusion: Tau-induced neurodegeneration is one key pathway by which AD pathology (p-tau) affects memory impairment. Furthermore, in individuals with lower levels of tau-induced neurodegeneration, higher levels of p-tau were required for memory impairment. Our findings suggest that t-tau plays a significant role in how early AD pathology affects cognitive outcomes.

Guan-yong Ou, Wen-wen Lin, Wei-jiang Zhao
Construction of Long Noncoding RNA-Associated ceRNA Networks Reveals Potential Biomarkers in Alzheimer’s Disease
Abstract:Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that seriously impairs both cognitive and memory functions mainly in the elderly, and its incidence increases with age. Recent studies demonstrated that long noncoding RNAs (lncRNAs) play important roles in AD by acting as competing endogenous RNAs (ceRNAs). Objective: In this study, we aimed to construct lncRNA-associated ceRNA regulatory networks composed of potential biomarkers in AD based on the ceRNA hypothesis. Methods: A total of 20 genes (10 upregulated genes and 10 downregulated genes) were identified as the hub differentially expressed genes (DEGs). The functional enrichment analysis showed that the most significant pathways of DEGs involved include retrograde endocannabinoid signaling, synaptic vesicle circle, and AD. The upregulated hub genes were mainly enriched in the cytokine-cytokine receptor interaction pathway, whereas downregulated hub genes were involved in the neuroactive ligand-receptor interaction pathway. After convergent functional genomic (CFG) ranks and expression level analysis in different brain regions of hub genes, we found that CXCR4, GFAP, and GNG3 were significantly correlated with AD. We further identified crucial miRNAs and lncRNAs of targeted genes to construct lncRNA-associated ceRNA regulatory networks. Results: The results showed that two lncRNAs (NEAT1, MIAT), three miRNAs (hsa-miR-551a, hsa-miR-133b and hsa-miR-206), and two mRNA (CXCR4 and GNG3), which are highly related to AD, were preliminarily identified as potential AD biomarkers. Conclusion: Our study provides new insights for understanding the pathogenic mechanism underlying AD, which may potentially contribute to the ceRNA mechanism in AD.

Tianqi Wang, Yin Hong, Quanyi Wang, Rongfeng Su, Manwa Lawrence Ng, Jun Xu, Lan Wang, Nan Yan
Identification of Mild Cognitive Impairment Among Chinese Based on Multiple Spoken Tasks
Abstract: Background: Previous studies explored the use of noninvasive biomarkers of speech and language for the detection of mild cognitive impairment (MCI). Yet, most of them employed single task which might not have adequately captured all aspects of their cognitive functions. Objective: The present study aimed to achieve the state-of-the-art accuracy in detecting individuals with MCI using multiple spoken tasks and uncover task-specific contributions with a tentative interpretation of features. Methods: Fifty patients clinically diagnosed with MCI and 60 healthy controls completed three spoken tasks (picture description, semantic fluency, and sentence repetition), from which multidimensional features were extracted to train machine learning classifiers. With a late-fusion configuration, predictions from multiple tasks were combined and correlated with the participants’ cognitive ability assessed using the Montreal Cognitive Assessment (MoCA). Statistical analyses on pre-defined features were carried out to explore their association with the diagnosis. Results: The late-fusion configuration could effectively boost the final classification result (SVM: F1 = 0.95; RF: F1 = 0.96; LR: F1 = 0.93), outperforming each individual task classifier. Besides, the probability estimates of MCI were strongly correlated with the MoCA scores (SVM: -0.74; RF: -0.71; LR: -0.72). Conclusion: Each single task tapped more dominantly to distinct cognitive processes and have specific contributions to the prediction of MCI. Specifically, picture description task characterized communications at the discourse level, while semantic fluency task was more specific to the controlled lexical retrieval processes. With greater demands on working memory load, sentence repetition task uncovered memory deficits through modified speech patterns in the reproduced sentences.

Chenhui Mao, Longze Sha, Jie Li, Xinying Huang, Shanshan Chu, Dan Lei, Jie Wang, Liling Dong, Caiyan Liu, Qi Xu, Bin Peng, Jing Gao
Relationship Between General Cognition, Visual Assessed Cortical Atrophy, and Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease: A Cross-Sectional Study from a Chinese PUMCH Cohort
Abstract: Background: Cerebrospinal fluid (CSF) biomarkers are widely accepted as manifestations of Alzheimer’s disease (AD) pathogenesis and incorporated into biological definition of AD. However, the correlations between CSF and other biomarkers such as neuroimaging and neuropsychiatric evaluation are complicated and inconsistent. Objective: We aimed to better interpreting CSF biomarkers results accompanying with other indexes in improving accurate diagnosis of AD. Methods: 112 AD patients and 30 cognitive normal controls were selected. Commercial accessible ELISA kits were introduced for measurement of CSF t-tau, p-tau181, Aβ1-42, and NfL based on standard protocol. MRI examinations were performed using a 3-T MRI scanner and visual rating scales including medial temporal atrophy score and Koedam’s scale were used to evaluate medial temporal atrophy and posterior region atrophy. Results: CSF biomarkers’ profile including decreased concentration of Aβ1-42, increased concentration of t-tau, p-tau181, t-tau/Aβ1-42, and NfL were diagnostic between AD and control. CSF biomarkers profile was not influenced by the APOE genotype. Increased concentration of t-tau and NfL, as well as ratio of t-tau/Aβ1-42 were related to decrease of Mini-Mental State Examination (MMSE) score while concentration of Aβ1-42 not. Visual assessed cortical atrophy was related to MMSE score, but most of the CSF biomarkers were not related to atrophy, except that increased concentration of p-tau181 was significantly associated with atrophy of posterior cortical region. Conclusion: Our results supported CSF biomarkers were helpful in diagnosis of AD. However, CSF biomarkers were cross-sectional reflection of pathogenesis, which did not correlate well with clinical progression. CSF biomarkers should be interpreted in combination with MRI and cognitive evaluation in clinical use.

