Low TGF-ß1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-ß1 (TGF-ß1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-ß1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-ß1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-ß1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-ß1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-ß1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-ß1 concentrations in DS subjects at higher risk to develop cognitive decline.

Executive Functions and Attention Processes in Adolescents and Young Adults with Intellectual Disability.

(1) Background: We made a comprehensive evaluation of executive functions (EFs) and attention processes in a group of adolescents and young adults with mild intellectual disability (ID). (2) Methods: 27 adolescents and young adults (14 females and 13 males) with ID, aged between 15.1 and 23 years (M = 17.4; SD = 2.04), were compared to a control group free of cognitive problems and individually matched for gender and age. (3) Results: As for EFs, individuals with ID were severely impaired on all subtests of the Behavioral Assessment of Dysexecutive Syndrome (BADS) battery. However, we also found appreciable individual differences, with eight individuals (approximately 30%) scoring within normal limits. On the attention tests, individuals with ID were not generally slower but presented specific deficits only on some attention tests (i.e., Choice Reaction Times, Color Naming and Color-Word Interference, and Shifting of Attention for Verbal and for Visual Targets).The role of a global factor (i.e., cognitive speed) was modest in contributing to the group differences; i.e., when present, group differences were selectively associated with specific task manipulations, not global differences in cognitive speed. (4) Conclusions: The study confirmed large group differences in EFs; deficits in attentional processing were more specific and occurred primarily in tasks taxing the selective dimension of attention, with performance on intensive tasks almost entirely spared.

The evolution of self-injurious behaviors in people with intellectual disability and epilepsy: A follow-up study.

PURPOSE: Longitudinal studies of the evolution of Self-Injurious Behaviors (SIBs) in people with Intellectual Disability (ID) and epilepsy are not common. This study aimed to analyze the evolution (in terms of remission and persistence) and changes in the type, localization, frequency, and intensity of SIBs. METHODS: SIBs were assessed in a sample of 52 people with ID and epilepsy, and re-evaluated after a seven-year interval, using the "Scale for the Assessment of Self-Injurious Behaviors". The scale was administered to caregivers (parents or health professionals) through a semi-structured interview conducted by a specifically trained psychologist. RESULTS: The most frequent types of SIBs identified were: self-biting, self-hitting with objects, self-hitting with hand, object-finger in cavities. The main localizations of SIBs were: hands, mouth, head and cheeks. SIBs were found to be maintained after seven years, for type, localization, frequency, and intensity, in 90.4% of the sample. SIB types were stable over time, as were the affected areas. Global SIB frequency and intensity scores were found to be unchanged. Finally, a positive correlation was found between the frequency of SIBs and levels of intellectual disability. SIBs (frequency and intensity) and seizure frequency showed no correlation. CONCLUSION: Given the negative impact of SIBs on the adaptation and quality of life of people with ID and epilepsy, we believe that further studies on biological, psychological and environmental aspects are needed in order to identify any potential factors that might explain the persistence of SIBs and to find effective interventions to reduce them.

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation.

INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aß, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aß40 and Aß42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aß correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aß42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aß and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.