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Background: Conflicting research on retinal biomarkers of Alzheimer's disease and related dementias (AD/ADRD) is likely related to limited sample sizes, study design, and protocol differences. Objective: The prospective Eye Adult Changes in Thought (Eye ACT) seeks to address these gaps. Methods: Eye ACT participants are recruited from ACT, an ongoing cohort of dementia-free, older adults followed biennially until AD/ADRD, and undergo visual function and retinal imaging assessment either in clinic or at home. Results: 330 participants were recruited as of 03/2023. Compared to ACT participants not in Eye ACT (N = 1868), Eye ACT participants (N = 330) are younger (mean age: 70.3 versus 71.2, p = 0.014), newer to ACT (median ACT visits since baseline: 3 versus 4, p < 0.001), have more years of education (17.7 versus 16.2, p < 0.001) and had lower rates of visual impairment (12% versus 22%, p < 0.001). Compared to those seen in clinic (N = 300), Eye ACT participants seen at home (N = 30) are older (77.2 versus 74.9, p = 0.015), more frequently female (60% versus 49%, p = 0.026), and have significantly worse visual acuity (71.1 versus 78.9 Early Treatment Diabetic Retinopathy Study letters, p < 0.001) and contrast sensitivity (-1.9 versus -2.1 mean log units at 3 cycles per degree, p = 0.002). Cognitive scores and retinal imaging measurements are similar between the two groups. Conclusions: Participants assessed at home had significantly worse visual function than those seen in clinic. By including these participants, Eye ACT provides a unique longitudinal cohort for evaluating potential retinal biomarkers of dementia.

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Background: To compare short-term cognitive outcomes among groups with and without neuropsychiatric symptoms (NPSs) or antipsychotic prescription and to determine which disease status or treatment modality is associated with relatively faster cognitive decline. Methods: We retrospectively analyzed a prospective cohort of patients diagnosed with dementia and mild cognitive impairment. All participants were evaluated using the Cognitive Abilities Screening Instrument (CASI) during their initial clinical assessments and at the annual follow-up. The dependent variable was annual delta CASI. Multivariate linear regression analysis was used to assess the degree of association between NPS, antipsychotic use, and cognitive decline after adjusting for confounding factors. Neuropsychiatric symptoms were examined individually to determine their predictive value for cognitive decline. Results: A total of 407 (N = 407) patients were included in the study. NPSs, rather than antipsychotic use, led to faster cognitive decline. A higher baseline NPI total score predicted a significantly faster decline in CASI scores (1-year delta CASI = -0.22, 95% CI = -0.38~ -0.05, p = 0.010). Specific items (delusions, agitation, depression, anxiety, euphoria, and apathy) in the NPS significantly increased cognitive decline. Conclusion: Certain neuropsychiatric symptoms, rather than antipsychotic use, lead to faster cognitive decline in a dementia collaborative care model. Checking for and providing appropriate interventions for NPS in people with dementia and their caregivers are highlighted.

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L5, the most electronegative subfraction of low-density lipoprotein cholesterol (LDL-C), may play a role in the pathogenesis of cerebrovascular dysfunction and neurodegeneration. We hypothesized that serum L5 is associated with cognitive impairment and investigated the association between serum L5 levels and cognitive performance in patients with mild cognitive impairment (MCI). This cross-sectional study conducted in Taiwan included 22 patients with MCI and 40 older people with normal cognition (healthy controls). All participants were assessed with the Cognitive Abilities Screening Instrument (CASI) and a CASI-estimated Mini-Mental State Examination (MMSE-CE). We compared the serum total cholesterol (TC), LDL-C, and L5 levels between the MCI and control groups and examined the association between lipid profiles and cognitive performance in these groups. The serum L5 concentration and total CASI scores were significantly negatively correlated in the MCI group. Serum L5% was negatively correlated with MMSE-CE and total CASI scores, particularly in the orientation and language subdomains. No significant correlation between the serum L5 level and cognitive performance was noted in the control group. Conclusions: Serum L5, instead of TC or total LDL-C, could be associated with cognitive impairment through a disease stage-dependent mode that occurs during neurodegeneration.

