Interactions between weight loss and plasma neurodegenerative markers for determining cognitive decline among community-dwelling older adults

This study aimed to investigate the interaction between weight loss (WL) and plasma amyloid-β42/40 (Aβ42/40), neurofilament light chain (NfL), progranulin, and their association with cognitive decline over time among older adults. This 5-year observational approach included 470 participants from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8y (SD=4.5), 59.4% women. WL was defined as ≥5% decrease over the first year. Biomarkers were measured at 12 months. Cognitive function was assessed yearly from 12 months onwards by Mini-Mental State Examination (MMSE); Clinical Dementia Rating sum of boxes (CDR-SB); a composite score based on Category Naming Test, Digit Symbol Substitution Test, ten MMSE orientation items (MMSEO) and Free and total recall of the Free and Cued Selective Reminding test; and these tests individually. Twenty-seven participants (5.7%) presented WL. In adjusted analyses, combined WL+lower Aβ42/40 (≤0.103, lowest quartile) was related with more pronounced 4-year cognitive decline according to CDR-SB (p<0.0001) and MMSEO (p=0.021), compared to non-WL+higher Aβ42/40. WL+higher NfL (>94.55pg/mL, highest quartile) or progranulin (>38.4ng/mL, three higher quartiles) were related with higher cognitive decline according to CDR-SB, MMSE, MMSEO and composite score (all p<0.03), compared to non-WL+lower NfL or higher progranulin. Regrouping progranulin quartiles (Q1-Q3 vs. Q4) revealed higher cognitive decline among the WL+lower progranulin group compared to non-WL+lower progranulin. In conclusion, 1-year WL was associated with subsequent higher 4-year cognitive decline among older adults presenting low Aβ42/40 or high NfL. Future studies combining plasma biomarker assessments and body weight surveillance may be useful for identifying people at risk of cognitive impairment.

Rare Genetic Variants Correlate with Better Processing Speed

We conducted a genome-wide association study (GWAS) of Digit Symbol Substitution Test (DSST) scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ~15M genetic variants with quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from two Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p-value < 5x10-8). Among these, 18 variants had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059 on chromosome 3, which were replicated in the combined Danish twin cohort. These SNPs are located in/near two genes, THRB and RARB, that belonged to thyroid hormone receptors family that may influence speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these two genes are associated with processing speed.

Financial Incapacity of Patients with Mild Alzheimer’s Disease: What Neurologists Need to Know about Where the Impairment Lies

Research in the last decade has focused on assessing financial capacity and incapacity mainly in old age, but new research has turned to address the question of how financial incapacity can be predicted by cognitive factors. The aim of this study was to identify which cognitive domains predict financial capacity and the relevant cognitive skills of patients with mild Alzheimer’s disease (AD) in order to assist neurologists in functional assessment and further patient referral. In this study, 109 patients diagnosed with mild AD were examined with a number of neuropsychological tests: Mini-Mental State Examination (MMSE), Functional Rating Scale for Symptoms of Dementia (FRSSD), Functional Cognitive Assessment Scale (FUCAS), Trail Making Test (TMT)-Part B, Rey-Osterrieth Complex Figure Test (ROCFT)-copy condition and delayed recall condition, Rey Auditory Verbal Learning Test (RAVLT), Boston Naming Test, Rivermead Behavioural Memory Test (RBMT), digit span forward and backward, WAIS-R digit symbol substitution test, Neuropsychiatric Inventory (NPI), Geriatric Depression Scale (GDS-15), and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS). LCPLTAS total score and relevant subdomains were best predicted only by the score of one item coming from MMSE: subtraction of serial sevens. This is the only measure of arithmetic testing in use for the Greek geriatric population. Financial capacity is severely impaired in the group of mild AD patients. In order to prevent financial exploitation cases, neurologists, neuropsychologists, psychiatrists, and geriatrists should pay close attention to the information from the relevant arithmetic question of MMSE, as it is one of the most widely administered screening tests in clinical settings.

Association Between Urinary Flow Rate and Cognition in the Elderly: A Cross-Sectional Study

