Dataset Information

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

ABSTRACT:

Background and objectives

Cognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets.

Methods

LASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy.

Results

PreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test-retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume.

Discussion

The LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD.

SUBMITTER: Sierra LA

PROVIDER: S-EPMC10393264 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

Sierra Luis A LA Hughes Shelby B SB Ullman Clementina J CJ Hall Andrew A Pandeya Sarbesh R SR Schubert Robin R Frank Samuel A SA Halko Mark A MA Corey-Bloom Jody J Laganiere Simon S

Frontiers in neurology 20230718

<h4>Background and objectives</h4>Cognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current ...[more]

PMID: 37533473

Similar Datasets

Project description:There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington’s Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within n = 21,045 participants, we identified n = 1901 premanifest and n = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. n = 841 premanifest and n = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all p < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all p < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all p < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all p < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects.

Project description:Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

Project description:Huntington's disease (HD) is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain. In particular, cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals' mental state may emerge many years before the motor symptoms. This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose: 1) the impairment of emotion recognition in HD is moderated by the emotions' valence, and 2) inhibitory control is impaired in HD. Forty manifest and 20 pre-manifest HD patients and their age- and gender-matched controls completed both the traditional "Stroop Color and Word Test" (SCWT) and the newly created "Stroop Emotion Recognition under Word Interference Task" (SERWIT), which consist in 120 photographs of sad, calm, or happy faces with either congruent or incongruent word interference. On the SERWIT, impaired emotion recognition in manifest HD was moderated by emotion type, with deficits being larger in recognizing sadness and calmness than in recognizing happiness, but it was not moderated by stimulus congruency. On the SCWT, six different interference scores yielded as many different patterns of group effects. Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions' valence, but do not provide evidence for the hypothesis that inhibitory control is impaired in HD. Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD, and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD. Looking beyond this study, the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders. The research was approved by the Ethics Committee of the "Istituto Leonarda Vaccari", Rome on January 24, 2018.

Project description:Involuntary choreiform movements are a clinical hallmark of Huntington's disease. Studies in clinically affected patients suggest a shift of motor activations to parietal cortices in response to progressive neurodegeneration. Here, we studied pre-symptomatic gene carriers to examine the compensatory mechanisms that underlie the phenomenon of retained motor function in the presence of degenerative change. Fifteen pre-symptomatic gene carriers and 12 matched controls performed button presses paced by a metronome at either 0.5 or 2 Hz with four fingers of the right hand whilst being scanned with functional magnetic resonance imaging. Subjects pressed buttons either in the order of a previously learnt 10-item finger sequence, from left to right, or kept still. Error rates ranged from 2% to 7% in the pre-symptomatic gene carriers and from 0.5% to 4% in controls, depending on the condition. No significant difference in task performance was found between groups for any of the conditions. Activations in the supplementary motor area (SMA) and superior parietal lobe differed with gene status. Compared with healthy controls, gene carriers showed greater activations of left caudal SMA with all movement conditions. Activations correlated with increasing speed of movement were greater the closer the gene carriers were to estimated clinical diagnosis, defined by the onset of unequivocal motor signs. Activations associated with increased movement complexity (i.e. with the pre-learnt 10-item sequence) decreased in the rostral SMA with nearing diagnostic onset. The left superior parietal lobe showed reduced activation with increased movement complexity in gene carriers compared with controls, and in the right superior parietal lobe showed greater activations with all but the most demanding movements. We identified a complex pattern of motor compensation in pre-symptomatic gene carriers. The results show that preclinical compensation goes beyond a simple shift of activity from premotor to parietal regions involving multiple compensatory mechanisms in executive and cognitive motor areas. Critically, the pattern of motor compensation is flexible depending on the actual task demands on motor control.

Dataset Information

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

Background and objectives

Methods

Results

Discussion

Publications

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets