Volume 87, Number 3, IN PRESS

Systematic Review
Yan Zhao, Yan Li, Lijing Wang, Zihe Song, Tengsen Di, Xinyi Dong, Xiaohan Song, Xintong Han, Yanyan Zhao, Bingfei Wang, HuiXian Cui, Haiying Chen, Sha Li (Handling Associate Editor: Li-Yong Wu)
Physical Activity and Cognition in Sedentary Older Adults: A Systematic Review and Meta-Analysis
Abstract: Background: Epidemiologic evidence suggests that physical activity benefits cognition, but results from randomized trials in sedentary individuals are limited and inconsistent. Objective: To evaluate the effects of physical activity on cognition among sedentary older adults. Methods: A systematic literature search for eligible studies published up to January 1, 2021, was performed on six international (PubMed, Cochrane Library, Web of Science, Sinomed, FMRS, and OVID) and three Chinese databases (Wanfang, China National Knowledge Infrastructure, and VIP). We estimated the effect of physical activity on the cognition of sedentary elderly by standardized mean differences (SMD) and 95% confidence intervals (CI) using a random-effects model. We evaluated publication bias using funnel plots and heterogeneity using I2 statistics. Subgroup analyses were conducted by baseline cognition, intervention duration, activity type, and country. Results: Seven randomized controlled trials (RCTs) comprising 321 (experimental group, 164; control group, 157) sedentary older adults were included in the meta-analysis. Physical activity significantly improved cognition in sedentary elderly adults compared with controls (SMD: 0.50, 95% CI:0.09–0.92). Subgroup analyses showed significant effects of baseline cognition impairment (SMD: 9.80, 95% CI: 5.81–13.80), intervention duration >12 weeks (SMD: 2.85, 95% CI: 0.73–4.96), aerobic exercise (SMD: 0.74, CI: 0.19–1.29), and countries other than the United States (SMD: 10.50, 95% CI: 7.08–13.92). Conclusion: Physical activity might have a general positive effect on the cognition of sedentary older adults. Intervention >12 weeks and aerobic exercise can effectively delay their cognitive decline; however, more rigorous RCTs are needed to support our findings.

Systematic Review
Alicia Graham, Gill Livingston, Lucy Purnell, Jonathan Huntley
Mild Traumatic Brain Injuries and Future Risk of Developing Alzheimer’s Disease: Systematic Review and Meta-Analysis
Abstract: Background: Traumatic brain injury (TBI) increases the risk of future dementia and Alzheimer’s disease (AD). However, it is unclear whether this is true for mild TBI (mTBI). Objective: To explore the association between mTBI and subsequent risk of developing AD. Method: We systematically searched four electronic databases from January 1954 to April 2020. We included studies reporting primary data and where mTBI preceded AD by ≥5 years. We meta-analyzed included studies for both high quality studies and studies with a follow up of >10 years. Result: We included 5 of the 10,435 results found. Meta-analysis found a history of mTBI increased risk of AD (pooled relative risk=1.18, 95% CI 1.11–1.25, N=3,149,740). The sensitivity analysis including only studies in which mTBI preceded AD by >10 years, excluded two very large studies and resulted in wider confidence intervals (RR = 2.02, 95% CI 0.66- 6.21, N = 2307). Conclusion: There is an increased risk of AD following mTBI. Our findings of increased risk even with mTBI means it cannot be assumed that mild head injuries from sports are harmless. The sensitivity analysis suggests that we cannot exclude reverse causation, and longer follow up times are needed. Implementation of policy to reduce mTBIs, including in children and sportsmen, are urgently needed. Further research is needed on the effect of frequency and age at injury of mTBIs.

Stefanie Sandra Wiloth, Anna Kiefer, Maren Wittek, Tatjana Arroyo y Villora, Monika Obermeier, Eric Schmitt, Andreas Kruse
Rethinking a Traditional Method of Participation: "Town-Hall Meetings" to Support Family Carers of People with Dementia
Abstract: A growing number of people with dementia, a simultaneous decline of professional caregivers, and changing family structures clearly illustrate the societal relevance of the question of how dementia care can be arranged and delivered in the future. The demand for innovative solutions especially to support family carers requires a deeper insight into their life situation and a focused perception of their needs. This article presents the main hypothesis that specific forms of social integration and participation based on an equal dialogue between family caregivers, the public, and policymakers is needed to achieve that. Therefore, the main point here is to give family caregivers of people with dementia a voice to learn how to better support them in caring as well as self-care. A learning process triggered by a dialogue might result in a higher level of community readiness to implement new forms of support or social innovations. The hypothesis will be supported by John Dewey’s theory of political and democratic learning and the model of transformative learning according to Jack Mezirow indicating that learning particularly succeeds in interpersonal communication. In this context, the Town-Hall Meeting method and its potential to promote interpersonal communication and reflexive learning is discussed. The article addresses an important debate, namely that of how dementia care and support of family carers can succeed. It also sets the direction for future empirical research as the Town-Hall Meeting method might be applicable for gerontological action and participatory research.

Short Communication
Andrea Pilotto , Marta Parigi, Giulio Bonzi, Beatrice Battaglio, Elisabetta Ferrari, Lorenza Mensi, Alberto Benussi, Salvatore Caratozzolo, Maura Cosseddu, Rosanna Turrone, Silvana Archetti, Nicholas J Ashton, Henrik Zetterberg, Silvia Giliani, Alessandro Padovani
Differences Between Plasma and Cerebrospinal Fluid p-tau181 and p-tau231 in Early Alzheimer’s Disease
Abstract: Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer’s disease (AD) pathology. In this cross-sectional study including 91 subjects, plasma and cerebrospinal fluid (CSF) p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD. Plasma p-tau231 and p-tau181 were strongly related to CSF phosphorylated tau, total tau and amyloid and exhibited a high accuracy—close to CSF p-tau231 and p-tau181—to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings.