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OBJECTIVE: The Cognitive Abilities Screening Instrument (CASI) is a screening test of global cognitive function used in research and clinical settings. However, the CASI was developed using face validity and has not been investigated via empirical tests such as factor analyses. Thus, we aimed to develop and test a parsimonious conceptualization of the CASI rooted in cognitive aging literature reflective of crystallized and fluid abilities. DESIGN: Secondary data analysis implementing confirmatory factor analyses where we tested the proposed two-factor solution, an alternate one-factor solution, and conducted a χ2 difference test to determine which model had a significantly better fit. SETTING: N/A. PARTICIPANTS: Data came from 3,491 men from the Kuakini Honolulu-Asia Aging Study. MEASUREMENTS: The Cognitive Abilities Screening Instrument. RESULTS: Findings demonstrated that both models fit the data; however, the two-factor model had a significantly better fit than the one-factor model. Criterion validity tests indicated that participant age was negatively associated with both factors and that education was positively associated with both factors. Further tests demonstrated that fluid abilities were significantly and negatively associated with a later-life dementia diagnosis. CONCLUSIONS: We encourage investigators to use the two-factor model of the CASI as it could shed light on underlying cognitive processes, which may be more informative than using a global measure of cognition.

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STUDY OBJECTIVES: Dementia is associated with sleep disorders. However, the relationship between dementia and sleep arousal remains unclear. This study explored the associations among sleep parameters, arousal responses, and risk of mild cognitive impairment (MCI). METHODS: Participants with the chief complaints of memory problems and sleep disorders, from the sleep center database of Taipei Medical University Shuang-Ho Hospital, were screened, and the parameters related to the Cognitive Abilities Screening Instrument, Clinical Dementia Rating, and polysomnography were determined. All examinations were conducted within 6 months and without a particular order. The participants were divided into those without cognitive impairment (Clinical Dementia Rating = 0) and those with MCI (Clinical Dementia Rating = 0.5). Mean comparison, linear regression models, and logistic regression models were employed to investigate the associations among obtained variables. RESULTS: This study included 31 participants without MCI and 37 with MCI (17 with amnestic MCI, 20 with multidomain MCI). Patients with MCI had significantly higher mean values of the spontaneous arousal index and spontaneous arousal index in the non-rapid eye movement stage than those without MCI. An increased risk of MCI was significantly associated with increased spontaneous arousal index and spontaneous arousal index in the non-rapid eye movement stage with various adjustments. Significant associations between the Cognitive Abilities Screening Instrument scores and the oximetry parameters and sleep disorder indexes were observed. CONCLUSIONS: Repetitive respiratory events with hypoxia were associated with cognitive dysfunction. Spontaneous arousal, especially in non-rapid eye movement sleep, was related to the risk of MCI. However, additional longitudinal studies are required to confirm their causality. CITATION: Tsai C-Y, Hsu W-H, Lin Y-T, et al. Associations among sleep-disordered breathing, arousal response, and risk of mild cognitive impairment in a northern Taiwan population. J Clin Sleep Med. 2022;18(4): 1003-1012.

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BACKGROUND: The Cognitive Abilities Screening Instrument (CASI) is increasingly used to assess general cognitive function in people with dementia. The Mini-Mental State Examination (MMSE) score can be converted from the CASI (i.e., the estimated MMSE). Recognizing that measurement equivalence is critical to meaningfully representing one with the other, we aimed to determine whether the estimated MMSE score obtained from the CASI was equivalent to the original MMSE in people with dementia. METHODS: We obtained 110 data points for the MMSE and CASI scores in people with dementia. The intraclass correlation coefficient (ICC), Pearson's r, percent of standard error of measurement (SEM%), paired t-test, and effect size (Cohen's d) were used to investigate the equivalence. RESULTS: To examine the equivalence between the original and estimated MMSE score, the ICC and Pearson's r of the total score and six domains were 0.62-0.95 and 0.62-0.96, respectively. The SEM% of the total score and six domains were 0.6-8.9%. The paired t-test results showed a significant difference (p < 0.05) between the total score and the three domains. The Cohen's d of the total score and six domains were 0.06-0.27. CONCLUSIONS: The estimated MMSE score was found to have moderate to excellent equivalence to the original MMSE score. The three domains (i.e., registration, attention and calculation, and visual-constructional ability) with moderate equivalence should be used cautiously to interchange with the original MMSE in people with dementia.