Lars Frings, Franziska Henninger, Martin Treppner, Göran Köber, Martin Boeker, Philipp T. Meyer (Handling Associate Editor: Robert Perneczky)
DAT SPECT Predicts Survival in Patients Assessed for Differential Diagnosis of Dementia
Abstract: Background: Dopamine transporter (DAT) SPECT is an established diagnostic procedure in dementia diagnostics, yet its prognostic value is currently unknown. Objective: We evaluated the prognostic value of DAT SPECT in patients assessed for differential diagnosis of dementia. Methods: We included all patients who had received DAT SPECT for differential diagnosis of dementia from 10/2008 to 06/2016 at our site and whose survival status could be obtained in 09/2019. Clinical SPECT reports, categorizing scans into positive or negative for nigrostriatal degeneration (NSD), were tested for their prognostic value (Cox regressions, adjusted for age and sex). In addition, an automated region-of-interest analysis (striatum, occipital cortex as reference) was performed. Results: Median follow-up of 97 included patients was 6.6 years. Patients with NSD had a significantly higher mortality risk than those without NSD (HR=3.6 [2.0-6.7], p < 0.001). Results were confirmed by region-of-interest analysis: higher mortality risk was associated with lower striatal DAT binding (HR = 1.8 per standard deviation loss). Conclusion: Beyond its established utility in dementia diagnostics, DAT SPECT also conveys important prognostic information.

Lilah Besser, Lun-Ching Chang, Kelly R. Evenson, Jana Hirsch, Yvonne Michael, James E. Galvin, Stephen R. Rapp, Annette L. Fitzpatrick, Susan R. Heckbert, Joel D. Kaufman, Timothy M. Hughes
Associations Between Neighborhood Park Access and Longitudinal Change in Cognition in Older Adults: The Multi-Ethnic Study of Atherosclerosis
Abstract: Background: Preliminary evidence suggests associations between neighborhood park access and better late-life cognition and reduced Alzheimer’s disease (AD) risk. Objective: Examine associations between neighborhood park access and longitudinal change in cognition among U.S. older adults without dementia. Methods: We used 2000-2018 observational data from the population-based, multi-site Multi-Ethnic Study of Atherosclerosis (n=1,733). Measures included proportion of neighborhood park space (park access), distance to nearest park, and 6-year dichotomous and continuous change in scores on the Cognitive Abilities Screening Instrument (CASI; global cognition) and Digit Symbol Coding task (processing speed). Multivariable random intercept models tested main associations and mediation by depressive symptoms, physical activity, and PM2.5 exposure. Effect modification by race (African Americans/Blacks versus Whites) was tested using interaction terms. Results: Greater park access (equivalent to 10% more in ½-mile around home) was associated with maintained/improved CASI score over six years independent of several covariates including individual- and neighborhood-level socioeconomic status (Odds ratio: 1.04; 95% confidence interval: 1.00-1.08). No other associations were observed with the dichotomous or continuous measures of cognitive change and no mediators were found. While a borderline association was seen between greater park access and maintained/improved CASI for African Americans/Blacks but not for Whites, effect modification was not confirmed by testing interaction terms. Conclusion: Neighborhood park access may help maintain/improve late-life global cognition. However, our findings need replication in other population-based studies and regions. Additionally, studies are needed to determine if associations between park access and change in cognition vary by race/ethnicity to inform intervention efforts.

