Marjorie Weaver

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.

Ten-year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease†

Longitudinal studies of neurocognitive function in prediagnosis Huntington disease (pre‐HD) have been few, and duration of follow‐up has been brief. In this study, 155 individuals at‐risk for HD completed a battery of cognitive and motor tasks at two study visits ∼10 years apart. Participants were classified as: (1) at‐risk, without the CAG expansion (healthy controls, NC; n = 112), or (2) CAG expanded (CAG+; n = 43). To examine the rate of decline at different stages of the pre‐HD period, participants in the CAG+ group were further characterized as converters (i.e., individuals who developed manifest HD over the course of the study; n = 21) or nonconverters (n = 22), and their performances were compared. The CAG+ group exhibited faster rates of neurocognitive decline over the course of the study, relative to the NC group. In addition, more rapid decline was associated with closer proximity to estimated age of disease onset in the CAG+ group. Faster rates of motor and psychomotor decline were observed in the CAG+ converter group, relative to the nonconverters. These findings suggest that neurocognitive decline in pre‐HD, particularly in motor and psychomotor domains, begins insidiously and accelerates as individuals approach disease onset.

Multiple step pattern as a biomarker in Parkinson disease

OBJECTIVEnTo evaluate quantitative measures of saccades as possible biomarkers in early stages of Parkinson disease (PD) and in a population at-risk for PD.nnnMETHODSnThe 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.nnnRESULTSnPD 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.nnnCONCLUSIONSnAbnormalities 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.

Are cognitive changes progressive in prediagnostic HD

ObjectiveTo characterize neurocognitive signs of disease progression in prediagnosis and early Huntington disease (HD) and compare the sensitivity of 2 disease staging classification schemes for detecting these signs. MethodsThree hundred and six individuals at-risk for or recently diagnosed with HD completed the Unified Huntingtons Disease Rating Scale, genetic testing, and a neurocognitive battery. Two schemes were used to estimate latency to onset of disease. One was based on genetic information (CAG repeat length) and the other was based on the extent of motor signs. Effect sizes were compared to assess the relative sensitivity of the 2 schemes for detecting signs of disease progression. ResultsCAG-expanded participants far from estimated diagnosis performed similarly to controls, whereas those near to estimated diagnosis were impaired relative to controls. Overall, the method employing genetic information yielded larger effect sizes than the motor scheme, particularly for strategic and executive function measures; the motor scheme resulted in a larger effect size for a measure of motor/psychomotor function. ConclusionsNeurocognitive function is not uniformly affected in prediagnosis and early HD; individuals near to their estimated age of diagnosis have cognitive signs similar to HD, whereas individuals far from estimated diagnosis appear cognitively normal. Classification schemes that incorporate both genetic and phenotypic information may be more sensitive for tracking neurocognitive signs of disease progression.

Test Retest Reliability of Saccadic Measures in Subjects at Risk for Huntington Disease

PURPOSEnAbnormalities 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).nnnMETHODSnThe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnGood 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.

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.