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INTRODUCTION: We modeled associations between glycated hemoglobin (HbA1c) levels (<7%, 7% to 8%, and >8%) and cognitive and physical function among adults 80+ years of age with diabetes and determined whether associations differ by frailty, multimorbidity, and disability. METHODS: A total of 316, adults with diabetes, 80+ years of age, were from the Adult Changes in Thought Study. The Cognitive Abilities Screening Instrument Item Response Theory (CASI-IRT) measured cognition. Short performance-based physical function (sPPF) and gait speed measured physical function. Glycosylated hemoglobin (HbA1c) levels were from clinical measurements. Analyses estimated associations between average HbA1c levels (<7%, 7% to 8%, and >8%) and functional outcomes using linear regressions estimated with generalized estimating equations. RESULTS: sPPF scores did not differ significantly by HbA1c levels. Gait speed did, but only for non-frail individuals; those with HbA1c >8% were slower (-0.10 m/s [95% CI, -0.16 to -0.04]) compared to those with HbA1c 7% to 8%. The association between HbA1c and CASI-IRT varied with age (interaction P = 0.04). At age 80, for example, relative to people with HbA1c levels of 7% to 8%, CASI-IRT scores were, on average, 0.18 points lower (95% CI, -0.35 to -0.02) for people with HbA1c <7% and 0.22 points lower (95% CI, -0.40 to -0.05) for people with HbA1c >8%. At older ages, these estimated differences were attenuated. Estimated associations were not modified by multimorbidity or disability. DISCUSSION: Moderate HbA1c levels of 7% to 8% were associated with better cognition in early but not late octogenarians with diabetes. Furthermore, HbA1c >8% was associated with slower gait speed among those without frailty. These results add to an evidence base for determining glucose targets for very old adults with diabetes.

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BACKGROUND: Cognitive impairment is a public health burden. Our objective was to investigate associations between work hours and cognitive function. METHODS: Multi-Ethnic Study of Atherosclerosis (MESA) participants (n = 2,497; 50.7% men; age range 44-84 years) reported hours per week worked in all jobs in Exams 1 (2000-2002), 2 (2002-2004), 3 (2004-2005), and 5 (2010-2011). Cognitive function was assessed (Exam 5) using the Cognitive Abilities Screening Instrument (version 2), a measure of global cognitive functioning; the Digit Symbol Coding, a measure of processing speed; and the Digit Span test, a measure of attention and working memory. We used a prospective approach and linear regression to assess associations for every 10 hours of work. RESULTS: Among all participants, associations of hours worked with cognitive function of any type were not statistically significant. In occupation-stratified analyses (interaction p = 0.051), longer work hours were associated with poorer global cognitive function among Sales/Office and blue-collar workers, after adjustment for age, sex, physical activity, body mass index, race/ethnicity, educational level, annual income, history of heart attack, diabetes, apolipoprotein E-epsilon 4 allele (ApoE4) status, birth-place, number of years in the United States, language spoken at MESA Exam 1, and work hours at Exam 5 (ß = -0.55, 95% CI = -0.99, -0.09) and (ß = -0.80, -1.51, -0.09), respectively. In occupation-stratified analyses (interaction p = 0.040), we also observed an inverse association with processing speed among blue-collar workers (adjusted ß = -0.80, -1.52, -0.07). Sex, race/ethnicity, and ApoE4 did not significantly modify associations between work hours and cognitive function. CONCLUSION: Weak inverse associations were observed between work hours and cognitive function among Sales/Office and blue-collar workers.

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BACKGROUND: Cognitive dysfunction has been recognized as a diabetes-related complication. Whether hyperglycemia or elevated fasting glucose are associated with cognitive decline remains controversial. We aimed to investigate the relationship between fasting glucose levels and cognitive function in diabetic and non-diabetic individuals. METHODS: Participants were Japanese diabetic (n = 191) and non-diabetic (n = 616) men, aged 46-81 years, from 2010-2014. Blood samples were taken after a 12 h fast. The Cognitive Ability Screening Instrument (CASI), with a maximum score of 100, was used for cognitive assessment. Cognitive domains of CASI were also investigated. Fractional logit regression with covariate adjustment for potential confounders was used to model cross-sectional relationships between fasting blood glucose and CASI score. RESULTS: For diabetic individuals, CASI score was 0.38 (95% confidence interval: 0.66-0.12) lower per 1 mmol/L higher fasting glucose level. Short-term memory domain also exhibited an inverse association. For non-diabetic individuals, a reverse U-shaped relationship was observed between fasting glucose and cognitive function, identifying a threshold for highest cognitive performance of 91.8 CASI score at 3.97-6.20 mmol/L (71.5-111.6 mg/dL) fasting glucose. Language ability domain displayed a similar relationship with fasting glucose. CONCLUSIONS: Elevated fasting glucose levels in diabetic men were associated with lower cognitive function, in which short-term memory was the main associated domain. Interestingly, in non-diabetic men, we identified a threshold for the inverse relationship of elevated fasting glucose with cognitive function. Contrastingly to diabetic men, language ability was the main associated cognitive domain among non-diabetic men.

