Improving validity of the trail making test with alphabet support

The Trail Making Test (TMT) is commonly used worldwide to evaluate cognitive decline and car driving ability. However, it has received critique for its dependence on the Latin alphabet and thus, the risk of misclassifying some participants. Alphabet support potentially increases test validity by avoiding misclassification of executive dysfunction in participants with dyslexia and those with insufficient automatization of the Latin alphabet. However, Alphabet support might render the test less sensitive to set-shifting, thus compromising the validity of the test. This study compares two versions of the TMT: with and without alphabet support. Methods: We compared the TMT-A, TMT-B, and TMT-B:A ratios in two independent normative samples with (n = 220) and without (n = 64) alphabet support using multiple regression analysis adjusted for age and education. The sample comprised Scandinavians aged 70–84 years. Alphabet support was included by adding the Latin alphabet A–L on top of the page on the TMT-B. We hypothesized that alphabet support would not change the TMT-B:A ratio. Results: After adjusting for age and years of education, there were no significant differences between the two samples in the TMT-A, TMT-B, or the ratio score (TMT-B:A). Conclusion: Our results suggest that the inclusion of alphabet support does not alter TMT’s ability to measure set-shifting in a sample of older Scandinavian adults

Regression-based norms for the FAS phonemic fluency test for ages 40–84 based on a Norwegian sample

The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway. However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on n = 204 healthy Norwegian controls between the ages 40−84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of n = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation

Regression-based norms for the FAS phonemic fluency test for ages 40–84 based on a Norwegian sample

The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway. However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on n = 204 healthy Norwegian controls between the ages 40−84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of n = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation

Association of Klotho protein levels and KL-VS heterozygosity with Alzheimer disease and amyloid and tau burden

Importance Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. Design, Setting, and Participants This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Main Outcomes and Measures Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. Results A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = −0.884; 95% CI, 0.223 to −0.395; P < .001; CSF phosphorylated tau levels: β = −0.672; 95% CI, −1.022 to −0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). Conclusions and Relevance The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered

Demographically adjusted Rey-Osterrieth Complex Figure Test norms in a Swedish and Norwegian cohort aged 49-77?years and comparison with North American norms

Introduction: The Rey–Osterrieth Complex Figure Test (RCFT) is one of the most commonly used neuropsychological tests in Sweden and Norway. However, no publications provide normative data for this population. The objective of this study was to present demographically adjusted norms for a Swedish and Norwegian population and to evaluate these in an independent comparison group. Methods: The RCFT was administrated to 344 healthy controls recruited from the Swedish Gothenburg MCI study, the Norwegian Dementia Disease Initiation study, and the Swedish Cardiopulmonary Bioimage Study. Age ranged from 49 to 77 years (mean = 62.4 years, SD = 5.0 years), and education ranged from 6 to 24 years (mean = 13.3 years, SD = 3.0 years). Using a regression-based procedure, we investigated the effects of age, sex, and years of education on test performance. We compared and evaluated our Swedish and Norwegian norms with North American norms in an independent comparison group of 145 individuals. Results: In healthy controls, age and education were associated with performance on the RCFT. When comparing normative RCFT performance in an independent comparison group, North American norms generally overestimated immediate and delayed recall performance. In contrast, our Swedish and Norwegian norms appear to better take into account factors of age and education. Conclusions: We presented demographically adjusted norms for the RCFT in a Swedish and Norwegian sample. This is the first normative study of the RCFT that presents normative data for this population. In addition, we showed that North American norms might produce inaccurate normative estimations in an independent comparison group

Effects of purified anthocyanins in people at risk for dementia: Study protocol for a phase II randomized controlled trial

Background: The number of people with dementia is increasing, with huge challenges for society and health-care systems. There are no disease-modifying therapies available. There is, therefore, an urgent need to identify strategies to reduce the risk of developing dementia. Anthocyanins are a class of compounds found in dark berries and fruits with some effects that might reduce the risk for cognitive decline and the development of dementia in older people. Aim: This phase II three-center, randomized, 24-week, placebo-controlled study, ongoing in Norway, aims to evaluate the safety, and efficacy of anthocyanins in modifying key dementia-related mechanisms and maintain cognitive functioning in older people at risk for dementia. Methods: Participants (220 individuals aged 60–80 years) who meet the inclusion criteria (either mild cognitive impairment or two or more cardiometabolic disorders) are being enrolled in this study at three different centers in Norway. Participants are block randomized to identically appearing capsules containing 80 mg of naturally purified anthocyanins or placebo 1:1. Dosage is 2 + 2 capsules per day for 24 weeks. The primary outcome will be the quality of episodic memory score, a composite measure from the extensively validated online cognitive test battery CogTrack®, which is administered at baseline and monthly for the next 6 months. Secondary outcomes include other major scores from CogTrack, as well as a range of neuroimaging and other biomarkers. Anthocyanin metabolites will be measured in blood and cerebrospinal fluid. The change from baseline scores will be subject to a mixed model for repeated measures analysis of covariance. The primary comparison will be the contrast (difference in the least-square means) between active and placebo at the end of the study (week 24). The primary study population will be a modified intention-to-treat population (ClinicalTrials.gov, NCT03419039). Discussion: This study aims to demonstrate whether there are beneficial effects of purified anthocyanins on cognition and relevant biological functions in people at increased risk for dementia. Forthcoming results may contribute to further improvement of intervention strategies to prevent or delay the onset of dementia, including a potential decision to take anthocyanins toward phase III trials.publishedVersio

Regression-based normative data for the D-KEFS Color-Word Interference Test in Norwegian adults ages 20–85

Objective: The Delis-Kaplan Executive Function System (D-KEFS) Color-Word-Interference Test (CWIT; AKA Stroop test) is a widely used measure of processing speed and executive function. While test materials and instructions have been translated to Norwegian, only American age-adjusted norms from D-KEFS are available in Norway. We here develop norms in a sample of 1011 Norwegians between 20 and 85 years. We provide indexes for stability over time and assess demographic adjustments applying the D-KEFS norms. Method: Participants were healthy Norwegian adults from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 899), the Dementia Disease Initiation (n = 77), and Oslo MCI (n = 35). Using regression-based norming, we estimated linear and non-linear effects of age, education, and sex on the CWIT 1-4 subtests. Stability over time was assessed with intraclass correlation coefficients (ICC). The normative adjustment of the D-KEFS norms was assessed with linear regression models. Results: Increasing age was associated with slower completion on all CWIT subtests in a non-linear fashion (accelerated lowering of performance with older age). Women performed better on CWIT-1&3. Higher education predicted faster completion time on CWIT-3&4. The original age-adjusted norms from D-KEFS did not adjust for sex or education. Furthermore, we observed significant, albeit small effects of age on all CWIT subtests. ICC analyses indicated moderate to good stability over time. Conclusion: We present demographically adjusted regression-based norms and stability indexes for the D-KEFS CWIT subtests. US D-KEFS norms may be inaccurate for Norwegians with high or low educational attainment, especially women

Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer’s disease

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer’s disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer’s disease pathology. Linear regression was used to assess the influence of CSF determined Aβ-plaque (Aβ-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aβ-/Aβ+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aβ+ compared to Aβ- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aβ- vs. Aβ+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.publishedVersio

Demographically adjusted Rey–Osterrieth Complex Figure Test norms in a Swedish and Norwegian cohort aged 49–77 years and comparison with North American norms

Introduction The Rey–Osterrieth Complex Figure Test (RCFT) is one of the most commonly used neuropsychological tests in Sweden and Norway. However, no publications provide normative data for this population. The objective of this study was to present demographically adjusted norms for a Swedish and Norwegian population and to evaluate these in an independent comparison group. Methods The RCFT was administrated to 344 healthy controls recruited from the Swedish Gothenburg MCI study, the Norwegian Dementia Disease Initiation study, and the Swedish Cardiopulmonary Bioimage Study. Age ranged from 49 to 77 years (mean = 62.4 years, SD = 5.0 years), and education ranged from 6 to 24 years (mean = 13.3 years, SD = 3.0 years). Using a regression-based procedure, we investigated the effects of age, sex, and years of education on test performance. We compared and evaluated our Swedish and Norwegian norms with North American norms in an independent comparison group of 145 individuals. Results In healthy controls, age and education were associated with performance on the RCFT. When comparing normative RCFT performance in an independent comparison group, North American norms generally overestimated immediate and delayed recall performance. In contrast, our Swedish and Norwegian norms appear to better take into account factors of age and education. Conclusions We presented demographically adjusted norms for the RCFT in a Swedish and Norwegian sample. This is the first normative study of the RCFT that presents normative data for this population. In addition, we showed that North American norms might produce inaccurate normative estimations in an independent comparison group

A Randomised Placebo-Controlled Study of Purified Anthocyanins on Cognition in Individuals at Increased Risk for Dementia

Importance Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic. Objective To study the safety and effect of anthocyanins in maintaining cognitive functioning in people at increased risk for dementia. Design, setting, and participants Participants (206 individuals, aged 60–80 years) diagnosed with either mild cognitive impairment (MCI) or two or more cardiometabolic disorders (i.e., diabetes, hypertension, obesity) were enrolled at three different centres in Norway. Intervention Participants were randomly assigned to four capsules with a total of 320 mg/d of naturally purified anthocyanins or placebo 1:1 for 24 weeks. Main outcomes and measures The primary outcome was the Quality of Episodic Memory composite measure (0–100) from an online cognitive test battery CogTrack, which was administered at baseline and monthly for the next 24 weeks. Secondary outcomes included other cognitive scores from the CogTrack battery. We applied mixed effects models with a baseline test score, group, time and their interaction as fixed effects, as well as other predefined baseline covariates. The primary comparison was the group difference at week 24 based on a modified intention-to-treat principle. Results : The primary analysis did not show a significant group difference at 24 weeks (78.2 versus 76.8; adjusted mean difference 1.4 (95% confidence interval -0.9–3.7); effect size 0.15; p = 0.23). However, there was a significant difference in slopes during weeks 8–24 (p = 0.007); the anthocyanin group improved while the placebo group worsened. No differences were found for the secondary cognitive outcomes. Anthocyanin capsules were well-tolerated and safe to use. Conclusion Anthocyanin supplementation for 24 weeks was safe and well tolerated in people with MCI or cardiometabolic disorders. We found no significant group difference in episodic memory at the end of the study but statistically significant differences in slopes. Further studies are warranted to explore whether anthocyanins supplementation can reduce cognitive decline in people at increased risk of dementia.publishedVersio