Michele Lauriola, Grazia D’Onofrio, Filomena Ciccone, Carmela Germano, Leandro Cascavilla, Francesco Paris, Antonio Greco
Relationship of Homocysteine Plasma Levels with Mild Cognitive Impairment, Alzheimer’s Disease, Vascular Dementia, Psychobehavioral, and Functional Complications
Abstract: Background: Alzheimer’s disease (AD) may be a vascular disorder with neurodegenerative consequences opening possibility of preventing AD by targeting vascular risk factors including homocysteine. Objective: The study aims were to assess homocysteine distribution in different forms and severity of cognitive impairment (CogI) [mild cognitive impairment (MCI), probable AD (Prob-AD), possible AD (Poss-AD), and vascular dementia (VaD)] and in NoCogI, and to estimate possible association between hyperhomocysteinemia levels with functional deficit severity and psychobehavioral complications. Methods: In total, 929 (M=366, F=563; mean age of 72.55±6.24 years) patients were evaluated with cognitive, neuropsychiatric, affective, and functional assessment scales. Homocysteine serum was set on two levels: between 0 and 10 μmol/L and >10 μmol/L. For each patient, blood concentration of folate, vitamin B12, hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), cholesterol, triglycerides, and glycemia were measured. Results: CogI patients demonstrated significantly a higher frequency of homocysteine>10 (p=0.003), than NoCogI patients. Patients with moderate and severe dementia had a higher frequency of homocysteine>10 (p<0.0001), than MCI and mild dementia. Poss-AD and VaD had a higher frequency of homocysteine>10 (p=0.003), than Prob-AD patients. Homocysteine>10 frequency is directly proportional to increased neuropsychiatric symptom severity (p<0.0001), and functional impairment severity respectively for ADL (p<0.0001) and IADL (p<0.0001). Conclusion: Higher homocysteine level seems to be significantly related to cognitive impairment frequency and severity, possible AD and VaD, neuropsychiatric symptom severity, and functional impairment severity.

Mitzi M. Gonzales, Jasmeet Samra, Adrienne O’Donnell, R. Scott Mackin, Joel Salinas, Mini Jacob, Claudia L. Satizabal, Hugo J. Aparicio, Emma G. Thibault, Justin S. Sanchez, Rebecca Finney, Zoe B. Rubinstein, Danielle V. Mayblyum, Ron J. Killiany, Charlie S. Decarli, Keith A. Johnson, Alexa S. Beiser, Sudha Seshadri (Handling Associate Editor: Kaarin Anstey)
Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study
Abstract: Background: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. Objective: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ε4 allele as a moderator. Methods: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ε4 allele were explored. Results: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ε4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β=0.446, SE=0.155, p=0.006) and amygdala (β=0.350, SE=0.133, p=0.012). Conclusion: Although longitudinal studies are necessary, the results suggest that APOE ε4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

Jinbiao Zhang, Haiyan Chi, Tong Wang, Shukun Zhang, Tengqun Shen, Bing Leng, Hairong Sun, Zhenguang Li, Fang Li
Altered Amyloid-β and Tau Proteins in Neural-Derived Plasma Exosomes of Type 2 Diabetes Patients with Orthostatic Hypotension
Abstract: Background: Emerging evidence suggests a role for orthostatic hypotension (OH) in contributing to the progression of Alzheimer’s disease (AD). The exosomes in the blood can reflect the pathological changes in the brain. Objective: To investigate whether neural-derived plasma pathogenic proteins of AD levels are associated with OH in diabetes mellitus (DM) patients. Methods: There were 274 subjects without dementia included in the study: 81 control participants (controls), 101 normotensive patients with DM without OH, and 92 patients with DM and neurogenic OH (DMOH). Neural-derived exosomal proteins were measured by ELISA kits for amyloid-β (Aβ) and tau. Results: The neural-derived exosome levels of Aβ42, total tau (T-tau), and tau phosphorylated at threonine 181 (P-T181-tau) in the DM with OH group were higher than those in the DM and control groups. Multivariable linear regression analysis showed that the presence of OH in patients with DM was associated with elevated exosomal Aβ42 (β = 0.172, p = 0.018), T-tau (β = 0.159, p = 0.030), and P-T181-tau (β = 0.220, p = 0.003) levels after adjustment for age, sex, APOE ε4, duration of type 2 diabetes, HbA1c, and cardiovascular risk factors. Furthermore, the levels of Aβ42, T-tau, and P-T181-tau in neural-derived exosomes were correlated with HIF-1α levels and the drop in mean cerebral blood flow velocity from the supine to upright position. Conclusion: The presence of OH in DM patients was independently associated with elevated the Aβ42, T-tau, and P-T181-tau levels in neural-derived plasma exosomes. Cerebral hypoperfusion from DM with OH are likely candidate mechanisms.

Wen-Jie Cai, Yan Tian, Ya-Hui Ma, Qiang Dong, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yong Liu)
Associations of Anxiety with Amyloid, Tau, and Neurodegeneration in Older Adults without Dementia: A Longitudinal Study
Abstract: Background: The pathophysiological process of amyloid-β, tau deposition, and neurodegeneration of Alzheimer’s disease (AD) begin in a preclinical phase, while anxiety is associated with an increased risk of AD in preclinical phase. Objective: To examine the relationships between anxiety and amyloid-β, tau deposition, and neurodegeneration. To test the hypothesis that anxiety could predict clinical progression in the elderly without dementia. Methods: 1,400 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included in the study and were studied over a median period of 3 years. In multivariable models, the cross-sectional and longitudinal associations between anxiety and amyloid-β PET, tau PET, and FDG PET SUVRs in participants without dementia were explored using Spearman rank correlation, logistic regression model, multiple linear regression model, Kaplan-Meier survival curves, and Cox proportional hazards model. The association between baseline anxiety and clinical progression was also explored. Results: There was a positive correlation between anxiety and amyloid-β deposition (r = 0.11, p = 0.0017) and a negative correlation between anxiety and neurodegeneration (r = - 0.13, p = 0.00022). MCI participants with anxiety showed a faster clinical progression of dementia (HR = 1.56, p =0.04). Non-anxious participants with more amyloid-β deposition or more severe neurodegeneration displayed accelerated development into anxiety (HR = 2.352, p < 0.0001; HR=2.254, p < 0.0001). Conclusion: Anxiety was associated with amyloid-β deposition and neurodegeneration in non-dementia elderly. Anxiety in MCI predicted conversion to dementia. Anxiety may play a selective role and prediction of disease progression in the early phase of AD.

Xuejun Yin*, Qixing Xie*, Lieyu Huang, Liming Liu, Elizabeth Armstrong, Miaomiao Zhen, Jingnian Ni, Jing Shi, Jingzhou Tian**, Wei Cheng** *These authors contributed equally to this work. **Co-corresponding authors
Assessment of the Psychological Burden Among Family Caregivers of People Living with Alzheimer’s Disease Using the Zarit Burden Interview
Abstract: Background: In China, family caregivers play a major role in caring for people living with Alzheimer’s disease (PLWAD), but little is known about the burden this creates. Objective: This study aimed to investigate the burden among family caregivers of PLWAD and the factors influenced it. Methods: Family caregivers of PLWAD were recruited from a hospital in China from January 2018 to July 2018. All data were collected online using the Chinese version of the Zarit Burden Interview (ZBI), and the participants’ sociodemographic and caregiving details were obtained. T-tests and Kruskal-Wallis H (K) tests were used to compare ZBI scores between groups. Factors related to the caregiver psychological burden were analyzed using multiple linear regression analysis. Results: A total of 300 participants were assessed, of which 213 (71.00%) were female. More than half of the caregivers were the patient's daughter (51.0%, n=153). The average ZBI score of the caregivers was 43.05 (13.42). The level of burden was influenced by age, the relationship of the caregiver to the patient, the severity of AD, the caregiver's retirement status, the income level of the caregiver, and the caring time. Regression analysis showed that retired caregivers were more likely to have higher levels of burden and that burden increased with AD severity. Conclusion: Most family caregivers of PLWAD have a considerable caregiver psychological burden. The findings increase the understanding of factors that influence family caregiver burden, and pave the way for potential interventions, such as social support and caregiver empowerment, to reduce their burden.

Wenna Duan, Grace D. Zhou, Arvind Balachandrasekaran, Ashish B. Bhumkar, Paresh B. Boraste, James T. Becker, Lewis H Kuller, Oscar L. Lopez, H. Michael Gach, Weiying Dai
Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer’s Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study
Abstract: Background: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD. Methods: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed. Results: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p=0.00010) and right inferior frontal and insula (p=0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p=0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p=0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p=0.0043), bilateral superior medial frontal regions (BSMF) (p=0.012), and left inferior frontal (p=0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p<0.05; not significant after multiple corrections). Conclusion: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.

Hongqiao Zhang, Carla D’Agostino, Henry Jay Forman, Mafalda Cacciottolo, Max Thorwald, William J. Mack, Qinghai Liu, Kristina Shkirkova, Krista Lamorie-Foote, Constantinos Sioutas, Milad Pirhadi, Wendy Jean Mack, Todd E. Morgan, Caleb E. Finch
Urban Air Pollution Nanoparticles from Los Angeles: Recently Decreased Neurotoxicity
Abstract: Background: Air pollution is widely associated with accelerated cognitive decline at later ages and risk of Alzheimer’s disease (AD). Correspondingly, rodent models demonstrate the neurotoxicity of ambient air pollution and its components. Our studies with nano-sized particulate matter (nPM) from urban Los Angeles collected since 2009 have shown pro-amyloidogenic and pro-inflammatory responses. However, recent batches of nPM have diminished induction of the glutamate receptor GluA1 subunit, Iba1, TNFα, Aβ42 peptide, and white matter damage. The same methods, materials, and mouse genotypes were used throughout. Objective: Expand the nPM batch comparisons and evaluate archived brain samples to identify the earliest change in nPM potency. Methods: Batches of nPM were analyzed by in vitro cell assays for NF-κB and Nrf2 induction for comparison with in vivo responses of mouse brain regions from mice exposed to these batches, analyzed by PCR and western blot. Results: Five older nPM batches (2009-2017) and four recent nPM batches (2018, 2019) for NF-κB and Nrf2 induction showed declines in nPM potency after 2017 that paralleled declines of in vivo activity from independent exposures in different years. Conclusion: Transcription-based in vitro assays of nPM corresponded to the loss of in vivo potency for inflammatory and oxidative responses. These recent decreases of nPM neurotoxicity give a rationale for evaluating possible benefits to the risk of dementia and stroke in Los Angeles populations.

Mouna Tahmi, Brady Rippon, Priya Palta, Greysi Sherwood, Gabriela Hernandez, Luisa Soto, Fernando Ceballos, Michelle Pardo, Krystal Laing, Kay Igwe, Hengda He, Jeanne A. Teresi, Herman Moreno, Qolamreza Razlighi, Adam M. Brickman, José A. Luchsinger
In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics
Abstract: Background: The National Institute on Aging (NIA)/Alzheimer’s Association (AA) 2018 framework conceptualizes Alzheimer’s disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer’s continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. Objective: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. Methods: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15 ± 3.34; 72.0% women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). Results: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). Conclusion: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer’s continuum, was related to verbal learning.

Karissa Barthelson, Yang Dong, Morgan Newman, Michael Lardelli
PRESENILIN 1 Mutations Causing Early-Onset Familial Alzheimer’s Disease or Familial Acne Inversa Differ in Their Effects on Genes Facilitating Energy Metabolism and Signal Transduction
Abstract: Background: The most common cause of early-onset familial Alzheimer’s disease (EOfAD) is mutations in PRESENILIN 1 (PSEN1) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored. Objective: To analyze brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity for psen1 mutations causing EOfAD or fAI. Methods: RNA sequencing was performed on mRNA isolated from the brains of a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenous psen1 gene. Results: Both mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signaling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signaling revealed possible increases in γ-secretase activity due to heterozygosity for either psen1 mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident. Conclusion: We observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases.

Luz Fernández-Aguilar, Yaiza Lora, Encarnación Satorres, Laura Ros, Juan C. Melendez, Jose M. Latorre
Dimensional and Discrete Emotional Reactivity in Alzheimer’s Disease: Film Clips as a Research Tool in Dementia
Abstract: Background: No studies have been conducted to date on the dimensional and discrete classification of emotions to study the emotional reactivity of older adults with Alzheimer’s disease (AD). Additionally, the presentation of film clips with affective content is currently one of the most effective and widely used Mood Induction Procedures (MIPS). However, it has been scarcely used in AD patients. Objective: Based on the dimensional and discrete models of emotion, this study examines the emotional reactivity of older adults with AD, using a popular set of film clips to induce emotions. Methods: We compared the responses of older adults aged 65 years with mild to moderate AD (n=17) and a healthy comparison group (n=17) to six target emotions: disgust, fear, anger, sadness, amusement, and tenderness. Results: The results showed significant differences in the reactivity of fear, anger, and sadness between AD patients and healthy comparison group. However, the responses of the two groups to positive film clips were similar. Only in the amusement clip did the AD participants show a higher intensity response. Conclusion: These findings suggest that the characteristic loss of cognitive abilities in AD is related to a reduction in the ability to react to emotional stimuli, especially negative ones. However, these abilities seem to be preserved when it comes to positive emotions. Future research is necessary to investigate whether the positivity effect is present in AD patients.

Adam S. Bernstein, Steven Z. Rapcsak, Michael Hornberger, Manojkumar Saranathan, the Alzheimer’s Disease Neuroimaging Initiative
Structural Changes in Thalamic Nuclei Across Prodromal and Clinical Alzheimer’s Disease
Abstract: Background: Increasing evidence suggests that thalamic nuclei may atrophy in Alzheimer’s disease (AD). We hypothesized that there will be significant atrophy of limbic thalamic nuclei associated with declining memory and cognition across the AD continuum. Objective: The objective of this work was to characterize volume differences in thalamic nuclei in subjects with early and late mild cognitive impairment (MCI) as well as AD when compared to healthy control (HC) subjects using a novel MRI-based thalamic segmentation technique (THOMAS). Methods: MPRAGE data from the ADNI database were used in this study (n=540). Healthy control (n=125), early MCI (n=212), late MCI (n=114), and AD subjects (n=89) were selected, and their MRI data were parcellated to determine the volumes of 11 thalamic nuclei for each subject. Volumes across the different clinical subgroups were compared using ANCOVA. Results: There were significant differences in thalamic nuclei volumes between HC, late MCI, and AD subjects. The anteroventral, mediodorsal, pulvinar, medial geniculate, and centromedian nuclei were significantly smaller in subjects with late MCI and AD when compared to HC subjects. Furthermore, the mediodorsal, pulvinar, and medial geniculate nuclei were significantly smaller in early MCI when compared to HC subjects. Conclusion: This work highlights nucleus specific atrophy within the thalamus in subjects with early and late MCI and AD. This is consistent with the hypothesis that memory and cognitive changes in AD are mediated by damage to a large-scale integrated neural network that extends beyond the medial temporal lobes.