Background Age-related lower urinary tract symptoms (LUTS) is a common disease in the elderly. The reduction of urinary flow rate (UFR) as an assessment of LUTS is associated with cognitive impairment. The association between UFR and cognitive performance has not been studied to date. Methods We used data from the 2011 to 2014 U.S. National Health and Nutrition Examination Survey (NHANES). Finally, 2,724 participants aged 65-80 with available data on UFR and cognitive assessments were included. The cognitive function assessment used the digit symbol substitution test (DSST), Animal Fluency Test (AFT) and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) immediate recall test. Multivariate logistic regressions were used to assess the association between UFR (exposure) and cognitive performance (outcome). Additionally, to ensure the reliability of data analysis, we converted UFR into categorical variables through tertile and then calculated the P for trend. Results Among 2,724 participants, the mean (SD) age was 69.26 (6.65) years, and 54.56% were women. After adjusting for covariates, UFR showed a positive correlation with DSST score (β = 2.00, [95%Cl:1.20-2.80], P<0.0001), AFT score (β = 0.57,[95%Cl:0.28-0.87], P=0.0001), CERAD immediate score(β = 0.24, [95%Cl:0.01-0.47], P=0.0435). In addition, we found a similar linear trend when UFR was regarded as a categorical variable (tertile) (P for trend <0.0001(both in AFT and DSST); P for trend =0.0403 in CERAD immediate test). Conclusions The decrease of UFR is related to cognitive decline in the elderly, which may suggest that UFR may be a clinical marker of predicting cognitive decline.

Age Related Prevalence of Mild Cognitive Impairment in Type 2 Diabetes Mellitus Patients in the Indian Population and Association of Serum Lipids With Cognitive Dysfunction

The magnitude of type 2 diabetes mellitus (T2DM) is ever-increasing in India, and at present, ~77 million people live with diabetes. Studies have established that T2DM increases the risk of neurodegenerative disorders. This study aimed to determine the age-related prevalence of mild cognitive impairment (MCI) in T2DM patients in the Indian population and to identify link between cognitive dysfunction in T2DM patients and serum lipid composition through untargeted and targeted lipidomic studies. Using a cross-sectional study, we evaluated 1278 T2DM patients with Montreal cognitive assessment test (MoCA) and digit symbol substitution test (DSST) for cognitive functions. As per MoCA, the prevalences of MCI in T2DM patients in age groups below 40, 41-50, 51-60, 61-70, 71-80 and 81-90 years were 13.7, 20.5, 33.5, 43.7, 57.1 and 75% with DSST scores of 45.8, 41.7, 34.4, 30.5, 24.2 and 18.8% respectively. Binomial logistic regression analysis revealed serum HbA1c ≥ 7.51, duration of T2DM over 20 years, age above 41 years, and females were independent contributors for cognitive dysfunction in T2DM patients. Preliminary studies with untargeted lipidomics of the serum from 20 T2DM patients, including MCI and normal cognition (NC) group, identified a total of 646 lipids. Among the identified lipids, 33 lipids were significantly different between MCI and NC group, which comprised of triglycerides (TGs, 14), sphingolipids (SL, 11), and phosphatidylcholines (PC, 5). Importantly, 10 TGs and 3 PCs containing long-chain polyunsaturated fatty acids (PUFA) were lower, while 8 sphingolipids were increased in the MCI group. Since brain-derived sphingolipids are known to get enriched in the serum, we further quantified sphingolipids from the same 20 serum samples through targeted lipidomic analysis, which identified a total of 173 lipids. Quantitation revealed elevation of 3 species of ceramides, namely Cer (d18:1_24:1), Hex1Cer (d16:0_22:6), and Hex2Cer (d28:1) in the MCI group compared to the NC group of T2DM patients. Overall, this study demonstrated an age-related prevalence of MCI in T2DM patients and highlighted reduced levels of several species of PUFA containing TGs and PCs and increased levels of specific ceramides in T2DM patients exhibiting MCI. Large-scale lipidomic studies in future could help understand the cognitive dysfunction domain in T2DM patients, while studies with preclinical models are required to understand the functional significance of the identified lipids.

Individual and Combined Associations of Glucose Metabolic Components With Cognitive Function Modified by Obesity

AimWe aimed to detect the individual and combined effect of glucose metabolic components on cognitive function in particular domains among older adults.MethodsData of 2,925 adults aged over 60 years from the 2011 to 2014 National Health and Nutrition Examination Survey were analyzed. Individuals’ cognitive function was evaluated using the Digit Symbol Substitution Test (DSST), the Animal Fluency Test (AF), the Consortium to Establish a Registry for Alzheimer’s Disease Immediate Recall (CERAD-IR), and CERAD Delayed Recall (CERAD-DR). Participants’ glucose metabolic health status was determined based on fasting plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), and 2-h postload glucose. Linear regression models were used to delineate the associations of cognitive function with individual glucose metabolic component and with metformin use. Logistic regression models were performed to evaluate the associations of cognition with the number of glucose metabolic risk components.ResultsCERAD-IR was significantly associated with HOMA-IR and insulin. HbA1c was related to all the cognitive tests except AF. Among participants without obesity, HOMA-IR and insulin were both negatively associated with CERAD-IR and CERAD-DR. Odds of scoring low in DSST increased with the number of glucose metabolic risk components (odds ratio 1.94, 95% confidence interval [CI] 1.26 to 2.98). Metformin use was associated with better performance in DSST among diabetes patients (β = 4.184, 95% CI 1.655 to 6.713).ConclusionsOur findings support the associations of insulin resistance and glycemic level with cognitive function in key domains, especially among adults without obesity. There is a positive association between metformin use and cognition.

