Tanya Blekher

Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington’s disease

We compared oculomotor control among individuals in the early stages of Huntingtons disease (HD), with that of individuals who are presymptomatic HD gene carriers (PSGC) and nongene carriers (NGC). The oculomotor testing paradigm included both traditional tests and a novel experimental procedure to assess visual scanning. Traditional tests elicited saccades, pursuit and optokinetic nystagmus (OKN). HD patients demonstrated marked delay in the initiation of volitional saccades (anti-saccade and memory-guided saccades), a reduced number of correct volitional saccades, reduced velocity of saccades, and a decreased OKN gain. We also studied visual scanning while the participants completed the Digit Symbol Subscale of the Wechsler Adult Intelligence Survey-Revised (WAIS-R). The HD participants demonstrated an abnormal gaze strategy, which may be associated with attention and/or planning deficits. Differences between the PSGC and NGC groups were only observed for two measures: PSGC had a decreased number of memory-guided saccades and a subtle delay in the initiation of volitional saccades. Our results suggest that oculomotor measures are a sensitive biomarker in the early stage of HD and demonstrate that the combination of more traditional oculomotor tests with visual scanning tests is useful in the evaluation of visual performance.

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≤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.

Effects of acupuncture on foveation characteristics in congenital nystagmus

AIMS/BACKGROUND To examine the effects of acupuncture at the sternocleidomastoid muscles on foveation characteristics in congenital nystagmus. METHODS Six patients with congenital nystagmus (CN) received a series of treatments consisting of two needles inserted into each sternocleidomastoid, stimulated by tapping gently every 5 minutes, for 20 minutes per session. Their eye movements were recorded using scleral search coils and changes in their CN waveforms analysed at each point in the treatment. Changes in the stability and duration of foveation periods were examined. RESULTS Four of the six patients showed improved foveation at the commencement of treatment; three maintained this response throughout the treatment period and after the needles were removed. In two, the CN waveform itself was modified. CONCLUSION This study and others involving afferent stimulation to the neck and face suggest that projections from these areas to the reticular formation and vestibular nucleus may alter the behaviour of the pathophysiological mechanism underlying congenital nystagmus.

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.

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 Fishers z-transformation was used to evaluate the effects of group (PDHD and NC) and the subjects 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.

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

OBJECTIVE Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntingtons 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).

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 subjects 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 Huntingtons 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.