Ryan McGrath, Sheria G. Robinson-Lane, Brian C. Clark, Julie A. Suhr, Bruno J. Giordani, Brenda M. Vincent
Self-Reported Dementia-Related Diagnosis Underestimates the Prevalence of Older Americans Living with Possible Dementia
Abstract: Background: Dementia screening is an important step for appropriate dementia-related referrals to diagnosis and treat possible dementia. Objective: We sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally representative sample of older Americans with a cognitive impairment consistent with dementia (CICD). Methods: The weighted analytical sample included 6,036,224 Americans aged at least 65 years old that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 Health and Retirement Study. The adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤6 were considered as having a CICD. Healthcare provider dementia-related diagnosis was self-reported. Age, sex, educational achievement, and race and ethnicity were also self-reported. Results: The overall estimated prevalence of no reported dementia-related diagnosis for older Americans with a CICD was 91.4% (95% confidence interval (CI): 87.7%-94.1%). Persons with a CICD who identified as non-Hispanic black had a high prevalence of no reported dementia-related diagnosis (93.3%; CI: 89.8%-95.6%). The estimated prevalence of no reported dementia-related diagnosis was greater in males with a CICD (99.7%; CI: 99.6%-99.8%) than females (90.2%; CI: 85.6%-93.4%). Moreover, the estimated prevalence of no reported dementia-related diagnosis for non-high school graduates with a CICD was 93.5% (CI: 89.3%-96.1%), but 90.9% (CI: 84.7%-94.7%) for those with at least a high school education. Conclusion: Dementia screening should be encouraged during routine geriatric health assessments. Continued research that evaluates the utility of self-reported dementia-related measures is also warranted.

Jay L.P. Fieldhouse, Flora T. Gossink, Thomas C. Feenstra, Sterre C.M. de Boer, Afina W. Lemstra, Niels D. Prins, Femke Bouwman, Ted Koene, Hanneke F.M. Rhodius-Meester, Freek Gillissen, Charlotte E. Teunissen, Wiesje M. van der Flier, Philip Scheltens, Annemiek Dols, Everard G.B. Vijverberg, Yolande A.L. Pijnenburg
Clinical Phenotypes of Behavioral Variant Frontotemporal Dementia by Age at Onset
Abstract: Background: Behavioral variant frontotemporal dementia (bvFTD) is generally considered a young-onset dementia, although age at onset is highly variable. While several studies indicate clinical differences regarding age at onset, no biomarker validated cohort studies with updated clinical criteria have been performed. bjective: We aimed to examine behavior, cognition, and mortality over the full age spectrum in a cohort of bvFTD patients with neuroimaging, genetic, or histopathological confirmation and exclusion of positive Alzheimer’s disease biomarkers or severe cerebrovascular damage. Methods: In total, 315 patients with a clinical diagnosis of probable or definite bvFTD were included from the Amsterdam Dementia Cohort and grouped into quartiles by age-at-diagnosis. Neuropsychiatric symptoms and cognitive functioning were assessed with the neuropsychiatric inventory, the geriatric depression scale and a neuropsychological test battery. Data on mortality was obtained from the Dutch municipal register. Associations between age-at-diagnosis and clinical features and mortality risk were examined. Results: Age-at-diagnosis ranged from 26 to 85 years and established quartiles with mean ages of 52±6, 61±2, 66±2, and 74±3 years. In the total sample, 44.4% exceeded an age of 65 years at time of diagnosis. Earlier age-at-diagnosis was associated with more severe behavioral symptoms, while later age-at-diagnosis was associated with more severe memory impairment. Unexpectedly, mortality risk was not associated with age-at-diagnosis. Conclusion: In bvFTD, symptom profile is associated with age-at-diagnosis. This should be taken into account with regard to diagnostics, patient management, and trial design. Additionally, based on our sample, the prevalence of late-onset bvFTD is higher than generally thought.

Heba M. Tawfik, Rehab R. Desouki, Hamdi A. Singab, Sarah A. Hamza, Salma M.S. El Said
Multidimentional Preoperative Frailty Assessment and Postoperative Complication Risk in Egyptian Geriatric Patients Undergoing Elective Cardiac Surgery
Abstract: Background: Frailty affects up to 51% of the geriatric population in developing countries which leads to increased morbidity and mortality. Objective: To determine the association between pre-operative frailty through multidimentional assessment score, and the incidence of post-operative complications and to validate Robinson score in geriatric Egyptian patients undergoing elective cardiac surgery. Methods: We recruited 180 elderly participants aged 60 years old and above, who underwent elective cardiac surgery. They were divided into frail, pre-frail, and non-frail groups after application of Robinson score (which includes cognitive and functional and fall risk assessment, number of comorbidities, and different laboratory data). Type and duration of operations and the presence and severity of complications at days 3 and 7 post-surgery, and the 30-day readmission rate were assessed. Results: Operation duration and the occurrence of postoperative complications at days 3 and 7 were lowest in non-frail and highest in the frail group (p < 0.001 for both). Length of hospital stay and 30-day readmission rate also increased in the frail group. A positive, moderate correlation between frailty and blood transfusion (r=0.405) and functional dependence (r=0.552) was found at day-3 post-surgery. Finally, logistic regression analysis identified a 6-fold increase in postoperative complications in the frail group (OR=6). Conclusion: Preoperative frailty was associated with higher incidence of postoperative complications among geriatric patients undergoing elective cardiac surgery. Frailty assessment by Robinson score can be considered as an accurate tool to predict postoperative complications during preoperative assessment of elderly patients.

Silvia Rodrigo-Herrero, Andrea Luque-Tirado, Carlota Méndez-Barrio, David García-Solís, María Bernal Sánchez-Arjona, Juan Manuel Oropesa-Ruiz, Didier Maillet, Emilio Franco-Macías
TMA-93 Validation by Alzheimer’s Disease Biomarkers: A Comparison with the Free and Cued Selective Reminding Test on a Biobank Sample
Abstract: Background: The Memory Associative Test TMA-93 examines visual relational binding, characteristically affected in early-AD stages. Objective: We aim to validate the TMA-93 by biomarkers determination and compare its diagnostic characteristics with the Free and Cued Selective Reminding Test (FCSRT). Methods: Retrospective analysis of a Biobank database. Patients’ records initially consulted for memory complaints, scored MMSE ≥22, had TMA-93 and FCSRT tested, and AD biomarker determination (Amyloid-PET or CSF), either positive or negative, were selected. As cutoffs, we considered the 10-percentile for TMA-93 (P10/TMA-93), and "total free recall" (TFR) 21/22, total recall (TR) 43/44, and Cued Index < 0.77 for FCSRT from previous Spanish validation and normative studies. Diagnostic utilities were calculated using ROC curves and compared by the DeLong method. We studied if one test improved the other test's prediction, following a forward stepwise logistic regression model. Results: We selected 105 records: 64 "positive" and 41 "negative" biomarkers. TMA-93 total score diagnostic utility (AUC=0.72; 95%CI:0.62-0.82) was higher than those of the FCSRT: TFR (AUC=0.70; 95%CI: 0.60-0.80), TR (AUC=0.63; 95%CI:0.53-0.74), and Cued Index (AUC=0.62; 95%CI:0.52-0.73). The P10/TMA-93 cutoff showed 86% sensitivity, similar to that of the most sensitive FCSRT cutoff (TFR21/22, 89%) and 29% specificity, lower than that of the most specific FCSRT cutoff (Cued Index<0.77, 57%). 32.8% of the positive-biomarker group scored above CI/0.77 but below p10TMA-93. The addition of TMA-93 total score to FCSRT variables improved significantly the biomarkers results’ prediction. Conclusion: TMA-93 demonstrated "reasonable" diagnostic utility, similar to FCSRT, for discriminating AD biomarker groups. TMA-93 total score improved the AD biomarker result prediction when added to FCSRT variables.

See Ann Soo*, Kok Pin Ng*, Fennie Wong, Seyed Ehsan Saffari, Chathuri Yatawara, Zahinoor Ismail, Nagaendran Kandiah *These authors contributed equally to this work.
The Association Between Diabetes Mellitus and Mild Behavioral Impairment Among Mild Cognitive Impairment: Findings from Singapore
Abstract: Background: Mild behavioral impairment (MBI) describes persistent behavioral changes in later life as an at-risk state for dementia. While cardiovascular risk factors (CVRFs) are linked to dementia, it is uncertain how CVRFs are associated with MBI. Objective: To determine the prevalence of MBI and its association with CVRFs among cognitively normal (CN) and mild cognitive impairment (MCI) individuals in Singapore. Methods: 172 individuals (79 CN and 93 MCI) completed the MBI-checklist (MBI-C). The prevalence of MBI and MBI-C sub-domain characteristics among CN and MCI were examined. Regression models evaluated the relationships between MBI-C sub-domain scores with CVRFs. Results: The prevalence of MBI and mean MBI-C total score were significantly higher among MCI than CN (34.4% versus 20.3%, p=0.022 and 7.01 versus 4.12, p=0.04). The highest and lowest-rated sub-domains among CN and MCI were impulse dyscontrol and abnormal thoughts and perception respectively. Within the MCI cohort, a higher proportion of individuals with diabetes mellitus (DM) had MBI compared to individuals without DM (28.1% versus 10.4%, p=0.025). The interaction of DM and MCI cohort resulted in significantly higher mean MBI-C total, decreased motivation, emotional dysregulation, impulse dyscontrol, and abnormal thoughts and perception sub-domain scores. Conclusion: The prevalence of MBI is higher among a Singapore cohort compared to Caucasian cohorts. The associations of DM with both the presence and severity of MBI among MCI suggest that DM may be a risk factor for MBI. The optimization of DM may be a potential therapeutic approach to improve clinical outcomes among MCI with MBI.

