Elsdon Storey

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.

Objective: As high-acuity vision is limited to a very small visual angle, examination of a scene requires multiple fixations. Simultanagnosia, a disorder wherein elements of a scene can be perceived correctly but cannot be integrated into a coherent whole, has been parsed into dorsal and ventral forms. In ventral simultanagnosia, limited visual integration is possible. This case study was the first to record gaze during the presentation of a series of visual stimuli, which required the processing of local and global elements. We hypothesised that gaze patterns would differ with successful processing and that feature integration could be disrupted by distractors. Methods: The patient received a neuropsychological assessment and underwent CT and MRI. Eye movements were recorded during the following tasks: (1) famous face identification, (2) facial emotion recognition, (3) identification of Ishihara colour plates, and (4) identification of both local and global letters in Navon composite letters, presented either alone or surrounded by filled black circles, which we hypothesised would impair global processing by disrupting fixation. Results: The patients identified no famous faces but scanned them qualitatively normally. The only emotion to be consistently recognised was happiness, whose scanpath differed from the other emotions. She identified none of the Ishihara plates, although her colour vision was normal on the FM-15, even mapping an unseen digit with fixations and tracing it with her finger. For plain Navon figures, she correctly identified 20/20 local and global letters; for the "dotted" figures, she was correct 19/20 times for local letters and 0/20 for global letters (chi-squared NS for local, p < 0.0001, global), with similar fixation of salient elements for both. Conclusions: Contrary to our hypothesis, gaze behaviour was largely independent of the ability to process global stimuli, showing for the first time that normal acquisition of visual information did not ensure its integration into a percept. The core defect lay in processing, not acquisition. In the novel Navon task, adding distractors abolished feature integration without affecting the fixation of the salient elements, confirming for the first time that distractors could disrupt the processing, not the acquisition, of visual information in this disorder.

Age-related hearing loss is common in an aging population, affecting communication and contributing to a worsened quality of life. It occurs as a result of cochlear degeneration and may be further exacerbated by inflammation and microvascular changes, as observed in animal models. To compare the effect of daily low-dose aspirin vs placebo on the progression of age-related hearing loss in healthy older adults. A prespecified secondary analysis was conducted of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial. Participants were 279 healthy community-dwelling individuals living in Australia who were aged 70 years or older and free of overt cardiovascular diseases, dementia, and life-limiting illnesses. Participants were recruited between January 1, 2010, and December 31, 2014, and followed up over 3 years. Statistical analysis was completed from June to December 2023. A 100-mg daily dose of enteric-coated aspirin or matching placebo. Hearing measures were air conduction audiometry and binaural speech perception in noise. Assessments were conducted at baseline, 18 months, and 3 years. The change from baseline hearing measures were analyzed using an intention to treat approach. Aspirin and placebo were compared using mixed linear regression models adjusting for age, sex, diabetes, and smoking. Of 279 participants, 154 (55%) were male, and the median age at baseline was 73.1 years (IQR, 71.5-76.2 years). A total of 98 of 138 participants (71%) in the aspirin group and 94 of 141 participants (67%) in the placebo group reported experiencing hearing loss at baseline. Compared with placebo, aspirin did not affect the changes in mean (SD) 4-frequency average hearing threshold from baseline to year 3 (aspirin: baseline, 27.8 [13.3] dB; year 3, 30.7 [13.7] dB; difference, 3.3 [3.9] dB; placebo: baseline, 27.5 [12.6] dB; year 3, 30.9 [13.8] dB; difference, 3.0 [4.8] dB; P = .55) nor any other tested frequencies. An increase in air conduction threshold indicates a deterioration in hearing. Similarly, for the mean (SD) speech reception threshold, there was no significant difference observed between the aspirin and placebo group at the year 3 follow-up assessment (aspirin: baseline, -9.9 [3.8] dB; year 3, -9.1 [3.8] dB; difference, 0.9 [2.9] dB; placebo: baseline, -10.5 [7.1] dB; year 3, -9.6 [4.1] dB; difference, 0.9 [5.9] dB; P = .86). The findings were consistent across sex, age groups, diabetic and smoking status. In this secondary analysis of the ASPREE randomized clinical trial, low-dose aspirin did not affect the progression of age-related hearing loss. More investigation is warranted on whether a longer follow-up or the use of a more powerful anti-inflammatory agent might prove beneficial. anzctr.org.au Identifier: ACTRN12614000496617.

Background: Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers. Methods: The Genome-wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non-affected male and female adult carriers of the premutation. The medians for the Parkinson's Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models. Results: There was a significant difference between the medians from the asymptomatic versus neurologically affected (FXTAS+) groups (p = 0.009). The FXTAS+ status was significantly associated with age at testing (p < 0.001), gender (p = 0.026), and with PD PRS (p = 0.021). The contribution of PD PRS remained significant after adjusting for age and gender (p = 0.044). Conclusions: We have obtained the first evidence for the relationship between PD PRS and the risk of FXTAS or lesser neurological involvements in the FMR1 premutation carriers. This suggests the role of Parkinson's disease polygenic variants as genetic modifiers of the risk of late onset neurological changes in these carriers.

Obstructive sleep apnoea (OSA) may increase the risk of dementia; however, studies have reported variable findings. We investigated if undiagnosed OSA in healthy older adults is associated with cognitive decline, and whether low-dose aspirin could attenuate this. This was conducted as a substudy of the ASPirin in Reducing Events in the Elderly study. Participants were aged 70 years and above, free of dementia, cardiovascular disease and known OSA. A limited channel home sleep study calculated the oxygen desaturation index. Participants were randomised to daily aspirin 100 mg or placebo. Outcomes were the association of OSA, and the interaction of aspirin with OSA, with change in the Modified Mini-Mental State examination (3MS), a test of global cognition, over 3 years. Secondary outcomes were changes in domain-specific cognitive tests. Analyses were adjusted for relevant demographic, lifestyle and cardiometabolic factors. Mild OSA, detected in 630 (49.0%) participants, and moderate/severe OSA, detected in 405 (31.5%) participants, were associated with lower 3MS scores over 3 years (mild OSA: β -0.58, 95% CI -1.15 to -0.00, p=0.049; moderate/severe OSA: β -0.69, 95% CI -1.32 to -0.05, p=0.035), compared to the 250 (19.5%) participants without OSA. No associations of OSA with decline in domain-specific cognitive tests were observed. Interaction terms were not significant for the effects of aspirin with OSA on change in any cognitive test score. OSA was associated with a small decline in global cognition over 3 years in this healthy older cohort. This decline was not attenuated by aspirin.