Utility of the Huntington's Disease Prognostic Index Score for a Perimanifest Clinical Trial.

BACKGROUND: Subtle neurodegenerative motor and cognitive impairments accumulate over a prodromal period several years before clinical diagnosis of Huntington's disease (HD). The inclusion of prodromal individuals in therapeutic trials would facilitate testing of therapies early in the disease course and the development of treatments intended to prevent or delay disability. OBJECTIVES: We evaluate the normalized prognostic index (PIN) score as a tool to select participants for a perimanifest trial. We explore anticipated PIN-based inclusion rates from the preHD screening population and estimate sample-size requirements based on PIN threshold, trial duration, and outcome measure. METHODS: Individual participant data from ENROLL-HD were used to fit mixed effect linear models to assess longitudinal changes in clinical metrics for participants with early-manifest HD and PIN-stratified preHD subcohorts. RESULTS: A PIN threshold of 0.0 was met by 40% of the preHD participants in ENROLL-HD; 39.4% and 55.2% progressed to new diagnoses of early-manifest HD within 2 and 3 years, respectively. Various PIN thresholds also enabled the selection of specified ratios of prodromal preHD to early manifest HD participants for a perimanifest trial. Estimated sample sizes for a trial enrolling prodromal preHD (PIN > 0.0) and stage 1 and 2 motor-diagnosed participants varied depending on the composition of the screening pool, the length of follow-up (1, 2, or 3 years), and outcome measure. CONCLUSIONS: The composition of a perimanifest clinical trial population can be defined using preselected PIN thresholds, facilitating the assessment of potential disease-modifying therapies in HD. © 2022 Voyager Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial.

BACKGROUND AND OBJECTIVES: To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations. METHODS: PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg. RESULTS: No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. DISCUSSIONS: VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. TRIAL REGISTRATION INFORMATION: NCT01973543. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

The role of attention in binding shape to color.

Pictures of easily-identifiable objects with novel colors (e.g. a blue frog) or of forms with arbitrary colors (e.g. a green triangle) were presented briefly at 10.6 degrees eccentricity. Stimuli had strong outlines and vivid fill colors (red, green, yellow, blue, or purple). The same pictures were repeated once in each block of 30 trials for 6, 9, or 12 blocks, and recognition was probed after each block. Shapes were acquired quickly, within 3-4 blocks, whether attention was focused on the pictures or split to a demanding foveal task. Color-shape acquisition was also fast with focused attention, but stabilized at a low level with split attention. Delaying the foveal task restored color-shape acquisition. We suggest that attention facilitates the creation and maintenance of novel color-shape bindings in the visual periphery; without attention, binding is less effective.

Distinguishing between the precision of attentional localization and attentional resolution.

Attentional resolution is a construct that refers to the minimal separation that allows one stimulus to be attended separately from nearby stimuli. The attentional walk task, which requires a series of covert shifts of attention within variably dense arrays of stimuli, was introduced as a method of measuring attentional resolution. Using a cuing task, we show that individual items within arrays that are too dense to support an attentional walk can nonetheless be attended. We note that the precision with which attention can be localized is, in principle, a limitation separate from attentional resolution and conclude that performance in the attentional walk task is better suited for measuring this limitation than for measuring attentional resolution per se.

Nonspatial attributes of stimuli can influence spatial limitations of attentional control.

A wide variety of psychophysical and neurophysiological research suggests that when stimuli are very close together, they cannot be attended separately. As a consequence, they cannot be represented as individual items with specific feature information associated with them. Here we report evidence that the spatial control of attention can be modulated by nonspatial features of the stimuli (such as color and luminance). Observers shifted attention from item to item within highly dense arrays of stimuli. Performance was extremely poor when all of the items in the array were an identical gray. In contrast, performance improved when items differed in color. This finding indicates that nonspatial features, such as color, can facilitate spatial selection and suggests moreover that features can be reliably associated with particular items even when the items are densely clustered.

Fixational eye movements are not an index of covert attention.

The debate about the nature of fixational eye movements has revived recently with the claim that microsaccades reflect the direction of attentional shifts. A number of studies have shown an association between the direction of attentional cues and the direction of microsaccades. We sought to determine whether microsaccades in attentional tasks are causally related to behavior. Is reaction time (RT) faster when microsaccades point toward the target than when they point in the opposite direction? We used a dual-Purkinje-image eyetracker to measure gaze position while 3 observers (2 of the authors, 1 naive observer) performed an attentional cuing task under three different response conditions: saccadic localization, manual localization, and manual detection. Critical trials were those on which microsaccades moved away from the cue. On these trials, RTs were slower when microsaccades were oriented toward the target than when they were oriented away from the target. We obtained similar results for direction of drift. Cues, not fixational eye movements, predicted behavior.

The relative benefit of word context is a constant proportion of letter identification time.

Letter identification is reduced when the target letter is surrounded by other, flanking letters. This visual crowding is known to be impacted by physical changes to the target and flanks, such as spatial frequency content, polarity, and interletter spacing. There is also evidence that visual crowding is reduced when the flanking letters and the target letter form a word. The research reported here investigated whether these two phenomena are independent of each other or whether the degree of visual crowding impacts the benefit of word context. Stimulus duration thresholds for letters presented alone and for the middle letters of 3-letter words and nonwords were determined for stimuli presented at the fovea and at the periphery. In Experiment 1, the benefit of word context was found to be the same at the fovea, where visual crowding is minimal, and at the periphery, where visual crowding is substantial. In Experiment 2, visual crowding was manipulated by changing the interletter spacing. Here, too, the benefit of word context was fairly constant for the two retinal locations (fovea or periphery), as well as with changes in interletter spacing. These data call into question both the idea that the benefit of word context is greater when stimulus quality is reduced (as is the case with visual crowding) and the idea that words are processed more effectively when they are presented at the fovea.