Comparison of vertical and horizontal saccade measures and their relation to gray matter changes in premanifest and manifest Huntington disease.

Saccades are a potentially important biomarker of Huntington disease (HD) progression, as saccadic abnormalities can be detected both cross-sectionally and longitudinally. Although vertical saccadic impairment was reported decades ago, recent studies have focused on horizontal saccades. This study investigated antisaccade (AS) and memory guided saccade (MG) impairment in both the horizontal and vertical directions in individuals with the disease-causing CAG expansion (CAG+; n = 74), using those without the expansion (CAG-; n = 47) as controls. Percentage of errors, latency, and variability of latency were used to measure saccadic performance. We evaluated the benefits of measuring saccades in both directions by comparing effect sizes of horizontal and vertical measures, and by investigating the correlation of saccadic measures with underlying gray matter loss. Consistent with previous studies, AS and MG impairments were detected prior to the onset of manifest disease. Furthermore, the largest effect sizes were found for vertical saccades. A subset of participants (12 CAG-, 12 premanifest CAG+, 7 manifest HD) underwent magnetic resonance imaging, and an automated parcellation and segmentation procedure was used to extract thickness and volume measures in saccade-generating and inhibiting regions. These measures were then tested for associations with saccadic impairment. Latency of vertical AS was significantly associated with atrophy in the left superior frontal gyrus, left inferior parietal lobule, and bilateral caudate nuclei. This study suggests an important role for measuring vertical saccades. Vertical saccades may possess more statistical power than horizontal saccades, and the latency of vertical AS is associated with gray matter loss in both cortical and subcortical regions important in saccade function.

Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease.

OBJECTIVE: Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington's disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance. METHOD: Three groups of participants were recruited: (1) Imminent and early manifest HD (early HD, n = 8); (2) premanifest (presymptomatic) CAG+ (preHD, n = 10); and (3) CAG unexpanded (CAG-) controls (n = 12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional MRI during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis. RESULTS: Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG- group decreased progressively in a well-documented reward detection network that includes the presupplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG- group. CONCLUSIONS: These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Progression in prediagnostic Huntington disease.

OBJECTIVE: To examine rates of decline in individuals at risk for Huntington disease (HD). METHODS: 106 individuals at risk for HD completed a battery of neurocognitive, psychomotor and oculomotor tasks at two visits, approximately 2.5 years apart. Participants were classified as: (1) without the CAG expansion (normal controls, NC; n=68) or (2) with the CAG expansion (CAG+; n=38). The CAG+ group was further subdivided into those near to (near; n=19) or far from (far; n=19) their estimated age of onset. Longitudinal performance in the CAG+ group was evaluated with a repeated measures model with two main effects (time to onset, visit) and their interaction. Analysis of covariance was employed to detect differences in longitudinal performance in the three groups (NC, near and far). RESULTS: In the CAG+, the interaction term was significant (p < or = 0.02) for four measures (movement time, alternate button tapping, variability of latency for a memory guided task and percentage of errors for a more complex memory guided task), suggesting the rate of decline was more rapid as subjects approached onset. Longitudinal progression in the three groups differed for several variables (p<0.05). In most, the near group had significantly faster progression than NC; however, comparisons of the NC and far groups were less consistent. CONCLUSIONS: Different patterns of progression were observed during the prediagnostic period. For some measures, CAG+ subjects closer to estimated onset showed a more rapid decline while for other measures the CAG+ group had a constant rate of decline throughout the prediagnostic period that was more rapid than in NC.

Test-retest reliability of saccadic measures in subjects at risk for Huntington disease.

PURPOSE: Abnormalities in saccades appear to be sensitive and specific biomarkers in the prediagnostic stages of Huntington disease (HD). The goal of this study was to evaluate test-retest reliability of saccadic measures in prediagnostic carriers of the HD gene expansion (PDHD) and normal controls (NC). METHODS: The study sample included 9 PDHD and 12 NC who completed two study visits within an approximate 1-month interval. At the first visit, all participants completed a uniform clinical evaluation. A high-resolution, video-based system was used to record eye movements during completion of a battery of visually guided, antisaccade, and memory-guided tasks. Latency, velocity, gain, and percentage of errors were quantified. Test-retest reliability was estimated by calculating the intraclass correlation (ICC) of the saccade measures collected at the first and second visits. In addition, an equality test based on Fisher's z-transformation was used to evaluate the effects of group (PDHD and NC) and the subject's sex on ICC. RESULTS: The percentage of errors showed moderate to high reliability in the antisaccade and memory-guided tasks (ICC = 0.64-0.93). The latency of the saccades also demonstrated moderate to high reliability (ICC = 0.55-0.87) across all tasks. The velocity and gain of the saccades showed moderate reliability. The ICC was similar in the PDHD and NC groups. There was no significant effect of sex on the ICC. CONCLUSIONS: Good reliability of saccadic latency and percentage of errors in both antisaccade and memory-guided tasks suggests that these measures could serve as biomarkers to evaluate progression in HD.

Multiple step pattern as a biomarker in Parkinson disease.

