Assessing the integrity of auditory processing and sensory memory in adults with cystinosis (CTNS gene mutations)

Abstract

Background Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function in adulthood. We previously demonstrated intact auditory sensory processing, accompanied by mild sensory memory difficulties, in children and adolescents with cystinosis. Methods We investigated whether further progressive decrements in these processes would be observed in adults with cystinosis, comparing high-density auditory-evoked potential (AEP) recordings from adults with cystinosis (N = 15; ages: 19–38 years) to those of age-matched controls (N = 17). We employed a duration oddball paradigm with different stimulation rates, in which participants passively listened to regularly occurring standard tones interspersed with infrequently occurring deviant tones. Analyses focused on AEP components reflecting auditory sensory-perceptual processing (N1 and P2), sensory memory (mismatch negativity, MMN), and attentional orienting (P3a). Results Overall, adults with cystinosis produced highly similar sensory-perceptual AEP responses to those observed in controls suggesting intact early auditory cortical processing. However, significantly increased P2 and P3a amplitudes and reduced MMN at slower stimulation rates were observed, suggesting mild-to-moderate changes in auditory sensory memory and attentional processing. While cognitive testing revealed lower scores on verbal IQ and perceptual reasoning in cystinosis, these did not correlate with the AEP measures. Conclusions These neurophysiological data point to the emergence of subtle auditory processing deficits in early adulthood in cystinosis, warranting further investigation of memory and attentional processes in this population, and of their consequences for perceptual and cognitive function.

Response inhibition and error-monitoring in cystinosis (CTNS gene mutations): Behavioral and electrophysiological evidence of a diverse set of difficulties

“…Interestingly, the amplitude enhancement in cystinosis amplitude appears to start much earlier, around 200 ms and to propagate steadily through time until around 700 ms after stimulus onset. We have previously reported increased P2 and P3a amplitudes in a sample of adults with cystinosis engaged in a passive auditory task (34) and argued that individuals with cystinosis may engage attention differently, which the current findings could be further evidence of. In future research, other processes potentially related to inhibition should be investigated in cystinosis.…”

“…For instance, while Ballantyne and colleagues showed worse performance across different components of executive functioning in those with cystinosis (32), Besouw et al observed differences between individuals with and without cystinosis only in sustained attention, not in other executive functioning components (14). Our own work suggests no (behavioral) verbal working memory difficulties in a small group of adults living with cystinosis (34), but some differences between individuals with cystinosis and age-matched controls in the amplitude of event-related potentials (ERPs) associated with sensory memory and attentional processes (34,35).…”

“…Failure to do so at adequate levels of activation will probably result in marked difficulties in response inhibition processes (77,79). Evidence regarding working memory difficulties in cystinosis is mixed (32,34,80), but our previous EEG work suggests difficulties in sensory memory in this population (34,35), difficulties that could impact subsequent processing in working memory (81). Overall, a more detailed interrogation of the different components of response inhibition could be meaningful in clarifying the neural processes underlying the behavioral differences in inhibitory processing that we see here in cystinosis.…”

Event-related potential (ERP) evidence of early visual processing differences in cystinosis

“…Though abnormally high levels of cystine have been observed in different brain regions (12)(13)(14), cystinosis' impact on brain activity is still not well understood. In our previous work, mainly focused on auditory processing and sensory memory, we reported maintained sensory processing, but some differences in sensory memory in children and adults living with cystinosis (15,16).…”

Central Nervous System Complications in Cystinosis: The Role of Neuroimaging

“…Adults with cystinosis produce highly similar sensory perceptual auditorily evoked potential responses to controls, suggesting intact early auditory cortical processing. However, significantly increased auditory sensory perceptual processing amplitudes, increased attentional orienting, and reduced sensory memory at slower stimulation rates are observed, suggesting mild-to-moderate changes in auditory sensory memory and attentional processing [ 54 ].…”