Principales conclusiones acordadas durante la cumbre sobre discapacidad intelectual y demencia

First paragraph: Este breve informe resume las recomendaciones de la Cumbre Internacional sobre Discapacidad Intelectual y Demencia, celebrada en Glasgow, Escocia, del 13 al 14 de octubre de 2016, organizada por la Universidad de Stirling y la Universidad del Oeste de Escocia, financiada por el RS MacDonald Trust, el Gobierno escocés y Alzheimer Scotland. Los patrocinadores colaboradores incluyeron el Grupo de Trabajo Nacional sobre Discapacidades Intelectuales y Prácticas de Demencia (NTG) en los Estados Unidos y la Universidad de Illinois en Chicago. La cumbre fue copresidida por Karen Watchman, Ph.D. y Matthew P. Janicki, Ph.D., y tuvo representantes multidisciplinares de distintas organizaciones nacionales e internacionales con intereses en cuestiones relacionadas con los adultos con discapacidad intelectual afectados por demencia. El contenido de esta declaración fue parcialmente desarrollado gracias a una subvención del Departamento de Salud y Servicios Humanos de los Estados Unidos, Administración para la Vida Comunitaria (ACL), Beca del Instituto Nacional de Discapacidad, Vida Independiente e Investigación en Rehabilitación (NIDILRR) # 90RT5020-03-00. Sin embargo, esos contenidos no representan necesariamente la política del Departamento de Salud y Servicios Humanos de EE. UU., ni el respaldo del Gobierno Federal de EE. UU. Las opiniones expresadas representan las de los participantes de la Cumbre y del NTG

Increased Cortical Thickness and Caudate Volume Precede Atrophy in PSEN1 Mutation Carriers

Neuroimaging studies of familial Alzheimer's disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non-familial healthy controls. MC were classified as either asymptomatic (n=6) or symptomatic (n=5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images were reanalyzed with voxel-based morphometry methodology. Cerebrospinal fluid amyloid-β1-42 levels (Aβ) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p<0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p<0.01), increased caudate volumes (p<0.01), and decreased MD (p<0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Aβ values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC

Feasibility of lumbar puncture in the study of cerebrospinal fluid biomarkers for Alzheimer disease in subjects with Down syndrome

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

Kidins220 correlates with tau in Alzheimer's disease brain and cerebrospinal fluid

Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer's disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD

White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease

PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease

C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease

This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer's disease (AD). Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by η-secretase. The level of the 25-kDa APP-CTF was evaluated in three independent CSF sample sets of patients and controls. The CSF level of this 25-kDa CTF is higher in subjects with autosomal dominant AD linked to PSEN1 mutations, in demented Down syndrome individuals and in sporadic AD subjects compared to age-matched controls. Our data suggest that APP-CTF could be a potential diagnostic biomarker for AD

Evolving brain functional abnormalities in PSEN1 mutation carriers: A resting and visual encoding fMRI study

PSEN1 mutations are the most frequent cause of familial Alzheimer's disease and show nearly full penetrance. Here we studied alterations in brain function in a cohort of 19 PSEN1 mutation carriers: 8 symptomatic (SMC) and 11 asymptomatic (AMC). Asymptomatic carriers were, on average, 12 years younger than the predicted age of disease onset. Thirteen healthy subjects were used as a control group (CTR). Subjects underwent a 10-min resting-state functional magnetic resonance imaging (fMRI) scan and also performed a visual encoding task. The analysis of resting-state fMRI data revealed alterations in the default mode network, with increased frontal connectivity and reduced posterior connectivity in AMC and decreased frontal and increased posterior connectivity in SMC. During task-related fMRI, SMC showed reduced activity in regions of the left occipital and left prefrontal cortices, while both AMC and SMC showed increased activity in a region within the precuneus/posterior cingulate, all as compared to CTR. Our findings suggest that fMRI can detect evolving changes in brain mechanisms in PSEN1 mutation carriers and support the use of this technique as a biomarker in Alzheimer's disease, even before the appearance of clinical symptoms

Distinct functional activity of the precuneus and posterior cingulate cortex during encoding in the preclinical stage of Alzheimer's Disease

In this study functional magnetic resonance imaging (fMRI) is used to investigate the functional brain activation pattern in the preclinical stage of AD (pre-AD) subjects during a visual encoding memory task. Thirty subjects, eleven in the pre-AD stage, with decreased cerebrospinal fluid levels of Aβ42 (<500 pg/ml), and 19 controls with normal Aβ42 levels (CTR) were included. fMRI was acquired during a visual encoding task. Data were analyzed through an Independent Component Analysis (ICA) and region-of-interest-based univariate analysis of task-related BOLD signal change. From the ICA decomposition, we identified the main task-related component, which included the activation of visual associative areas and prefrontal executive regions, and the deactivation of the default-mode network. The activation was positively correlated with task performance in the CTR group (p < 0.0054). Within this pattern, subjects in the pre-AD stage had significantly greater activation of the precuneus and posterior cingulate cortex during encoding. Subjects in the pre-AD stage present distinct functional neural activity before the appearance of clinical symptomatology. These findings may represent that subtle changes in functional brain activity precede clinical and cognitive symptoms in the AD continuum. Present findings provide evidence suggesting that fMRI may be a suitable biomarker of preclinical AD

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer's Disease Risk.

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways