Predicting Early Mild Cognitive Impairment With Free Recall: The Primacy of Primacy.

OBJECTIVES: Serial position effects have been found to discriminate between normal and pathological aging, and to predict conversion from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD). Different scoring methods have been used to estimate the accuracy of these predictions. In the current study, we investigated delayed primacy as predictor of progression to early MCI over established diagnostic memory methods. We also compared three serial position methods (regional, standard and delayed scores) to determine which measure is the most sensitive in differentiating between individuals who develop early MCI from a baseline of cognitively intact older adults. METHOD: Data were analyzed with binary logistic regression and with receiver-operating characteristic (ROC). Baseline serial position scores were collected using the Rey's Auditory Verbal Learning Test and used to predict conversion to early MCI. The diagnosis of early MCI was obtained through statistical algorithm and consequent consensus conference. One hundred and ninety-one participants were included in the analyses. All participants were aged 60 or above and cognitively intact at baseline. RESULTS: The binary logistic regression showed that delayed primacy was the only predictor of conversion to early MCI, when compared to total and delayed recall. ROC curves showed that delayed primacy was still the most sensitive predictor of progression to early MCI when compared to other serial position measures. CONCLUSIONS: These findings are consistent with previous studies and support the hypothesis that delayed primacy may be a useful cognitive marker of early detection of neurodegeneration

Temporal contiguity and ageing: The role of memory organization in cognitive decline

The temporal contiguity effect is the tendency to form associations between items presented in nearby study positions. In the present study, we explored whether temporal contiguity predicted conversion to cognitively unimpaired‐declining (CUD) status from a baseline of unimpaired older adults. Data from 419 participants were drawn from the Wisconsin Registry of Alzheimer’s Prevention (WRAP) data set and analysed with binary logistic regressions. Temporal contiguity was calculated using the Rey Auditory Verbal Learning Test. Other predictors included age, years of education, sex, APOE‐ε4 status, and other measures of memory recall. Lower temporal contiguity predicted conversion to CUD after accounting for covariates. These findings support the hypothesis that temporal organization in memory is related to cognitive decline and suggest that temporal contiguity may be used for studies of early detection

The recency ratio as predictor of early MCI

Objectives: Individuals with Alzheimer’s disease (AD) present poor immediate primacy recall accompanied by intact or exaggerated recency, which then tends to decline after a delay. Bruno et al. (2016) have shown that higher ratio scores between immediate and delayed recency (i.e., the recency ratio; Rr) are associated with cognitive decline in high-functioning older individuals. We tested whether Rr predicted conversion to early mild cognitive impairment (early MCI) from a cognitively healthy baseline. Design: Data were analysed longitudinally with binomial regression. Baseline scores were used to predict conversion to early MCI after approximately 9 years. Setting: Data were collected at the Wisconsin Registry of Alzheimer’s Prevention (WRAP), in Madison, Wisconsin. Participants: For the study, 427 individuals were included in the analysis; all participants were 50 years of age or older and cognitively intact at baseline, and were native English speakers. Measurements: Memory data were collected using the Rey’s Auditory Verbal Learning Test, and the early MCI diagnosis was obtained via consensus conference. Results: Our results showed that higher Rr scores are correlated with greater risk of later early MCI diagnosis, and this association is independent of total recall performance. Conclusions: Rr is an emerging cognitive marker of cognitive decline

Variant repeats within the DMPK CTG expansion protect function in myotonic dystrophy type 1

Objective: We tested the hypothesis that variant repeat interruptions (RIs) within the DMPK CTG repeat tract lead to milder symptoms compared with pure repeats (PRs) in myotonic dystrophy type 1 (DM1). Methods: We evaluated motor, neurocognitive, and behavioral outcomes in a group of 6 participants with DM1 with RI compared with a case-matched sample of 12 participants with DM1 with PR and a case-matched sample of 12 unaffected healthy comparison participants (UA). Results: In every measure, the RI participants were intermediate between UA and PR participants. For muscle strength, the RI group was significantly less impaired than the PR group. For measures of Full Scale IQ, depression, and sleepiness, all 3 groups were significantly different from each other with UA > RI > PR in order of impairment. The RI group was different from unaffected, but not significantly different from PR (UA > RI = PR) in apathy and working memory. Finally, in finger tapping and processing speed, RI did not differ from UA comparisons, but PR had significantly lower scores than the UA comparisons (UA = RI > PR). Conclusions: Our results support the notion that patients affected by DM1 with RI demonstrate a milder phenotype with the same pattern of deficits as those with PR indicating a similar disease process

Hormone effects on fMRI and cognitive measures of encoding: Importance of hormone preparation

We compared fMRI and cognitive data from nine hormone therapy (HT)-naive women with data from women exposed to either opposed conjugated equine estrogens (CEE) (n = 10) or opposed estradiol (n = 4). Exposure to either form of HT was associated with healthier fMRI response; however, CEE-exposed women exhibited poorer memory performance than either HT-naive or estradiol-exposed subjects. These preliminary findings emphasize the need to characterize differential neural effects of various HTs. ©2006AAN Enterprises, Inc

The recency ratio is related to CSF Amyloid Beta 1-42 levels in MCI-AD

Objective. As anti-amyloid therapeutic interventions shift from enrolling patients with Alzheimer’s disease (AD) dementia to individuals with pre-clinical disease, the need for sensitive measures that allow for non-invasive, fast, disseminable and cost-effective identification of preclinical status increases in importance. The recency ratio (Rr) is a memory measure that relies on analysis of serial position performance, which has been found to predict cognitive decline and conversion to early mild cognitive impairment (MCI). The aim of this study was to test Rr’s sensitivity to cerebrospinal fluid (CSF) levels of the core AD biomarkers in individuals with MCI-AD and controls. Methods. Baseline data from 126 (110 controls and 16 MCI-AD) participants from the Wisconsin Alzheimer’s Disease Research Center were analysed. Partial correlations adjusting for demographics were carried out between CSF measure of amyloid beta (Aβ40, Aβ42 and the 40/42 ratio) and tau (total and phosphorylated), and memory measures (Rr, delayed recall and total recall) derived from the Rey’s Auditory Verbal Learning Test. Results. Results indicated that Rr was the most sensitive memory score to Aβ42 levels in MCI-AD, while no memory score correlated significantly with any biomarker in controls. Conclusions. This study shows that Rr is a sensitive cognitive index of underlying Amyloid β pathology in MCI-AD

Neurocognitive features of motor premanifest individuals with myotonic dystrophy type 1

Objective: The goal of the study was to identify brain and functional features associated with premanifest phases of adult-onset myotonic dystrophy type 1 (i.e., PreDM1). Methods: This cross-sectional study included 68 healthy adults (mean age = 43.4 years, SD = 12.9), 13 individuals with PreDM1 (mean age: 47.4 years, SD = 16.3), and 37 individuals with manifest DM1 (mean age = 45.2 years, SD = 9.3). The primary outcome measures included fractional anisotropy (FA), motor measures (Muscle Impairment Rating Scale, Grooved Pegboard, Finger-Tapping Test, and grip force), general cognitive abilities (Wechsler Adult Intelligence Scales), sleep quality (Scales for Outcomes in Parkinson's Disease–Sleep), and apathy (Apathy Evaluation Scale). Results: Individuals with PreDM1 exhibited an intermediate level of white matter FA abnormality, where whole-brain FA was lower relative to healthy controls (difference of the estimated marginal mean [EMMdifference] = 0.02, 95% confidence interval (CI) 0.01–0.03, p < 0.001), but the PreDM1 group had significantly higher FA than did individuals with manifest DM1 (EMMdifference = 0.02, 95% CI 0.009–0.03, p < 0.001). Individuals with PreDM1 exhibited reduced performance on the finger-tapping task relative to control peers (EMMdifference = 5.70, 95% CI 0.51–11.00, p = 0.03), but performance of the PreDM1 group was better than that of the manifest DM1 group (EMMdifference = 5.60, 95% CI 0.11–11.00, p = 0.05). Hypersomnolence in PreDM1 was intermediate between controls (EMMdifference = −1.70, 95% CI −3.10–0.35, p = 0.01) and manifest DM1 (EMMdifference = −2.10, 95% CI −3.50–0.60, p = 0.006). Conclusions: Our findings highlight key CNS and functional deficits associated with PreDM1, offering insight in early disease course

Associations Between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer\u27s Disease

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer\u27s disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer\u27s Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD

Serial position effects in the Logical Memory Test: Loss of primacy predicts amyloid positivity

Background Story recall is a frequently used neuropsychological test of episodic memory with clinical populations and for screening participants in drug trials for Alzheimer’s disease. However, it is unclear at this stage which underlying mechanisms confer the test its sensitivity. In this paper, we examined serial position effects, that is, better recall for items learned early and late on a list, in story recall, and their usefulness to predict early changes associated with neurodegenerative markers. Methods We analysed data from the Wisconsin Registry for Alzheimer’s Prevention. First, we tested whether serial position effects were present in story recall (measured with the Wechsler Memory Scale Logical Memory Task; LMT) across individuals who were classified as cognitively unimpaired – stable, cognitively unimpaired – declining, or as having mild cognitive impairment (MCI). Results Our results showed clear serial position effects for all groups, except for delayed recall among individuals with MCI, where no primacy effect was observed. Second, we tested whether loss of primacy from immediate to delayed recall was associated with amyloid burden (as measured with PiB PET) in individuals who were cognitively unimpaired at baseline. We found that more primacy loss predicted amyloid positivity, above and beyond the LMT total score. Conclusions This report is the first to show that loss of primacy between immediate and delayed story recall is associated with amyloid burden

Brain structural features of myotonic dystrophy type 1 and their relationship with CTG repeats

Background: Few adequately-powered studies have systematically evaluated brain morphology in adult-onset myotonic dystrophy type 1 (DM1). Objective: The goal of the present study was to determine structural brain differences between individuals with and without adult-onset DM1 in a multi-site, case-controlled cohort. We also explored correlations between brain structure and CTG repeat length. Methods: Neuroimaging data was acquired in 58 unaffected individuals (29 women) and 79 individuals with DM1 (50 women). CTG repeat length, expressed as estimated progenitor allele length (ePAL), was determined by small pool PCR. Statistical models were adjusted for age, sex, site, and intracranial volume (ICV). Results: ICV was reduced in DM1 subjects compared with controls. Accounting for the difference in ICV, the DM1 group exhibited smaller volume in frontal grey and white matter, parietal grey matter as well as smaller volume of the corpus callosum, thalamus, putamen, and accumbens. In contrast, volumes of the hippocampus and amygdala were significantly larger in DM1. Greater ePAL was associated with lower volumes of the putamen, occipital grey matter, and thalamus. A positive ePAL association was observed for amygdala volume and cerebellar white matter. Conclusions: Smaller ICV may be a marker of aberrant neurodevelopment in adult-onset DM1. Volumetric analysis revealed morphological differences, some associated with CTG repeat length, in structures with plausible links to key DM1 symptoms including cognitive deficits and excessive daytime somnolence. These data offer further insights into the basis of CNS disease in DM1, and highlight avenues for further work to identify therapeutic targets and imaging biomarkers