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Background: Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging)., Methods: This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ 1-42 , CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([ 18 F]-fluorodeoxyglucose positron emission tomography)., Results: Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r 2  = 0.2, p = 0.003), adults with DS (r 2  = 0.4, p < 0.0001) and sporadic AD (r 2  = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ 1-42 (r 2  > 0.3, p < 0.006), low CSF t-tau (r 2  > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05)., Conclusions: Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.

Down syndrome (DS) is the most common worldwide cause of intellectual disability of genetic origin and the most common chromosomal disorder affecting live-born infants. In addition to intellectual disability, individuals with DS have other comorbidities and complex medical conditions. The increase in the life expectancy of patients with DS requires expanding the knowledge about their clinical characteristics and related laboratory parameters. Several studies exploring laboratory tests in DS patients exist, but their focus is limited to specific areas of metabolism. Therefore, our main goal was to describe the biochemical and hematological findings in a DS cohort and to compare the values to those of a control population. A total of 248 DS individuals and 84 control subjects were enrolled. DS individuals had a higher frequency of several clinical conditions compared to control individuals and presented with significant differences with respect to the controls in both biochemical and hematological parameters. We found age- and sex-related differences in several of the parameters. A good understanding of the differences in our cohort might be of aid in the clinical follow-up of adults with DS, especially considering that the lifespan of DS individuals may reach 60 years of age in developed countries.

Introduction: We aimed to define prodromal Alzheimer's disease (AD) and AD dementia using normative neuropsychological data in a large population-based cohort of adults with Down syndrome (DS)., Methods: Cross-sectional study. DS participants were classified into asymptomatic, prodromal AD and AD dementia, based on neurologist's judgment blinded to neuropsychological data (Cambridge Cognitive Examination for Older Adults with Down's syndrome [CAMCOG-DS] and modified Cued Recall Test [mCRT]). We compared the cutoffs derived from the normative data in young adults with DS to those from receiver-operating characteristic curve (ROC) analysis., Results: Diagnostic performance of the CAMCOG-DS and modified Cued Recall Test (mCRT) in subjects with mild and moderate levels of intellectual disability (ID) was high, both for diagnosing prodromal AD and AD dementia (area under the curve [AUC] 0.73-0.83 and 0.90-1, respectively). The cutoffs derived from the normative data were similar to those derived from the ROC analyses., Discussion: Diagnosing prodromal AD and AD dementia in DS with mild and moderate ID using population norms for neuropsychological tests is possible with high diagnostic accuracy., Competing Interests: Dr. Fortea has received compensation for consultancies to Novartis and AC Immune. The remaining authors have no conflicts of interest to declare that are relevant for this article., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome., Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ 1-42/1-40 ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18 F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate., Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ 1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18 F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life., Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments., Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach., Methods: Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, 18 F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged., Results: The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases., Discussion: We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches., (© 2019 The Authors.)

Study Objectives: Sleep problems are often undetected in adults with Down syndrome (DS). Our objective was to determine the prevalence of sleep disorders in adults with DS through self-reported and objective sleep measures., Methods: We performed a community-based cross-sectional study of 54 adults with DS not referred for sleep disorders. Two polysomnography (PSG) sleep studies were performed. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the risk for the sleep apnea syndrome (OSA) was identified using the Berlin Questionnaire (BQ). Participants' sleep/wake pattern was assessed from sleep diaries and by wrist actigraphy. PSQI, ESS, and PSG measures were compared with 35 sex-, age-, and body mass index-matched patients in the control groups., Results: In PSG measures, adults with DS showed lower sleep efficiency (69 ± 17.7 versus 81.6 ± 11; P < .001), less rapid eye movement sleep (9.4 ± 5.8 versus 19.4 ± 5.1; P < .001), a higher prevalence of OSA (78% versus 14%; P < .001), and a higher apnea-hypopnea index (23.5 ± 24.5 versus 3.8 ± 10.5; P < .001) than patients in the control group. In the DS group, the questionnaires (mean PSQI 3.7 ± 2.9; mean ESS 6.3 ± 4.5 and mean BQ 1 ± 0) did not reflect the sleep disturbances detected on the PSG. Actigraphy data recorded daytime sleep that was not self-reported (118.2 ± 104.2 minutes)., Conclusions: Adults with DS show severe sleep disruption and a high prevalence of OSA, undetected by self-reported sleep measures. Actigraphy, PSG, and validated simplified devices for screening OSA should be routinely recommended for this population because treatment of sleep disorders can contribute to healthy aging., (© 2018 American Academy of Sleep Medicine.)

Background: Diagnosis of Alzheimer's disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population., Methods: We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimer's disease, or Alzheimer's disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ) 1-40 , Aβ 1-42 , total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimer's disease and between asymptomatic participants and those with Alzheimer's disease dementia., Findings: Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimer's disease, 49 Alzheimer's disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimer's disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimer's disease dementia group. In CSF, except for Aβ 1-40 concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimer's disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aβ 1-42 , 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimer's disease dementia comparison (AUC ≥0·90 for all except Aβ 1-40 [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001)., Interpretation: Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimer's disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimer's disease in Down syndrome in clinical practice and clinical trials., Funding: Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

Introduction: People with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS., Methods: Noradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40)., Results: In brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus non-DS controls, significantly decreased MHPG levels were noted in various brain regions, though to a lesser extent than for DS+AD versus EOAD. Apart from DOPAC, CSF/plasma concentrations were not altered between groups., Discussion: Monoamine neurotransmitters and metabolites were evidently impacted in DS, DS+AD, and EOAD. DS and DS+AD presented a remarkably similar monoaminergic profile, possibly related to early deposition of amyloid pathology in DS. To confirm whether monoaminergic alterations are indeed due to early amyloid β accumulation, future avenues include positron emission tomography studies of monoaminergic neurotransmission in relation to amyloid deposition, as well as relating monoaminergic concentrations to CSF/plasma levels of amyloid β and tau within individuals.

Introduction: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD])., Methods: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68)., Results: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA., Discussion: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population., Objective: To analyze the frequency of complications after a LP in DS., Methods: We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included., Results: There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group., Conclusion: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

Background: Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome., Methods: We enrolled adults (aged 16-34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711., Findings: The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: -4·58 s [-8·54 to -0·62], p=0·024; d -0·27 [-0·72 to -0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [-0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups., Interpretation: EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training., Funding: Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

Background: Counterfactual thinking is a specific type of conditional reasoning that enables the generation of mental simulations of alternatives to past factual events. Although it has been broadly studied in the general population, research on schizophrenia is still scarce. The aim of the current study was to further examine counterfactual reasoning in this illness., Methods: Forty schizophrenia patients and 40 controls completed a series of tests that assessed the influence of the "causal order effect" on counterfactual thinking, and the ability to generate counterfactual thoughts and counterfactually derive inferences from a hypothetical situation. Socio-demographic and clinical characteristics, as well as neurocognitive variables, were also examined., Results: Compared to controls, the schizophrenia patients generated fewer counterfactual thoughts when faced with a simulated scenario. The pattern of response when assessing the causality effect of the order was also different between the groups, with the patients being more frequently unable to attribute any ordering of events than the control subjects. Additionally, the schizophrenia patients showed more difficulties when deriving normative counterfactual inferences from hypothetical social situations. None of the counterfactual reasoning measures was associated to any of the cognitive functions or clinical and socio-demographic variables assessed., Conclusions: A global impairment in counterfactual thinking characterizes schizophrenia patients. Because of the potential impact of such deficits on psychosocial functioning, targeting counterfactual reasoning for improvement might be considered in future treatment approaches.

The assessment of memory decline in people with intellectual disability (ID) is more difficult than in the general population, due to a lack of appropriate instruments and to preexisting cognitive impairment. The aim of this study was to describe performance of healthy adults with Down syndrome (healthy-DS; prospectively cohort) on a Spanish version of the modified Cued Recall Test (mCRT). We also recruited retrospectively a cohort of DS subjects with Dementia of the Alzheimer's Type (DS-DAT). Healthy-DS obtained higher scores on free recall and total score than DS-DAT. Age was the main factor associated with decreasing mCRT scores. The mCRT was useful in DS subjects with ID at the upper end of the spectrum or ID in the middle range of the spectrum, and discriminated well between DS subjects with and without DAT.

The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS.

Scope: Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit., Methods and Results: Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study., Conclusion: We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Little is known about the regions involved in recovery from global aphasia in patients with malignant infarction after decompressive hemicraniectomy. This study reports a case of brain activation during speech perception in a right-handed patient with a massive left hemispheric infarction., Methods: Decompressive hemicraniectomy was performed in a 20-year old woman with space-occupying infarction of the speech dominant hemisphere. Complete anterior, middle and part of the posterior cerebral artery territories of the left hemisphere, as well as posterior regions of the right middle cerebral artery territory, were affected. Neuropsychological testing and functional magnetic resonance imaging (fMRI) during speech perception were performed 10 months after stroke., Results: The patient was able to walk, go up and down stairs independently and perform simple tasks at home. She was also well able to match visually and orally presented words with their corresponding pictures, despite large bilateral lesions in the posterior regions. fMRI revealed strong activation of the left temporo-occipital and parieto-occipital areas. In the right hemisphere was observed a small area of activation in the posterior part of the superior and middle temporal gyrus., Conclusions: In aphasic patients, the activation of posterior bilateral associative areas might be used to support language perception.

Object: Intracranial pressure (ICP) monitoring is increasingly used in the treatment of patients with malignant middle cerebral artery (MCA) infarction. However, neurological deterioration may exist independent from intracranial hypertension. This study aimed to present the findings of continuous ICP monitoring in a cohort of patients with malignant MCA infarction and to correlate these findings with clinical and radiological features., Methods: The authors studied a prospective cohort of 25 patients with malignant MCA infarction consecutively admitted to the neurotrauma intensive care unit of the Vall d'Hebron University Hospital between March 2002 and September 2006. The patients were treated using a combined protocol of initial moderate hypothermia and hemicraniectomy. The latter was performed when patients showed a midline shift (MLS) > or = 5 mm or ICP > 20 mm Hg. Six patients had an MLS > or = 5 mm on the first CT scan and underwent surgery without prior ICP monitoring. This study focuses on the subgroup of 19 patients who underwent intraparenchymatous ICP monitoring before surgery., Results: Intracranial pressure readings were evaluated and correlated with pupillary abnormalities, MLS, and ischemic tissue volume. In 12 of the 19 patients, ICP values were always < or = 20 mm Hg, despite a mean (+/- SD) MLS of 6.7 +/- 2 mm and a mean ischemic tissue volume of 241.3 +/- 83 cm(3). In 2 patients with anisocoria, ICP values were also normal., Conclusions: In patients with a malignant MCA infarction, pupillary abnormalities and severe brainstem compression may be present despite normal ICP values. Therefore, continuous ICP monitoring cannot substitute for close clinical and radiological follow-up in the management of these patients.

Object: The test-retest method is commonly used in the management of patients with normal-pressure hydrocephalus (NPH). One of the most widely used techniques in the diagnosis of this condition is evaluation of the patient's response to CSF evacuation by lumbar puncture (a so-called tap test or spinal tap). However, interpretation of improved results in subsequent evaluations is controversial because higher scores could reflect a real change in specific abilities or could be simply the result of a learning effect., Methods: To determine the effect of testing-retesting in patients with NPH, the authors analyzed changes documented on 5 neuropsychological tests (the Toulouse-Pieron, Trail Making Test A, Grooved Pegboard, Word Fluency, and Bingley Memory tests) and several motor ability scales (motor performance test, length of step, and walking speed tests) in a series of 32 patients with NPH who underwent the same battery on 4 consecutive days. The same tests were also applied in 30 healthy volunteers. In both groups, the authors used the generalized least-squares regression method with random effects to test for learning effects. To evaluate possible differences in response depending on the degree of cognitive impairment at baseline, the results were adjusted by using the Mini-Mental State Examination scores of patients and controls when these scores were significant in the model., Results: In patients with NPH there were no statistically significant differences in any of the neuropsychological or motor tests performed over the 4 consecutive days, except in the results of the Toulouse-Pieron test, which were significantly improved on Day 3. In contrast, healthy volunteers had statistically significant improvement in the results of the Toulouse-Pieron test, Trail Making Test A, and Grooved Pegboard test but not in the remaining neuropsychological tests. Patients in the healthy volunteer group also exhibited statistically significant improvement in the motor performance test but not in step length or walking speed., Conclusions: No learning effect was found in patients with NPH on any of the neuropsychological or motor tests. Clinical improvement after retesting in these patients reflects real changes, and this strategy can therefore be used in both the diagnosis and evaluation of surgical outcomes.

Malignant middle cerebral artery (MMCA) infarction is associated with a mortality rate of 80% under conservative treatment. Decompressive hemicraniectomy (DH) reduces mortality and improves the functional outcome of surviving patients. The purpose of this study was to examine quality of life (QoL) and neurobehavioral deficits in patients with space-occupying infarctions of the right- or left-sided hemisphere at 6 months after stroke. The Sickness Impact Profile (SIP) was used to assess QoL in 19 out of 29 consecutive patients that underwent DH after a malignant MCA infarction (14 on the right and 5 on the left hemisphere). Behavioral changes were evaluated with the Frontal Behavioral Inventory and the Beck Depression Inventory. Patients and relatives were also asked if, knowing the present outcome, they would agree again, in retrospect, to a DH. Barthel Index >60 was seen in 37% of our patients. Functional outcome was related to age. We found a higher reduction in the SIP's physical domain than in the psychosocial domain. Depressive symptoms were present in 50% of the patients. We didn't find significant differences in QoL or functional outcome between patients with right or left-sided infarctions. The most frequent neurobehavioral symptoms were decreased speech output, apathy, reduced spontaneity and irritability. Most patients and their relatives would again give consent to hemicraniectomy. The results show that younger patients had a significantly better outcome. QoL seems to be acceptable in both left- and right-sided infarctions, and retrospective agreement to hemicraniectomy is high in both patients and their relatives.

Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, urinary incontinence and dementia, and is associated with variable ventricular enlargement. The most accepted treatment of NPH is the placement of a cerebrospinal fluid shunt. Owing to the characteristics of the patients and the invasive nature of the surgical treatment, it is fundamental to detect those patients who could obtain a greater benefit from the treatment. Neuropsychological assessment of these patients could significantly contribute to a better diagnosis of NPH, determining a cognitive deterioration profile for these patients, allowing the assessment of treatment efficacy and helping to detect other additional causes of dementia. The aim of this study is to describe the cognitive deterioration profile of NPH patients and to present the clinical, functional and neuropsychological assessment protocol used in our hospital.

Malignant middle cerebral artery infarction (MMCAI) refers to an infarction type normally accompanied by massive cerebral edema, and associated with a high mortality rate under conventional therapeutic measures. Both moderate hypothermia and decompressive hemicraniectomy have been shown to significantly improve survival rate, although controversy still persists regarding the criteria for the selection of patients that could benefit from this type of treatment, and whether application of these measures is justified given the residual sequelae. In our centre, both measures are being applied simultaneously for the first time in humans. The present work is a literature review on the results of moderate hypothermia application and decompressive surgical techniques in patients suffering from MMCAI. We also introduce our management scheme for handling these patients in our centre, and propose a final result evaluation protocol that is easily applied in a clinical setting. This protocol includes an evaluation of patients with ischemic lesions specific for the right or left hemisphere, and allows for the description of specific neuropsychological sequelae and their repercussions on patients' quality of life.

The primary goal of this study was to determine the incidence of post-traumatic ventriculomegaly (Evans' index > or = 0.30) in 95 head-injured patients with a Glasgow Coma Scale (GCS) score of < or =13 at admission. Additional objectives were to determine the relationship between an increase in ventricular size and several clinical and radiological features and outcome. A planimetric study was carried out in the sequential control computed tomography (CT) scans of 34 moderately head-injured (GCS 9-13) and 61 severely head-injured (GCS 3-8) patients with a minimum follow-up of 2 months. Between two and six CT scans were evaluated in each patient. The presence of subarachnoid hemorrhage (SAH) was registered. Evans' index was determined in all CT scans. In the final CT scan of each patient, ventricular size was related to the admission GCS score, age, the presence of SAH in the initial CT scans, type of brain lesion (classified according to the final diagnosis in the Traumatic Coma Data Bank classification), and outcome. Ventriculomegaly was found in 39.3% of patients with severe head injury and in 27.3% of those with a moderate head injury. Increased ventricular size was evident 4 weeks after injury in 57.6% and 2 months after injury in 69.7%. No relationship was found between post-traumatic ventriculomegaly and age, initial GCS score, the presence of SAH, or type of lesion (focal or diffuse). Post-traumatic ventriculomegaly was significantly correlated with outcome. Post-traumatic ventriculomegaly is a frequent and early finding in patients with moderate or severe traumatic brain injury.