Genomics of speech and language disorders

Multiple factors involve speech and language. Investigating animal models, mainly through songbirds, has allowed a better understanding of the verbal communication process. Speech disorders, such as childhood apraxia of speech, dysarthria or stuttering, along with language disorders, like aphasia, dyslexia or developmental language disorder are the main examples. More complex syndromes such as Autism-spectrum disorders, Down’s syndrome or Fragile X syndrome have more variable features. Genetic factors, such as hereditary or de novo mutations may influence the development of all of these conditions. Besides, most of speech and language disorders are implicated in neurodevelopment with molecular mechanisms and pathways that interact with each other, and there may be co-morbidity with other communication disorders or phenotypes unrelated to communication. Genes with heterogeneous functions in speech and language such as FOXP1, FOXP2, KIAA0319, ROBO1, APOE or CNTNAP2 are some examples. Epigenetic factors, especially microRNAs, influence the expressiveness. The genomics of these disorders allows us to understand language acquisition, carry out early detection strategies, genetic counseling and optimize future treatments, not only in communication disorders but also the neurological alterations that incorporate these mutations

Resting-state network disruption and APOE genotype in Alzheimer's disease: a lagged functional connectivity study.

BACKGROUND: The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called "lagged phase synchronization". METHODOLOGY/PRINCIPAL FINDINGS: Resting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions. CONCLUSIONS/SIGNIFICANCE: In addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder

Link between Cancer and Alzheimer Disease via Oxidative Stress Induced by Nitric Oxide-Dependent Mitochondrial DNA Overproliferation and Deletion

Nitric oxide- (NO-) dependent oxidative stress results in mitochondrial ultrastructural alterations and DNA damage in cases of Alzheimer disease (AD). However, little is known about these pathways in human cancers, especially during the development as well as the progression of primary brain tumors and metastatic colorectal cancer. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We speculate that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Recent studies also demonstrate a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology in AD (in animal models that mimic human AD) correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases

Immunocytochemical Characterization of Alzheimer’s Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine

Introduction: APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for the human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of an AD-like pattern at early ages. This study aimed to characterize immunocytochemical patterns of the AD mouse brain, which is treated with the EB101 vaccine, as a model for human AD. Material and methods: In this novel vaccine, a new approach has been taken to circumvent past failures with Aβ vaccines by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Results: Our findings showed that the administration of amyloid-β1−42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before the onset of Aβ brain deposition (at 7 weeks of age) and/or at an older age (35 weeks of age) can be effective in both halting the progression and clearing the AD-like neuropathological hallmarks. In addition, passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. Conclusion: These results provide strong evidence that immunization with the EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice

Development of HuperTacrines as non-toxic, cholinesterase inhibitors for the potential treatment of Alzheimer's disease

12siThis paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.nonenoneChioua, Mourad; Pérez, Marta; Bautista-Aguilera, Oscar M; Yañez, Matilde; López, Manuela G; Romero, Alejandro; Cacabelos, Ramón; de la Bellacasa, Raimon Puig; Brogi, Simone; Butini, Stefania; Borrell, José I; Marco-Contelles, JoseChioua, Mourad; Pérez, Marta; Bautista Aguilera, Oscar M; Yañez, Matilde; López, Manuela G; Romero, Alejandro; Cacabelos, Ramón; de la Bellacasa, Raimon Puig; Brogi, Simone; Butini, Stefania; Borrell, José I; Marco Contelles, Jos

eLORETA wire diagram of significant correlations between theta <i>lagged</i> phase synchronization values and the Mini-Mental State Examination scores in patients with Alzheimer's disease and controls (threshold: <i>r</i> = −0.27; p<0.05, corrected).

<p>The blue color of the wires indicate a negative correlation. Results are displayed on a transparent fiducial cortical surface. The points to which the lines are connected represent the center of the ROIs. The bottom panel shows scatterplots of the strongest correlations. The results displayed correspond to the connectivity between A) left temporal-right prefrontal cortex, and B) left anterior temporal-right central cortex.</p