Peter J. Whitehouse, Vikas Saini
Making the Case for the Accelerated Withdrawal of Aducanumab
Abstract: U.S. Food and Drug Administration’s (FDA) approval of aducanumab (Aduhelm® in the US) as a treatment for mild cognitive impairment of the Alzheimer type and Alzheimer’s disease has raised such major concerns about efficacy, safety, FDA processes, and regulatory capture that Biogen’s license to market this biologic should be immediately withdrawn. Aducanumab has not demonstrated benefit to patients, failed to meet regulatory guidelines, and is likely to cause both individual and societal harm.

Meeting Report
Peter Whitehouse, Sam Gandy, Vikas Saini, Daniel R. George, Eric B. Larson, G. Caleb Alexander, Jerry Avorn, Shannon Brownlee, Cameron Camp, Howard Chertkow, Adriane Fugh-Berman, Rob Howard, Aaron Kesselheim, Kenneth M. Langa, George Perry, Edo Richard, Lon Schneider (Handling Editor: Paula Moreira)
Making the Case for Accelerated Withdrawal of Aducanumab
Abstract: The controversial approval in June 2021 by the Food and Drug Administration (FDA) of aducanumab (marketed as Aduhelm), Biogen’s monoclonal antibody for patients with Alzheimer’s disease, raises significant concerns for the dementia field and drug approval process, considering its lack of adequate evidence for clinical efficacy, safety issues, and cost. On 15 December 2021, an international group of clinicians, basic science experts, psychological and social science researchers, lay people with lived experience of dementia, and advocates for public health met to discuss making a recommendation for whether aducanumab’s approval should be withdrawn. Attendees considered arguments both in favor of and in opposition to withdrawal and voted unanimously to recommend that the FDA withdraw its approval for aducanumab and to support the Right Care Alliance’s filing of a formal Citizen Petition to this effect.

Tommaso Costa, Franco Cauda
A Bayesian Reanalysis of the Phase III Aducanumab (ADU) Trial
Background: In December 2019, in light of additional blinded data, Biogen claimed efficacy of the drug Aducanumab (ADU). Objective: We conducted a reanalysis of the phase III ADU summary statistics, focusing in particular on the Clinical Dementia Rating-Sum of Boxes. Methods: We used a Bayesian framework to mitigate the problems null-hypothesis significance testing framework. In particular, we used Bayes Factor (BF) to analyze the summary statistics. The BF is the comparison of how well two hypotheses predict the data. Results: Our results showed that the evidence for ADU efficacy is very low. The results show that the only data with a BF value in favor of the alternative hypothesis (i.e., drug efficacy) is the high-dose condition in the EMERGE trial. However, the obtained BF falls within the range of values considered anecdotal, meaning a low level of evidence. Conclusion: We provide a clearer interpretation of the results of the clinical trials based on the Bayesian framework, as this may be useful for future development and research in the field.

Lucy Beishon, Victoria Haunton, Caroline Bradbury-Jones, Hari Subramaniam, Elizabeta B. Mukaetova-Ladinska, Ronney B. Panerai, Thompson Robinson, Rachel Evley
The Cognition and Flow Study (CogFlowS): A Mixed Method Evaluation of a Randomized Feasibility Trial of Cognitive Training in Dementia
Abstract: Background: Cognitive training (CT) may be beneficial in delaying the onset or slowing dementia progression. CT has been evaluated quantitatively and qualitatively, but none have used mixed methods approaches. Objective: The aim of this study was to use a mixed methods approach to identify those who may selectively benefit from CT. Methods: This was an explanatory sequential mixed methods study involving a quantitative randomized trial of 12 weeks multi-domain CT in healthy older adults (HC, n=20), and people living with mild cognitive impairment (MCI; n=12) and dementia (n=24). Quantitative outcomes included: cognition, mood, quality of life, and activities of daily living. 28 (10 HC, 6 MCI, 12 dementia) training participants completed semi-structured interviews with their carer. Quantitative and qualitative data were integrated using joint displays. Results: Three participants dropped out from the training early-on, leaving 25 participants with follow-up data for full integration (10 HC, 6 MCI, 9 dementia). Dropouts and lower adherence to training were more common in dementia participants with greater non-modifiable barriers. High adherers were more resilient to negative emotions, and poorer or fluctuating performance. Integrated analysis found the majority of participants (n=24) benefited across outcomes, with no clear profile of individuals who benefited more than others. Participants made a number of key recommendations to improve adherence and minimize dropout to CT. Conclusion: Reasons for dropout and low adherence were identified, with recommendations provided for the design of CT for dementia. An individual approach to training should be adopted and low adherence should not preclude engagement with CT.

Valeria Isella*, Cristina Rosazza*, Francesca Ferri, Maria Gazzotti, Valentina Impagnatiello, Cristina Mapelli, Sabrina Morzenti, Cinzia Crivellaro, Ildebrando M. Appollonio, Carlo Ferrarese *These authors contributed equally to this work.
Learning From Mistakes: Cognitive and Metabolic Correlates of Errors on Picture Naming in the Alzheimer’s Disease Spectrum
Abstract: Background: Analysis of subtypes of picture naming errors produced by patients with Alzheimer’s disease (AD) have seldom been investigated yet may clarify the cognitive and neural underpinnings of naming in the AD spectrum. Objective: To elucidate the neurocognitive bases of picture naming in AD through a qualitative analysis of errors. Methods: Over 1000 naming errors produced by 70 patients with amnestic, visuospatial, linguistic, or frontal AD were correlated with general cognitive tests and with distribution of hypometabolism on FDG-PET. Results: Principal component analysis identified 1) a Visual processing factor clustering visuospatial tests and unrecognized stimuli, pure visual errors and visual-semantic errors, associated with right parieto-occipital hypometabolism; 2) a Concept-Lemma factor grouping language tests and anomias, circumlocutions, superordinates, and coordinates, correlated with left basal temporal hypometabolism; 3) a Lemma-Phonology factor including the digit span and phonological errors, linked with left temporo-parietal hypometabolism. Regression of brain metabolism on individual errors showed that errors due to impairment of basic and higher-order processing of object visual attributes, or of their interaction with semantics, were related with bilateral occipital and left occipito-temporal dysfunction. Omissions and superordinates were linked to degradation of broad and basic concepts in the left basal temporal cortex. Semantic-lexical errors derived from faulty semantically- and phonologically-driven lexical retrieval in the left superior and middle temporal gyri. Generation of nonwords was underpinned by impairment of phonological within the left inferior parietal cortex. Conclusion: Analysis of individual naming errors allowed to outline a comprehensive anatomo-functional model of picture naming in classical and atypical AD.

Koki Nagata, Kenji Tsunoda, Yuya Fujii, Taishi Tsuji, Tomohiro Okura
Physical Activity Intensity and Suspected Dementia in Older Japanese Adults: A Dose-Response Analysis Based on an 8-Year Longitudinal Study
Abstract: Background: Moderate- to vigorous-intensity physical activity (PA) may reduce the risk of dementia; however, few studies have examined the effects of PA intensity on dementia risk. Objective: To prospectively examine the dose-response relationship of PA intensity with the incidence of suspected dementia in community-dwelling older adults. Methods: We conducted a baseline mail survey with an 8-year follow-up of 3,722 older adults in Japan. We assessed PA levels using the International Physical Activity Questionnaire short form and calculated the amount of time per week spent performing moderate- and vigorous-intensity PA (VPA). Information regarding suspected dementia was obtained from the city database during the follow-up period. Cox proportional-hazard models with age as time scale, and delayed entry and restricted cubic spline regression as variables were used to estimate risk of developing suspected dementia, excluding cases occurring <1 year after baseline evaluation. Results: The cumulative incidence of suspected dementia during the follow-up period was 12.7%. Compared with those who did not practice moderate-intensity PA (MPA), those who practiced ≥300 min (hazard ratio, 0.73; 95% confidence interval 0.56–0.95) of MPA showed a lower risk of developing suspected dementia. Furthermore, when the dose-response relationship was examined, the hazard of developing suspected dementia decreased almost linearly with MPA. A significantly lower hazard was observed from 815 minutes/week. There was no significant association between VPA and suspected dementia. Conclusion: This study suggested that MPA is often practiced in older adults and this PA intensity has a sufficiently favorable effect on dementia prevention.

Lucio Marinelli, Carlo Trompetto, Luca Puce, Fiammetta Monacelli, Laura Mori, Carlo Serrati, Francesco Fattapposta, Maria Felice Ghilardi, Antonio Currà (Handling Associate Editor: Teresa Liu-Ambrose)
Electromyographic Patterns of Paratonia in Normal Subjects and in Patients with Mild Cognitive Impairment or Alzheimer’s Disease
Abstract: Background: Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia. Objective: To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects. Methods: We examined 18 patients with Alzheimer’s disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the “Paratonia Scale”. EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) and discontinuous (linear) movements were applied at 2 different velocities (fast and slow). Results: In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles. Conclusion: Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles.


Hongwei Wang, Ge Wang, Rebecca Billings, Daniel Li, Shakaye R. Haase, Pariya F. Wheeler, David E. Vance, Wei Li
Can Diet Supplements of Macular Pigment of Lutein, Zeaxanthin, and Meso-zeaxanthin Affect Cognition?
Abstract: Background: Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are collectively called macular pigment. MZ can be converted from L in the macula. In the recent decade, many studies have been performed to investigate the effects for taking carotenoids, especially L and Z or L, Z, and MZ, as diet supplements on human health. Objective: We examined if diet supplements of L+Z or L+Z+MZ have effects on cognitive function in adults. Methods: A systemic literature search was performed in March 2021 with the following keywords: lutein, zeaxanthin, meso-zeaxanthin, cognition, cognitive, and macular pigment. The searched databases included Medline EBSCOhost, Scopus, Elsevier, Cochrane Library, ProQuest, and ClinicalTrials.gov. Findings from eight clinical trials were presented as the strongest evidence on the studied topic. Results: Most studies have found that macular pigments (L+Z) in blood or macula are positively correlated with cognitive performance. As an index of the amount of macular pigments in the brain, macular pigment optical density is related to cognitive performance in adults. In addition, there is an inverse relationship between a higher amount of macular pigment in the blood and lower risk of mild cognitive impairments or Alzheimer’s disease. Based on the findings from the clinical trials, diet supplements of L+Z or L+Z+MZ are associated with improved cognition in adults. Conclusion: The diet supplements of L+Z or L+Z+MZ are associated with better cognitive functioning, which may be via their beneficial effects on the vision.

Danique R. Hutten, Jens H.J. Bos, Stijn de Vos, Eelko Hak
Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer’s Disease: A Retrospective Inception Cohort Study
Abstract: Background: Animal studies suggested that β2-Adrenergic receptors (β2AR) may be a potential target for the treatment of Alzheimer’s disease (AD). Objective: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the β2AR and the risk of starting treatment for AD in older adults. Methods: A retrospective inception cohort study was conducted among older adults who initiated either non-selective βAR antagonists or selective β2AR agonists using the University Groningen IADB.nl prescription database (study period 1994-2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). Results: The risk of developing AD was elevated among patients exposed to non-selective βAR antagonists (A: aHR 3.303, 95% CI 1.230–8.869, B: aHR 1.569, 95% CI 0.560–4.394) and reduced among patients exposed to selective β2AR agonists (A: aHR 0.049, 95% CI 0.003-0.795, B: aHR 0.834, 95% CI 0.075–9.273) compared to reference patients. Conclusion: These findings suggest that exposure to non-selective βAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective β2AR agonists.

Dilip Kumar*, Chathuri Yatawara*, Brian Wang, Benjamin Wong, Yi Jayne Tan, Fatin Zahra Zailan, Kok Pin Ng, Nagaendran Kandiah *These authors contributed equally to this work.
APOE4 and Confluent White Matter Hyperintensities Have a Synergistic Effect on Episodic Memory Impairment in Prodromal Dementia
Abstract: Background: White matter hyperintensities (WMH) are a known risk factor for cognitive decline. While the ε4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline, it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. Objective: To determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. Methods: Two-hundred-sixteen participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain wise), cardiovascular risk factor assessments, and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain-specific cognitive measures. The role of confluent and non-confluent WMH on cognition was additionally studied using logistic regression. Results: APOE4 carriers (n=49) had poorer memory and higher global WMH (10.01 mL versus 6.23 mL, p=0.04), temporal WMH (1.17 mL versus 0.58 mL, p=0.01), and occipital WMH (0.38mL versus 0.22 mL, p=0.02) compared to APOE4 non-carriers (n=167). Moderation analysis revealed that APOE4 positivity strengthened the relationship between higher global as well as lobar WMH burden and poorer episodic memory. Furthermore, APOE4 carriers with confluent WMH were 4.81 times more likely to have impaired episodic memory compared to non-confluent WMH and non-APOE carriers. Conclusion: The impact of WMH on memory may be strongest among APOE4 carriers. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.

Sohyun Jeong, Li-Kai Huang, Ming-Ju Tsai, Yi-Tyng Liao, Yow-Sien Lin, Chaur-Jong Hu, Yi-Hsiang Hsu
Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways
Abstract: Background: Differential abundance of gut microbiota has found to be associated with Alzheimer’s disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied. Objective: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI. Methods: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches. Results: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways were more enriched in MCI AD than dementia AD; and significantly associated with higher cognitive function scores. Conclusion: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.

Antoine Hone-Blanchet, Anastasia Bohsali, Lisa C. Krishnamurthy, Salman S. Shahid, Qixiang Lin, Liping Zhao, Aditya S. Bisht, Samantha E. John, David Loring, Felicia Goldstein, Allan Levey, James Lah, Deqiang Qiu, Bruce Crosson (Handling Associate Editor: Mark Bondi)
Frontal Metabolites and Alzheimer’s Disease Biomarkers in Healthy Older Women and Women Diagnosed with Mild Cognitive Impairment
Abstract: Background: Women account for two thirds of the prevalence and incidence of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aβ1-42) and tau, for which early detection is crucial in the prevention of the disease. Objective: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aβ1-42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. Methods: 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50-85). CSF samples of Aβ1-42 and tau and scores of general cognition were also obtained. Results: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. Conclusion: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aβ1-42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

Tali Cukierman-Yaffe, Shun-Fu Lee, Guillaume Pare, Matthew McQueen, Sibylle Hess, Hertzel C. Gerstein
Biomarkers of Prevalent and Incident Cognitive Dysfunction in People with Dysglycemia- Data from the ORIGIN Trial
Abstract: Background: Diabetes and cardiovascular disease increase the risk of incident cognitive dysfunction. Identification of novel biochemical markers for cognitive dysfunction may identify people at the highest risk while yielding insights regarding the pathophysiology of cognitive dysfunction. Objective: To identify cardiovascular biomarkers in serum that are independent predictors of cognitive dysfunction in individuals with dysglycemia. Methods: This analysis was conducted in 8,365 participants in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial whose stored serum was analyzed for 238 cardio-metabolic biomarkers and completed a baseline Mini-Mental State Examination (MMSE). Fine and Gray sub distribution hazard models accounting for the competing risk of death accounting for clinical risk factors and the baseline MMSE were used to identify biomarkers that predicted incident cognitive dysfunction (MMSE < 24 or dementia) using forward selection with an inclusion p-value < 0.0002 to account for multiplicity. Results: During a median follow-up period of 6.2 years, 939 individuals developed cognitive dysfunction. After accounting for 17 clinical risk factors, glargine allocation, and the baseline MMSE, three biomarkers (α-2 Macroglobulin, HR 1.19; 95%CI 1.12, 1.27; Macrophage Inflammatory Protein 1α, HR 1.11; 95%CI 1.06, 1.16; and Growth Hormone, HR 0.91; 95%CI 0.87, 0.96) independently predicted incident cognitive dysfunction (p<0.0002). Addition of these biomarkers to a model that included clinical risk factors, however, did not improve the ability to predict cognitive dysfunction. Conclusion: Addition of independent biomarkers to clinical risk factors for cognitive dysfunction in people with dysglycemia did not predict incident cognitive dysfunction better than clinical risk factors alone.


Momoyo Shimosaka, Hiroyuki Nishimoto, Ayae Kinoshita
Analysis of the Clock-Reading Ability in Patients with Cognitive Impairment: Comparison of Analog Clocks and Digital Clocks
Abstract: Background: Time disorientation is one of the main symptoms observed in patients with dementia; however, their clock-reading ability has not been fully reported. Objective: This study aimed to investigate the clock-reading ability of both digital and analog clocks in patients with dementia. We newly devised the clock-reading test (CRT) and the number-reading test (NRT) to assess cognitive factors that may affect clock-reading ability. Furthermore, the discriminating power of the CRT was calculated. Methods: 104 participants were categorized based on their Mini-Mental State Examination (MMSE) scores as follows: subjective cognitive decline ~ mild cognitive impairment (SCD~MCI, N = 43), early Alzheimer’s disease (AD) (N = 26), and middle-to-late AD (N = 35). Their cognitive abilities were evaluated using the clock-drawing test (CDT), CRT, and NRT. Results: Cognitive decline leads to impairment of clock-reading ability which is more pronounced in the analog clocks than digital ones. This deficit in clock-reading is attributed to a loss of semantic memory regarding clocks at all stages. Additionally, visuospatial dysfunction and reduced ability of number recognition may lead to deficit in clock-reading in the advanced stage of AD. The discriminating power of the CRT (analog) (AUC = 0.853) was high enough to detect cognitive decline. Conclusion: Digital clocks are more readable by patients with dementia. Since reading clocks is closely associated with daily life, the CRT has proved to be a useful tool. A decline of analog clock-reading may be an early detector for the onset of dementia in elderly patients.

Fred B. Ketchum, Claire M. Erickson, Nathaniel A. Chin, Carey E. Gleason, Nickolas H. Lambrou, Susan Flowers Benton, Lindsay R. Clark
What Influences the Willingness of Blacks and African Americans to Enroll in Preclinical Alzheimer’s Disease Biomarker Research? A Qualitative Vignette Analysis
Abstract: Background: Alzheimer’s disease (AD) begins with an asymptomatic “preclinical” phase, in which abnormal biomarkers indicate risk for developing cognitive impairment. Research is increasingly focused on validating biomarkers to improve reliable diagnosis and timely clinical treatment of AD. Most preclinical biomarker research lacks adequate representation of Black/African American and other racially and ethnically minoritized individuals, limiting the applicability of data to these groups. This may exacerbate existing disparities by hindering diagnosis and treatment among racially and ethnically minoritized individuals. Objective: Understand the factors influencing willingness of Blacks/African Americans to participate in AD biomarker research and identify opportunities to improve enrollment. Methods: We enrolled Blacks/African Americans (N=145) between 46-85 years of age who had previously participated in AD research. Participants gave open-ended responses to a vignette describing a hypothetical biomarker research study. Using qualitative content analysis, we identified themes that motivated and discouraged enrollment in AD biomarker research. Results: Participant responses were categorized into several themes. Themes motivating participation included a desire to know their biomarker results and to support research. Major themes discouraging participation included concerns about potential negative psychological outcomes to learning one’s increased risk for AD, doubt about the usefulness of testing, and worry about the potential physical harms of testing. Conclusion: Understanding themes motivating and discouraging AD preclinical biomarker research participation may inform research material development, approach to community engagement, and/or trial design to increase enrollment of Blacks/African Americans.


Seung-hyup Han, Dong-hee Noh, Eun-Ju Jo, Kyung-Yoon Kam
Effects of Apolipoprotein E ε4 and Risk Factors on Domains of Cognition in Mild Cognitive Impairment and Dementia
Abstract: Background: The apolipoprotein E (APOE) gene is the most potent genetic risk factor for dementia. However, there are few studies on how the APOE gene affects cognitive domain functions. Objective: This study aimed to investigate the effects of risk factors for dementia on cognitive function in patients with mild cognitive impairment and Alzheimer’s disease (AD). Methods: This study included subjects whose Clinical Dementia Rating scores ranged from 0.5 to 2 and who were older than 65 years. Risk factors for dementia included the APOE ε4 allele, age, education period, employment period, body mass index, and exercise. APOE genotyping was performed by polymerase chain reaction, and other factors were identified using medical charts or structured checklists. Cognitive function was measured using the Seoul Neuropsychological Screening Battery II. Results: General cognitive function did not show a significant difference according to APOE ε4 status. However, the score for delayed verbal memory was lower in the APOE ε4-carrier group than in the non-carrier group (p < 0.05). In addition, age, education period, employment period, and exercise were correlated with different cognitive function domains in the non-carrier group (p < 0.05); however, the carrier group was showed a significant correlation between age, body mass index, and cognitive domains. Conclusion: Our findings suggest that APOE ε4 significantly decreases verbal memory in patients with AD. Moreover, the effects of risk factors on cognitive function were significantly different according to the APOE ε4 status.

Takeshi Kawarabayashi, Takumi Nakamura, Kaoru Sato, Yusuke Seino, Sadanobu Ichii, Naoko Nakahata, Masamitsu Takatama, David Westaway, Peter St. George-Hyslop, Mikio Shoji
Lipid Rafts Act as a Common Platform for Amyloid-β Oligomer-Induced Alzheimer’s Disease Pathology
Abstract: Background: Amyloid-β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. Objective: We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. Methods: Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. Results: Aβ dimers, the cellular prion protein (PrPc), and Aβ dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice. Conclusion: Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.


Hiu Yi Wong, Huan Zhong, Mingqian Zhong, Xiaopu Zhou, Phillip Y.C. Chan, Timothy C.Y. Kwok, Kin Mok, John Hardy, Fanny C.F. Ip, Amy K.Y. Fu, Nancy Y. Ip (Handling Associate Editor: Jianping Jia)
Demographics and Medication Use of Patients with Late-Onset Alzheimer’s Disease in Hong Kong
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. Objective: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. Methods: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care of the Hospital Authority between January 1, 2007 and December 31, 2017. Results: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for >1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. Conclusion: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases.

