The mismatch negativity as an index of cognitive abilities in adults with Down syndrome.

Down syndrome (DS) is associated with an ultra-high risk of developing Alzheimer's disease (AD). Understanding variability in pre-AD cognitive abilities may help understand cognitive decline in this population. The mismatch negativity (MMN) is an event-related potential component reflecting the detection of deviant stimuli that is thought to represent underlying memory processes, with reduced MMN amplitudes being associated with cognitive decline. To further understand the MMN in adults with DS without AD, we explored the relationships between MMN, age, and cognitive abilities (memory, language, and attention) in 27 individuals (aged 17-51) using a passive auditory oddball task. Statistically significant MMN was present only in 18 individuals up to 41 years of age and the latency were longer than canonical parameters reported in the literature. Reduced MMN amplitude was associated with lower memory scores, while longer MMN latencies were associated with poorer memory, verbal abilities, and attention. Therefore, the MMN may represent a valuable index of cognitive abilities in DS. In combination with previous findings, we hypothesize that while MMN response and amplitude may be associated with AD-related memory loss, MMN latency may be associated with speech signal processing. Future studies may explore the potential impact of AD on MMN in people with DS.

Exploring semantic verbal fluency patterns and their relationship to age and Alzheimer's disease in adults with Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are at ultra-high risk of developing Alzheimer's disease (AD), characterized by poor episodic memory and semantic fluency in the preclinical phase in the general population. We explored semantic fluency performance in DS and its relationship to age, AD, and blood biomarkers. METHODS: A total of 302 adults with DS at baseline and 87 at follow-up from the London Down Syndrome Consortium cohort completed neuropsychological assessments. Blood biomarkers were measured with the single molecule array technique in a subset of 94 participants. RESULTS: Poorer verbal fluency performance was observed as age increases. Number of correct words declined in those with AD compared to those without over 2 years and was negatively correlated with neurofilament light (r = -0.37, P = .001) and glial fibrillary acidic protein (r = -0.31, P = .012). DISCUSSION: Semantic fluency may be useful as an early indicator of cognitive decline and provide additional information on AD-related change, showing associations with biomarkers in DS.

Influence of theta-burst transcranial magnetic stimulation over the dorsolateral prefrontal cortex on emotion processing in healthy volunteers.

Repetitive transcranial magnetic stimulation is a potential treatment option for depression, with the newer intermittent theta-burst stimulation (iTBS) protocols providing brief intervention. However, their mechanism of action remains unclear. We investigated the hypothesis that iTBS influences brain circuits involved in emotion processing that are also affected by antidepressants. We predicted that iTBS would lead to changes in performance on emotion-processing tasks. We investigated the effects of intermittent TBS (iTBS) over the left dorsolateral prefrontal cortex (DLPFC) on the processing of emotional information (word recall and categorization, facial emotion recognition, and decision-making) in 28 healthy volunteers by contrasting these effects with those of sham stimulation. Each volunteer received iTBS and sham stimulation in a blinded crossover design and completed the emotion-processing tasks before and after stimulation. Compared to sham stimulation, iTBS increased positive affective processing for word recall, yet had an unexpected effect on facial emotion recognition for happy and sad faces. There was no evidence of an effect on decision-making or word categorization. We found support for our hypothesis that iTBS influences emotion processing, though some changes were not in the expected direction. These findings suggest a possible common mechanism of action between iTBS and antidepressants, and a complex neural circuitry involved in emotion processing that could potentially be tapped into via brain stimulation. Future research should investigate the neural correlates of emotion processing more closely to inform future iTBS protocols.

Common mental health disorders and cognitive decline in a longitudinal Down syndrome cohort.

BACKGROUND: Down syndrome is the most common genetic cause of intellectual disability and Alzheimer's disease. In the general population, common mental disorders (CMDs), including anxiety, depression and obsessive-compulsive disorder, are linked to cognitive decline and higher risk for dementia. It is not known how CMDs affect longer-term cognitive outcomes in Down syndrome, and there is often diagnostic uncertainty in older people with Down syndrome and psychiatric comorbidity. AIMS: To study the influence of CMDs on cognitive ability and whether they are related longitudinally to development of clinical signs of Alzheimer's disease in Down syndrome. METHOD: We followed 115 individuals with Down syndrome, 27 of whom were diagnosed with a CMD, over approximately 3 years. Changes in cognitive and behavioural outcomes between baseline and follow-up assessment were analysed, with comparisons made between those with and without a comorbid CMD. Age, gender, apolipoprotein E status and level of intellectual disability were included as covariates. RESULTS: No significant association between presence of a CMD and poorer performance on cognitive tasks or informant-rated decline over time was observed (P > 0.05). CONCLUSIONS: Our results suggest that a diagnosis of a CMD does not have a significant negative effect on long-term cognitive or behavioural outcomes in individuals with Down syndrome. In individuals with stable or treated CMD, subsequent cognitive decline is likely indicative of Alzheimer's disease rather than a consequence of mental disorder.

Structural Connectivity in Down Syndrome and Alzheimer's Disease.

Down syndrome (DS) arises from the triplication of chromosome 21, which leads to an atypical neurodevelopment and the overproduction of the amyloid precursor protein, predisposing to early Alzheimer's disease (AD). Not surprisingly, trisomy 21 is widely considered a model to study predementia stages of AD. After decades, in which neural loss was the main focus, research in AD is now moving toward understanding the neurodegenerative aspects affecting white matter. Motivated by the development of magnetic resonance imaging (MRI)-based diffusion techniques, this shift in focus has led to several exploratory studies on both young and older individuals with DS. In this review, we synthesise the initial efforts made by researchers in characterising in-vivo structural connectivity in DS, together with the AD footprint on top of such pre-existing connectivity related to atypical brain development. The white matter structures found to be affected in DS are the corpus callosum and all the main long-association fibres, namely the inferior fronto-occipital fasciculus, the inferior and superior longitudinal fasciculus, the uncinate fasciculus and the cingulum bundle. Furthermore, the cingulum bundle and the corpus callosum appear to be particularly sensitive to early AD changes in this population. Findings are discussed in terms of their functional significance, alongside methodological considerations and implications for future research.

Depersonalization disorder as a systematic downregulation of interoceptive signals.

Depersonalisation disorder (DPD) is a psychopathological condition characterised by a feeling of detachment from one's own body and surrounding, and it is understood as emerging from the downregulation of interoceptive afferents. However, the precise mechanisms that drive this 'interoceptive silencing' are yet to be clarified. Here we present a computational and neurobiologically plausible model of DPD within the active inference framework. Specifically, we describe DPD as arising from disrupted interoceptive processing at higher levels of the cortical hierarchy where the interoceptive and exteroceptive streams are integrated. We simulated the behaviour of an agent subjected to a situation of high interoceptive activation despite the absence of a perceivable threat in the external environment. The simulation showed how a similar condition, if perceived as inescapable, would result in a downregulation of interoceptive signals, whilst leaving the exteroceptive ones unaffected. Such interoceptive silencing would force the agent to over-rely on exteroceptive information and would ultimately lead to the DPD phenomenology. Finally, our simulation shows that repeated exposure to similar situations over time will lead the agent to increasingly disengage from bodily responses even in the face of a less triggering situation, explaining how a single episode of depersonalization can lead to chronic DPD.