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BACKGROUND/AIMS: To detect cognitive decline in older adults, measures of verbal fluency and verbal memory are widely used. Less is known about performance in these measures in younger persons or according to education level and gender. We investigated cognitive performance according to age, education and gender among cognitively healthy adults aged 30-100 years. METHODS: The study population comprised 4,174 cognitively healthy persons participating in the nationally representative Finnish Health 2011 survey. Cognitive assessment included verbal fluency, word list memory, word list recall and word list savings from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. RESULTS: Total variance in the cognitive test performance explained by age, education and gender varied from 12.3 to 31.2%. A decreasing trend in cognitive performance existed in all subtests by advancing age, with differences appearing between 50 and 55 years. Persons with the highest-education level performed best for all measures. For the participants < 55 years, education explained part of the variance, while age and gender did not. CONCLUSIONS: When assessing cognition, age and education should be accounted for in more detail in research and clinical practice. Additionally, the cohort effect and its potential impact on the renewal cycle of future normative values for cognitive tests should be considered.

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OBJECTIVES: Cholinesterase inhibitors (ChEIs) are the mainstream treatment for delaying cognitive decline in Alzheimer's disease (AD). Low vitamin B12 is associated with cognitive dysfunction, and its supplementation has been applied as the treatment for certain types of reversible dementia. The present study hypothesized that baseline serum vitamin B12 is associated with the deterioration of cognitive function in people with AD undergoing ChEI treatment. MATERIALS AND METHODS: Between 2009 and 2016, medical records from 165 Taiwanese with mild to moderate AD who underwent ChEI treatment for at least 2 years were reviewed. Their baseline serum vitamin B12 levels were measured before treatment initiation. Their cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI). Student's t test and multivariable logistic regression were used to analyze the association between cognitive decline and vitamin B12 level. Statistical analyses were performed using SPSS 19.0. RESULTS: Overall, 122 participants were women. Their median age was 76 years (ranging from 54 to 91). For people with optimal baseline vitamin B12 (above the median level of 436 ng/L), the rates of MMSE and CASI decline were 0.78 ± 1.28 and 2.84 ± 4.21 per year, respectively, which were significantly slower than those with suboptimal vitamin B12 (1.42 ± 1.67 and 4.94 ± 5.88 per year; p = 0.007 and 0.009, respectively). After adjustment for age, sex, education level, hypertension, diabetes, history of stroke, and baseline cognitive function, the baseline serum vitamin B12 level was negatively associated with MMSE and CASI decline. CONCLUSION: Suboptimal baseline serum vitamin B12 level is associated with cognitive decline in people with AD undergoing ChEI treatment.

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Introduction: Subjective chronic tinnitus is a common medical syndrome with a high frequency of cognitive impairment; however, the characteristics of cognitive impairment in chronic tinnitus are poorly understood. Investigating the scope of cognitive impairment across the severity spectrum of tinnitus patients may shed light on the issue. Methods: A consecutive series of 207 subjective chronic tinnitus patients were classified into mild tinnitus group (n = 95) and severe tinnitus group (n = 112) by THI score (the cutoff THI scores were 37/38). These patients were assessed using the Cognitive Abilities Screening Instrument (CASI) and P300 event-related potential. Results: Although pure tone averages were not different between mild or severe tinnitus patients, severe tinnitus patients scored lower on the CASI assessment as well as almost all subdomains of CASI, particularly in items such as "short-term memory," "concentration or mental manipulation," "orientation," "abstraction and judgment," "language abilities," and "visual construction." Furthermore, compared to mild tinnitus patients, severe tinnitus patients exhibited longer N2 and P3 latencies. Finally, a correlation analysis revealed that tinnitus severity was negatively correlated with CASI score and positively correlated with N2 and P3 latencies. Conclusions: This study reveals that tinnitus patients on the severe end of the spectrum may be at risk for serious cognitive deficits, which may not be a secondary response to disease manifestations but a primary feature of the underlying disease.

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BACKGROUND: The longitudinal change of neuropsychological tests (NPTs) in treated Alzheimer's disease (AD) is essential to understand the interplay of a therapeutic response from medication and a disease decline due to degenerative processes. The aim of our study is to investigate the annual cognitive progression as measured by commonly used NPTs in treated AD patients and to assess the potential predictors of disease progression. METHODS: Participants (N=455) diagnosed with AD and treated with cholinesterase inhibitors (ChEIs) or memantine at memory clinics in three hospitals in southern Taiwan from January 2009 to December 2014 were enrolled in this prospectively registered study. The mean follow-up duration was 3.2 ± 0.9 years. The patients' severity of AD ranged from very mild (clinical dementia rating (CDR) scales = 0.5) to moderate (CDR = 2.0). At baseline and for each year, participants were assessed by various NPTs commonly used in clinical practice, including the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), CDR and CDR-sum of boxes (CDR-SB). All enrolled participants were assessed for at least two years during follow-up. We used mixed-effect models to examine annual progression in the whole group and to compare the cognitive progression between the subgroups with very mild AD and mild to moderate AD. Potential predictors of disease progression, including age, gender, the type of ChEI, and Apolipoprotein E (APOE) genotype, were also analyzed. RESULTS: Among the study population, the rate of change in MMSE scores were -1.15 points per year, CASI scores were -4.27 points per year, and CDR-SB scores were 0.81 points per year. The slope of annual changes of NPTs differed significantly between the CDR 0.5 group and the CDR 1 to 2 group. The most significant predictors of the faster progression were increasing age and higher CDR stage at entry; however, different types of ChEI therapy (donepezil vs. rivastigmine users), and APOE genotype were not associated with the rate of disease progression. CONCLUSIONS: This longitudinal data shows the mean annual change of the MMSE, CASI, CDR, and CDR-SB in treated AD patients. The data may provide clinicians with information regarding to the cognitive decline rate in every year while their AD patients receive approved pharmacological therapy in real-world practice. Increasing age and severity of dementia when receiving therapy are the main factors that associated with faster deterioration.

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BACKGROUND: Naming difficulties have recently garnered more interest in elderly individuals with mild cognitive impairment (MCI). We anticipate that naming tests with the consideration of response time can provide more informative and distinct neuropsychological profiles of individuals with MCI. METHODS: Naming tests were administered to 76 elderly individuals with MCI and 149 healthy elderly (HE). We analyzed the impact of MCI on naming performance and occurrence of "delayed" response. We also validated the predictive power of naming tests with a time-constrained scoring system. RESULTS: MCI participants performed poorer on the noun naming test than HE participants (p = 0.014). MCI was significantly associated with the occurrence of "delayed" response on the noun (odds ratio [OR] = 3.57; 95% confidence interval [CI] = 1.78-7.17) and verb naming tests (OR = 4.66; 95% CI = 2.07-10.46). The time-constrained naming scores were significantly better able to distinguish the MCI from the HE group than the conventional spontaneous naming score on both the noun (p < 0.001) and verb (p = 0.002) naming tests. CONCLUSIONS: Our findings broaden the knowledge related to the naming ability in individuals with MCI, with respect to the response time. We also confirmed the validity of the naming tests by applying the "delayed" responses as supplementary assessments in the diagnosis of MCI.

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Inflammatory process is considered to be a pathway that results in neurodegeneration, and numerous plasma cytokines have been examined for their association with cognitive function and depression. Interleukin-1 alpha (IL-1A) genetic polymorphism (rs1800587) has been found to be associated with Alzheimer's disease susceptibility. The aim of this study was to investigate the effect of IL-1A rs1800587 genetic effects on cognitive functions, loneliness and depression severity in elderly males without dementia or major depression. 192 non-demented Chinese elderly male were recruited and underwent Cognitive Abilities Screening Instrument (CASI), Wechsler Digit Span Task, Geriatric Depression Scale-short form, and UCLA Loneliness Scale assessment. IL-1A rs1800587 is a C to T transition at position -889. Compared to the C/C carriers, the T allele carriers had significantly overall higher CASI score (p=0.017) after using age and total education years as co-variates. This was especially true in the four distinct domains of long-term memory (p<0.001), orientation (p=0.017), visual construction (p=0.003), and list-generating fluency (p=0.020). This polymorphism is not associated with Geriatric Depression Scale-short form or UCLA Loneliness Scale. Our data supports that the T allele of IL-1A rs1800587 genetic polymorphism is associated with better cognitive function in the elderly. Further research will be needed to better understand the molecular mechanism for IL-1A genetic effects on cognitive function in the elderly.

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