Ying Zhang, Jing Wang, Tingting Sun, Luchun Wang, Tao Li, Huizi Li, Yaonan Zheng, Zili Fan, Ming Zhang, Lihui Tu, Xin Yu, Huali Wang
Decision-Making Profiles and Their Associations with Cognitive Performance in Mild Cognitive Impairment
Abstract: Background: It is crucial for older adults, especially those with mild cognitive impairment (MCI), to make profitable decisions routinely. However, the results regarding decision-making (DM) remain inconsistent. Objective: The present study assessed DM profiles under uncertainty conditions in individuals with MCI and their associations with multi-domain cognitive performance. Method: Fifty-three patients with MCI and forty-two age-, gender-, and education level-matched healthy controls (HCs) were administered a comprehensive neuropsychological battery test. The Iowa Gambling Task (IGT) and Game of Dice Task (GDT) were used to assess DM competence in conditions involving ambiguity and risk, respectively. In addition, Spearman's correlations were used to examine relationships between GDT and multi-domain cognitive performance. Result: The final capital (FC) and frequency of utilization of negative feedback (FUNF) and positive feedback (FUPF) in the GDT were lower in MCI patients than in HCs. In addition, the number of shifts between safe and risky alternatives was significantly different across groups. However, IGT performance was comparable across groups. In the MCI patients, risky DM performance was associated with language, whereas in HCs was correlated with memory and executive functions. Besides, in MCI, performance on IGT was significantly correlated with social cognition. Conclusion: Individuals with mild cognitive impairment have difficulty utilizing feedback to make optimal decisions under risky situations. The association between decision-making performance and cognitive function is divergent regarding situational uncertainty and individuals' cognitive status. In mild cognitive impairment and normal aging, decision-making under ambiguity needs further investigation.

Brady Rippon, Priya Palta, Mouna Tahmi, Greysi Sherwood, Luisa Soto, Sandino Cespedes, Yanette Mesen, Hengda He, Krystal Laing, Herman Moreno, Jeanne Teresi, Qolamreza Razlighi, Adam M. Brickman, Henrik Zetterberg, José A. Luchsinger
Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics
Abstract: Background: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. Objective: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (SimoaTM) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ε4 with plasma Aβ. Methods: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ42/Aβ40 ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. Results: Plasma Aβ42/Aβ40 ratio was inversely associated with global Aβ SUVR (β = -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ε4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p < 0.0001) showed that the optimal threshold for plasma Aβ42/Aβ40 ratio in relation to brain Aβ positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ε4 carriers had lower Aβ42/Aβ40 ratio and a higher Aβ positivity determined with the Aβ42/Aβ40 ratio threshold of 0.060. Conclusion: Plasma Aβ42/Aβ40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

Daniela Andriuta, Cherifa Si-Ahmed, Martine Roussel, Jean-Marc Constans, Malek Makki, Ardalan Aarabi, Damien Basille, Claire Andrejak, Olivier Godefroy
Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints
Abstract: Background: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants. Objective: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants. Methods: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance. Results: Repeated ANOVA showed a group effect (p=0.0001) due to overall lower performance for patients and a domain effect (p=0.0001) due to a lower (p=0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2=0.319, p=0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p<0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus. Conclusion: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.

Christopher E. Ramsden, Gregory S. Keyes, Elizabeth Calzada, Mark S. Horowitz, Daisy Zamora, Jahandar Jahanipour, Andrea Sedlock, Fred E. Indig, Ruin Moaddel, Dimitrios Kapogiannis, Dragan Maric
Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer’s Disease in Humans
Abstract: Background: Sporadic Alzheimer’s disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the core of neuritic plaques, hallmark plaques and tangles, and selective vulnerability of entorhinal-hippocampal structures. Objective: We hypothesized that 1) high expression of ApoER2 (receptor for ApoE and Reelin) helps explain this anatomical vulnerability; 2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting neuronal ApoE delivery and Reelin-ApoER2-Dab1 signaling cascades. Methods: In vitro biochemical experiments; Single-marker and multiplex fluorescence-immunohistochemistry (IHC) in postmortem specimens from 26 individuals who died cognitively normal, with mild cognitive impairment or with sAD. Results: ApoE and ApoER2 peptides and proteins were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using in situ hybridization alongside IHC, we observed that: 1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal ‘perforant path’ projections that underlie memory; 2) ApoE, lipid aldehyde-modified ApoE, Reelin, ApoER2, and the downstream Reelin-ApoER2 cascade components Dab1 and Thr19-phosphorylated PSD95 accumulated in the vicinity of neuritic plaques in perforant path terminal zones in sAD cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers were higher in sAD cases and positively correlated with histological progression and cognitive deficits. Conclusion: Results demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in sAD and provide proof-of-concept that ApoE and ApoER2 are vulnerable to aldehyde-induced adduction and crosslinking. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE and ApoE receptors in sAD.

Yuan Fang, Margaret F. Doyle, Michael L. Alosco, Jesse Mez, Claudia L. Satizabal, Wei Qiao Qiu, Kathryn L. Lunetta, Joanne M. Murabito (Handling Associate Editor: M. Arfan Ikram)
Cross-Sectional Association Between Blood Cell Phenotypes, Cognitive Function, and Brain Imaging Measures in the Community-Based Framingham Heart Study
Abstract: Background: Peripheral inflammation is associated with increased risk for dementia. Neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), are easily measured circulating blood cell phenotypes reflecting chronic peripheral inflammation, but their association with dementia status is unclear. Objective: We sought to investigate the cross-sectional association of these inflammatory measures with neuropsychological (NP) test performance, and brain magnetic resonance imaging (MRI) measures in the Framingham Heart Study (FHS) Offspring, Third-generation, and Omni cohorts. Methods: We identified FHS participants who attended an exam that included a complete blood cell count (CBC) and underwent NP testing (n = 3,396) or brain MRI (n = 2,770) within five years of blood draw. We investigated the association between NLR, RDW, and MPV and NP test performance and structural MRI-derived volumetric measurements using linear mixed effect models accounting for family relationships and adjusting for potential confounders. Results: Participants were on average 60 years old, 53% female, and about 80% attended some college. Higher NLR was significantly associated with poorer performance on visual memory, and visuospatial abilities, as well as with larger white matter hyperintensity volume. We also observed associations for higher RDW with poorer executive function and smaller total cerebral brain volume. Conclusion: Chronic peripheral inflammation as measured by NLR and RDW was associated with worse cognitive function, reduced brain volume, and greater microvascular disease in FHS participants. If confirmed in other samples, CBC may provide informative and cost-effective biomarkers of abnormal brain aging in the community.

Emilia Schwertner, Joana B. Pereira, Hong Xu, Juraj Secnik, Bengt Winblad, Maria Eriksdotter, Katarina Nägga, Dorota Religa
Behavioral and Psychological Symptoms of Dementia in Different Dementia Disorders: A Large-Scale Study of 10,000 Individuals
Abstract: Background: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden. Objective: To characterize BPSD in Alzheimer’s disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities. Methods: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs. Results: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD. Conclusion: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

Can Sheng, Kun Yang, Beiqi He, Taoran Li, Xiaoqi Wang, Wenying Du, Xiaochen Hu, Jiehui Jiang, Xueyan Jiang, Frank Jessen, Ying Han
Cross-Cultural Longitudinal Study on Cognitive Decline (CLoCODE) for Subjective Cognitive Decline in China and Germany: A Protocol for Study Design
Abstract: Background: Subjective cognitive decline (SCD) is considered as the first symptomatic manifestation of Alzheimer’s disease (AD), which is also affected by different cultural backgrounds. Establishing cross-cultural prediction models of SCD is challenging. Objective: To establish prediction models of SCD available for both the Chinese and European populations. Methods: In this project, 330 SCD from China and 380 SCD from Germany are intended to be recruited. For all participants, standardized assessments, including clinical, neuropsychological, apolipoprotein E (APOE) genotype, blood, and multi-parameter magnetic resonance imaging (MRI) at baseline will be conducted. Participants will voluntarily undergo amyloid positron emission tomography (PET) and are classified into amyloid-β (Aβ) positive SCD (SCD+) and Aβ negative SCD (SCD-). First, baseline data of all SCD individuals between the two cohorts will be compared. Then, key features associated with brain amyloidosis will be extracted in SCD+ individuals, and the diagnosis model will be established using the radiomics method. Finally, the follow-up visits will be conducted every 12 months and the primary outcome is the conversion to mild cognitive impairment or dementia. After a 4-year follow-up, we will extract factors associated with the conversion risk of SCD using Cox regression analysis. Results: At present, 141 SCD from China and 338 SCD from Germany have been recruited. Initial analysis showed significant differences in demographic information, neuropsychological tests, and regional brain atrophy in SCD compared with controls in both cohorts. Conclusion: This project may be of great value for future implications of SCD studies in different cultural backgrounds.

Elisabet Classon, Wobbie van den Hurk, Johan Lyth, Maria M. Johansson
Montreal Cognitive Assessment: Normative Data for Cognitively Healthy Swedish 80- to 94-Year-Olds
Abstract: Background: The Montreal Cognitive Assessment (MoCA) is sensitive to cognitive impairment; however, it is also sensitive to demographic and socio-cultural factors. This necessitates reliable sub-population norms, but these are often lacking for older adults. Objective: To present demographically adjusted regression-based MoCA norms for cognitively healthy Swedish older adults. Methods: A pseudo-random sample of community-dwelling 80- to 94-year-olds, stratified by age and gender, was invited to the study. Initial telephone interviews and medical records searches (n=218) were conducted to screen for cognitive impairment. N=181 eligible participants were administered a protocol including the Swedish version of the MoCA and assessments of global cognition (Mini-Mental State Examination, MMSE) and depression (Patient Health Questionnaire-9, PHQ-9). Individuals scoring in the range of possible cognitive impairment on the MMSE or more than mild depression on the PHQ-9 were excluded (n=23); three discontinued the test-session. Results: Norms were derived from the remaining n=158. They were evenly distributed by gender, on average 85 years old, and with a mean education of 11 years. MoCA scores were independently influenced by age and education, together explaining 17.2% of the total variance. Higher age and lower education were associated with lower performance and 46% performed below the original cut-off (<26/30). Conclusion: The negative impact of increasing age on MoCA performance continues linearly into the nineties in normal aging. Demographic factors should be considered when interpreting MoCA performance and a tool for computing demographically corrected standard scores is provided.

Ghazal Mirabnahrazam, Da Ma, Sieun Lee, Karteek Popuri, Hyunwoo Lee, Jiguo Cao, Lei Wang, James E. Galvin, Mirza Faisal Beg, and the Alzheimer’s Disease Neuroimaging Initiative
Machine Learning Based Multimodal Neuroimaging Genomics Dementia Score for Predicting Future Conversion to Alzheimer’s Disease
Abstract: Background: The increasing availability of databases containing both magnetic resonance imaging (MRI) and genetic data allows researchers to utilize multimodal data to better understand the characteristics of dementia of Alzheimer’s type (DAT). Objective: The goal of this study was to develop and analyze novel biomarkers that can help predict the development and progression of DAT. Methods: We used feature selection and ensemble learning classifier to develop an image/genotype-based DAT score that represents a subject’s likelihood of developing DAT in the future. Three feature types were used: MRI only, genetic only, and combined multimodal data. We used a novel data stratification method to better represent different stages of DAT. Using a pre-defined 0.5 threshold on DAT scores, we predicted whether a subject would develop DAT in the future. Results: Our results on Alzheimer’s Disease Neuroimaging Initiative (ADNI) database showed that dementia scores using genetic data could better predict future DAT progression for currently normal control subjects (Accuracy=0.857) compared to MRI (Accuracy=0.143), while MRI can better characterize subjects with stable mild cognitive impairment (Accuracy=0.614) compared to genetics (Accuracy=0.356). Combining MRI and genetic data showed improved classification performance in the remaining stratified groups. Conclusion: MRI and genetic data can contribute to DAT prediction in different ways. MRI data reflects anatomical changes in the brain, while genetic data can detect the risk of DAT progression prior to the symptomatic onset. Combining information from multimodal data in the right way can improve prediction performance.