Genetic Variants Correlate With Better Processing Speed

Some cognitive abilities, such as vocabulary, are resilient to brain aging, while others such as conceptual reasoning, memory, and processing speed, decline with age and their rate of decline is genetically regulated. Despite the strong genetic heritability of processing speed assessed by the digit symbol substitution test (DSST), previous studies have failed to identify robust common genetic variants associated with this test. The Long Life Family Study (LLFS) includes long lived individuals and their family members who maintain good DSST scores as they age and who may carry variants associated with better DSST. We therefore conducted a genome-wide association study (GWAS) of DSST in LLFS using ~15M genetic variants imputed to the HRC panel of 64,940 haplotypes with 39,635,008 sites and replicated the findings using genetic data imputed to the 1000 Genomes phase 3 reference panel combining two Danish cohorts: the Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants reaching genome-wide significance (p-value &lt; 5x10-8), including 18 variants associated with better processing speed with large effect size. The genetic associations of rs7623455, rs9821776, rs9821587, rs78704059 in chromosome 3 were replicated in the combined Danish cohort. These genetic variants tagged two hormone receptor related genes, THRB and RARB, both related to cognitive aging. Further gene-based tests in LLFS confirmed that these two genes have protective variants associated with better processing speed.

Relationship Between Type 2 Diabetes Control and Cognition in Older Adults: Findings From NHANES

Cognitive health has emerged as an important public health concern for America’s aging population. Type 2 Diabetes (T2D) may be associated with an exacerbated decline in cognitive performance. This study aimed to examine the relationship between T2D control and cognitive performance in older adults (≥60 years) using the 2013-2014 National Health and Nutrition Examination Surveys. Participants who completed the following cognitive assessments were included: 1) Consortium to Establish a Registry for Alzheimer’s Disease Word List (CERAD-WL), 2) Animal Fluency (AF), 3) Digit Symbol Substitution Test (DSST) (higher scores associated with better cognition). Participants were stratified by four groups: no T2D (N=557), treated/controlled T2D (controlled; N=41), treated/uncontrolled T2D (uncontrolled; N=120), untreated T2D (N=86), based on self-reported T2D treatment, fasting plasma glucose, and hemoglobin A1c. Logistic regression was used to examine the relationship between T2D control and cognition. We observed that those with uncontrolled and untreated T2D each had ~15% lower DSST than those with no T2D (P&lt;0.01). CERAD-WL and AF were similar across all groups. Unadjusted analyses showed that individuals with 1) lower CERAD-WL were more likely to have controlled and untreated T2D, 2) lower AF were more likely to have controlled and uncontrolled T2D, and 3) lower DSST were more likely to have uncontrolled and untreated T2D (P’s&lt;0.05). After adjusting for significant demographics and cardiovascular risk factors, only having uncontrolled T2D was associated with lower DSST (β=-3.164, P=0.04). These data indicate the need for longitudinal studies to further explore dynamic relationship and causal pathway between T2D control and cognitive impairment.

Association Between Diet And Cognitive Performance In Adults Aged 60 And Over: NHANES, 2011–2014

There is limited evidence examining associations between diet and cognitive performance (CP) in older adults. We used the 2011-2014 National Health and Nutrition Examination Survey to determine if meeting dietary recommendations was associated with CP in adults 60+ years of age. Diet was based on the healthy eating index (HEI) 2015 and categorized into quintiles (higher quintiles indicating healthier diet). CP was based on word list learning, animal naming, and digit symbol substitution test, with scores above 25th percentile indicating adequate performance. Multivariate logistic regression modeling was conducted and adjusted for potential cofounders. A total of 3,068 participants completed the CP tests. A slightly higher percentage of participants were female (54.0%), predominantly White (80.5%) and the largest percentage (54.7%) was 60 to 69 years of age. The mean HEI-2015 score (0-100) was 54.89 (SE = 0.56). High CP scores increased with healthier dietary quintiles. However, results were only significant (p for trend &lt;0.05) for digit symbol substitution test when comparing those in the highest quintile (82.53%) to those in the lowest (70.23%). Compared with participants in the lowest quintile of HEI-2015, participants in the highest quintile had a two-fold increased odds of better digit symbol substitution test scores, after adjusting for confounders (Odds Ratio [OR]: 1.96, 95% Confidence Interval [CI]: 1.28-3.01). Results showed that meeting healthy diet recommendations is associated with improved digit symbol substitution test, a marker of attention, processing speed and executive function. Future research should consider the role of diet in older adults to improve cognitive performance.

Association of low-frequency and rare coding variants with information processing speed

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.