OBJECTIVE: To evaluate quantitative measures of saccades as possible biomarkers in early stages of Parkinson disease (PD) and in a population at-risk for PD. METHODS: The study sample (n=68) included mildly to moderately affected PD patients, their unaffected siblings, and control individuals. All participants completed a clinical evaluation by a movement disorder neurologist. Genotyping of the G2019S mutation in the LRRK2 gene was performed in the PD patients and their unaffected siblings. A high resolution, video-based eye tracking system was employed to record eye positions during a battery of visually guided, anti-saccadic (AS), and two memory-guided (MG) tasks. Saccade measures (latency, velocity, gain, error rate, and multiple step pattern) were quantified. RESULTS: PD patients and a subgroup of their unaffected siblings had an abnormally high incidence of multiple step patterns (MSP) and reduced gain of saccades as compared with controls. The abnormalities were most pronounced in the more challenging version of the MG task. For this task, the MSP measure demonstrated good sensitivity (87%) and excellent specificity (96%) in the ability to discriminate PD patients from controls. PD patients and their siblings also made more errors in the AS task. CONCLUSIONS: Abnormalities in eye movement measures appear to be sensitive and specific measures in PD patients as well as a subset of those at-risk for PD. The inclusion of quantitative laboratory testing of saccadic movements may increase the sensitivity of the neurological examination to identify individuals who are at greater risk for PD.

Visual scanning and cognitive performance in prediagnostic and early-stage Huntington's disease.

The objective of this study was to evaluate visual scanning strategies in carriers of the Huntington disease (HD) gene expansion and to test whether there is an association between measures of visual scanning and cognitive performance. The study sample included control (NC, n = 23), prediagnostic (PDHD, n = 21), and subjects recently diagnosed with HD (HD, n = 19). All participants completed a uniform clinical evaluation that included examination by neurologist and molecular testing. Eye movements were recorded during completion of the Digit Symbol Subscale (DS) test. Quantitative measures of the subject's visual scanning were evaluated using joint analysis of eye movements and performance on the DS test. All participants employed a simple visual scanning strategy when completing the DS test. There was a significant group effect and a linear trend of decreasing frequency and regularity of visual scanning from NC to PDHD to HD. The performance of all groups improved slightly and in a parallel fashion across the duration of the DS test. There was a strong correlation between visual scanning measures and the DS cognitive scores. While all individuals employed a similar visual scanning strategy, the visual scanning measures grew progressively worse from NC to PDHD to HD. The deficits in visual scanning accounted, at least in part, for the decrease in the DS score.

Visual perception in prediagnostic and early stage Huntington's disease.

Disturbances of visual perception frequently accompany neurodegenerative disorders but have been little studied in Huntington's disease (HD) gene carriers. We used psychophysical tests to assess visual perception among individuals in the prediagnostic and early stages of HD. The sample comprised four groups, which included 201 nongene carriers (NG), 32 prediagnostic gene carriers with minimal neurological abnormalities (PD1); 20 prediagnostic gene carriers with moderate neurological abnormalities (PD2), and 36 gene carriers with diagnosed HD. Contrast sensitivity for stationary and moving sinusoidal gratings, and tests of form and motion discrimination, were used to probe different visual pathways. Patients with HD showed impaired contrast sensitivity for moving gratings. For one of the three contrast sensitivity tests, the prediagnostic gene carriers with greater neurological abnormality (PD2) also had impaired performance as compared with NG. These findings suggest that early stage HD disrupts visual functions associated with the magnocellular pathway. However, these changes are only observed in individuals diagnosed with HD or who are in the more symptomatic stages of prediagnostic HD.

Saccadic eye movements are associated with a family history of alcoholism at baseline and after exposure to alcohol.

OBJECTIVE: To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol. METHOD: Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history-positive) and 49 controls (family history-negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady-state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance. RESULTS: The family history-positive and family history-negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions ( p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased (p = 0.0001) and slowed the execution of saccades such that peak velocities decreased ( p = 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed (p = 0.1). Latency of AS saccades demonstrated a significant overall FHA effect (p = 0.02) and a significant interaction between FHA and response to alcohol over time (p = 0.02). CONCLUSIONS: Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml.

Recent drinking history: association with family history of alcoholism and the acute response to alcohol during a 60 mg% clamp.

OBJECTIVE: Family history of alcoholism (FHA) is associated with increased drinking history, which can be a confounding factor in studies of the influence of FHA on the acute response to alcohol. The objective of this analysis was to investigate the association between recent drinking history (RDH) and FHA in a sample of family history positive (FHP; n = 55, 28 women) and family history negative (FHN; n = 55, 29 women) subjects, and to explore the influence of RDH on the response to alcohol during a 60 mg% clamp. METHOD: RDH was measured using daily diary and timeline followback methods. The total number of drinks in the 4-week (TD28) and 1-week (TD07) intervals prior to the study were determined, as well as the number of drinking days in the same intervals. Dependent measures of brain function were obtained at baseline (B0), immediately after the target BrAC was achieved (B1) and 105 minutes later (B2). The alcohol response was quantified as an initial response (ira = B1-B0) and an adaptive response (ada = B2-B1). The association between RDH and the ira and ada measures was tested using multivariate regression. RESULTS: The RDH measures showed a large variance across subjects, with no significant differences between FHP and FHN groups in the study sample. The initial responses for subjective perceptions of "high" and "intoxicated," Alcohol Sensation Scale scores and scores for the grooved pegboardtask were significantly negatively associated with TD28. Acute tolerance to perceptions of "high" and "intoxication" was significantly negatively associated with TD28. CONCLUSIONS: Heavy drinking history is associated with a decreased initial response to alcohol and greater acute tolerance to alcohol, particularly for subjective measures. Although RDH was not associated with FHA in this study, it may be an important determinant of the response to alcohol.