Elizabeth Carolina Jiménez, Alba Sierra-Marcos, August Romeo, Amin Hashemi, Oleksii Leonovych, Patricia Bustos Valenzuela, Maria Solé Puig, Hans Supèr
Altered Vergence Eye Movements and Pupil Response of Patients with Alzheimer’s Disease and Mild Cognitive Impairment During an Oddball Task
Abstract: Background: Alzheimer’s disease (AD) is characterized by progressive deterioration of cognitive functions and may be preceded by mild cognitive impairment (MCI). Evidence shows changes in pupil and vergence responses related to cognitive processing of visual information. Objective: Here we test the hypothesis that MCI and AD are associated with specific patterns in vergence and pupil responses. Methods: We employed a visual oddball task. In the distractor condition (80% of the trials), a blue stimulus was presented whereas in the target condition (20% of trials) it was red. Participants (23 Controls, 33 MCI patients, and 18 AD patients) were instructed to press a button when a target appeared. Results: Participants briefly converged their eyes 200 ms after stimulus presentation. In controls, this transient peak response was followed by a delay response to targets but not to distractor stimuli. In the patient groups, delay responses to distractors were noticed. Consequently, the differential vergence response was strong in the control group, weak in the MCI group, and absent in the AD group. Pupils started to dilate 500-600 ms after the appearance of a target but slightly contracted after the presentation of a distractor. This differential pupil response was strongest in the AD group. Conclusion: Our findings support the idea of a role of vergence and pupil responses in attention and reveal altered responses in MCI and AD patients. Further studies should assess the value of vergence and pupil measurements as an objective support tool for early diagnosis of AD.

Namita Sharma, Geetanjali Murari, Susan Vandermorris, Nicolaas Paul L.G. Verhoeff, Nathan Herrmann, J. Jean Chen, Linda Mah
Functional Connectivity Between the Posterior Default Mode Network and Parahippocampal Gyrus Is Disrupted in Older Adults with Subjective Cognitive Decline and Correlates with Subjective Memory Ability
Abstract:Background: Subjective cognitive decline (SCD) is associated with increased risk of developing Alzheimer’s disease (AD). However, the underlying mechanisms for this association remain unclear. Neuroimaging studies suggest the earliest AD-related changes are large-scale network disruptions, beginning in the posterior default mode (pDMN) network. Objective: To examine the association between SCD and pDMN network connectivity with medial temporal lobe (MTL) regions using resting-state functional magnetic resonance imaging. Methods: Forty-nine participants with either SCD (n=23, 12 females; mean age: 70.7 (5.5)) or who were cognitively unimpaired (CU; n=26, 16 females, mean age: 71.42 (7.3)) completed the Memory Functioning Questionnaire, a measure of subjective memory, and underwent resting state functional MRI at 3 Tesla. Functional connectivity between the posterior cingulate cortex (PCC), as the key pDMN node, and MTL regions were compared between SCD and CU groups. Further, the association between pDMN-MTL connectivity and the Frequency of Forgetting subscale of the Memory Functioning Questionnaire was examined. Results: Connectivity between the PCC-MTL was observed in the CU group but was absent in SCD (t(47) = 2.69, p = 0.01). Across all participants, self-perception of frequency of forgetting, but not objective memory, was strongly correlated with connectivity between the PCC-left parahippocampal gyrus (r = 0.43, p = 0.002). Conclusion: These findings support the hypothesis that increased AD risk in SCD may be mediated by disrupted pDMN-parahippocampal connectivity. In addition, these findings suggest that frequency of forgetting may serve as a potential biomarker of SCD due to incipient AD.

Aurélie Pistono, Mehdi Senoussi, Laura Guerrier, Marie Rafiq, Mélanie Gimeno, Patrice Péran, Mélanie Jucla, Jérémie Pariente
Language Network Connectivity Increases in Early Alzheimer’s Disease
Abstract: Background: Language production deficits occur early in the course of Alzheimer's disease (AD); however, only a few studies have focused on language network’s functional connectivity in mild cognitive impairment (MCI) due to AD. Objective: The current study aims to uncover the extent of language alteration at the MCI stage, at a behavioral and neural level, using univariate and multivariate analyses of structural MRI and resting-state fMRI. Methods: Twenty-four MCI due to AD participants and 24 matched healthy controls underwent a comprehensive language evaluation, a structural T1-3D MRI, and resting-state fMRI. We performed seed-based analyses, using the left inferior frontal gyrus and left posterior temporal gyrus as seeds. Then, we analyzed connectivity between executive control networks and language network in each group. Finally, we used multivariate pattern analyses to test whether the two groups could be distinguished based on the pattern of atrophy within the language network; within the executive control networks, as well as the pattern of functional connectivity within the language network and within the executive control networks. Results: MCI due to AD participants had language impairment during standardized language tasks and connected-speech production. Regarding functional connectivity, univariate analyses were not able to discriminate participants, while multivariate pattern analyses could significantly predict participants’ group. Language network’s functional connectivity could discriminate MCI due to AD participants better than executive control networks. Most notably, they revealed an increased connectivity at the MCI stage, positively correlated with language performance. Conclusion: Multivariate analyses represent a useful tool for investigating the functional and structural (re-)organization of the neural bases of language.