Gilad Fefer*, Wojciech K. Panek*, Michael Z. Khan, Matthew Singer, Hans D. Westermeyer, Freya M. Mowat, David M. Murdoch, Beth Case, Natasha J. Olby, Margaret E. Gruen *These authors contributed equally to this work.
Use of Cognitive Testing, Questionnaires, and Plasma Biomarkers to Quantify Cognitive Impairment in an Aging Pet Dog Population
Abstract: Background: Aging dogs may suffer from canine cognitive dysfunction syndrome (CCDS), a condition in which cognitive decline is associated with amyloid pathology and cortical atrophy. Presumptive diagnosis is made through physical examination, exclusion of systemic/metabolic conditions, and completion of screening questionnaires by owners. Objective: This study aimed to determine whether cognitive function could be quantified in aging pet dogs, and to correlate cognitive testing with validated questionnaires and plasma neurofilament light chain (pNfL) concentration. Methods: Thirty-nine dogs from fifteen breeds were recruited (9.3 to 15.3 years). Owners completed the Canine Dementia Scale (CADES) and Canine Cognitive Dysfunction Rating scale (CCDR). Executive control and social cues were tested, and pNfL was measured with single molecule array assay. Comparisons were made between cognitive testing scores, CADES, CCDR scores, and pNfL. Results: CADES scoring classified five dogs as severe CCDS, six as moderate, ten as mild, and eighteen as normal. CCDR identified seven dogs at risk of CCDS and thirty-two as normal. Cognitive testing was possible in the majority of dogs, although severely affected dogs were unable to learn tasks. CADES score correlated with sustained attention duration (r=-0.47, p=0.002), inhibitory control (r=-0.51, p=0.002), detour (r=-0.43, p=0.001), and pNfL (r=0.41, p=0.025). Concentration of pNfL correlated with inhibitory control (r=-0.7, p0.001). The CCDR scale correlated with performance on inhibitory control (r=-0.46, p=0.005). Conclusion: Our findings suggest that a multi-dimensional approach using a combination of questionnaires, specific cognitive tests, and pNfL concentration can be used to quantify cognitive decline in aging pet dogs.

Josué Llamas-Rodríguez, Jan Oltmer, Douglas N. Greve, Emily Williams, Natalya Slepneva, Ruopeng Wang, Samantha Champion, Melanie Lang-Orsini, Bruce Fischl, Matthew P. Frosch, André J.W. van der Kouwe, Jean C. Augustinack (Handling Associate Editor: Goran Simic)
Entorhinal Subfield Vulnerability to Neurofibrillary Tangles in Aging and the Preclinical Stage of Alzheimer’s Disease
Abstract: Background: Neurofibrillary tangle (NFT) accumulation in the entorhinal cortex (EC) precedes the transformation from cognitive controls to mild cognitive impairment and Alzheimer’s disease (AD). While tauopathy has been described in the EC before, the order and degree to which the individual subfields within the EC are engulfed by NFTs in aging and the preclinical AD stage is unknown. Objective: We aimed to investigate substructures within the EC to map the populations of cortical neurons most vulnerable to tau pathology in aging and the preclinical AD stage. Methods: We characterized phosphorylated tau (CP13) in 10 cases at eight well-defined anterior-posterior levels and assessed NFT density within the eight entorhinal subfields (described by Insausti and colleagues) at the preclinical stages of AD. We validated with immunohistochemistry and labeled the NFT density ratings on ex vivo MRIs. We measured subfield cortical thickness and reconstructed the labels as three-dimensional isosurfaces, resulting in anatomically comprehensive, histopathologically validated tau “heat maps.” Results: We found the lateral EC subfields ELc, ECL, and ECs (lateral portion) to have the highest tau density in semi-quantitative scores and quantitative measurements. We observed significant stepwise higher tau from anterior to posterior levels (p < 0.001). We report an age-dependent anatomically-specific vulnerability, with all cases showing posterior tau pathology, yet older individuals displaying an additional anterior tau burden. Finally, cortical thickness of each subfield negatively correlated with respective tau scores (p < 0.05). Conclusion: Our findings indicate that posterior-lateral subfields within the EC are the most vulnerable to early NFTs and atrophy in aging and preclinical AD.

Lauren K.S. Lei, Bess Y.H. Lam, Daniel W.L. Lai, Xue Bai, Jessica Li, Zhi Zou, Chetwyn C.H. Chan (Handling Associate Editor: Stelios Zygouris)
Stability of Montreal Cognitive Assessment in Individuals with Mild Cognitive Impairment: Potential Influence of Practice Effect
Abstract: Background: The Montreal Cognitive Assessment (MoCA) is a standard test for screening and monitoring cognitive functions. Objective: This study explored the two-year changes in MoCA scores in older adults. Methods: Fifty-seven participants with mild cognitive impairment (MCI) and 87 participants with normal cognition completed the baseline and two-year follow-up assessments. Apart from MoCA, tests on visuospatial judgment, memory, and motor-related executive function were administered. Results: The results identified three MCI subgroups based on the differential changes in MoCA scores. They were the consistently low, consistently high, and low-to-high between-time performances. These heterogeneous test performances are on contrary to the significant deteriorations in executive function and finger dexterity across all subgroups. Repeated exposure to MoCA tests during the follow-up period was found to be a plausible indicator of the MCI subgroup categorization. Conclusion: Findings raise concerns over adopting brief clinical instrument for repeated testing, such as MoCA, for monitoring MCI conditions among older adults.

Book Review
The First Survivors of Alzheimer’s: How Patients Recovered Life and Hope in Their Own Words by Dale Bredesen, Avery, 2021, 272 pp. Reviewed by Timothy Daly and Ignacio Mastroleo