Familial Early-Onset Alzheimer's Caused by Novel Genetic Variant and APP Duplication: A Cross-Sectional Study.

BACKGROUND: The clinical characteristics of symptomatic and asymptomatic carriers of early- onset autosomal dominant Alzheimer's (EOADAD) due to a yet-undescribed chromosomal rearrangement may add to the available body of knowledge about Alzheimer's disease and may enlighten novel and modifier genes. We report the clinical and genetic characteristics of asymptomatic and symptomatic individuals carrying a novel APP duplication rearrangement. METHODS: Individuals belonging to a seven-generation pedigree with familial cognitive decline or intracerebral hemorrhages were recruited. Participants underwent medical, neurological, and neuropsychological evaluations. The genetic analysis included chromosomal microarray, Karyotype, fluorescence in situ hybridization, and whole genome sequencing. RESULTS: Of 68 individuals, six females presented with dementia, and four males presented with intracerebral hemorrhage. Of these, nine were found to carry Chromosome 21 copy number gain (chr21:27,224,097-27,871,284, GRCh37/hg19) including the APP locus (APP-dup). In seven, Chromosome 5 copy number gain (Chr5: 24,786,234-29,446,070, GRCh37/hg19) (Chr5-CNG) cosegregated with the APP-dup. Both duplications co-localized to chromosome 18q21.1 and segregated in 25 pre-symptomatic carriers. Compared to non-carriers, asymptomatic carriers manifested cognitive decline in their mid-thirties. A third of the affected individuals carried a diagnosis of a dis-immune condition. CONCLUSION: APP extra dosage, even in isolation and when located outside chromosome 21, is pathogenic. The clinical presentation of APP duplication varies and may be gender specific, i.e., ICH in males and cognitive-behavioral deterioration in females. The association with immune disorders is presently unclear but may prove relevant. The implication of Chr5-CNG co-segregation and the surrounding chromosome 18 genetic sequence needs further clarification.

[POTENTIAL CLINICAL APPLICATIONS OF RESTING-STATE-FMRI IN NEUROLOGY].

INTRODUCTION: Resting-state functional Magnetic Resonance Imaging (rs-fMRI) is a non-invasive technique allowing to characterize brain functional connectivity. Blood oxygenation, the basis of the fMRI signal, fluctuates in the resting brain. These fluctuations have been shown to correlate between anatomically connected regions, thus allowing to examine functional connectivity between local and distal brain regions. The ability to identify functional networks, and to characterize their inter- and intra-connectivity is the basis for the development of useful clinical applications, which are especially relevant for neurological and neuropsychiatric diseases and disorders, in which network organization is altered. In this article, I will describe this method, review results obtained with it and demonstrate its potential through the consideration of findings from Alzheimer's disease research.

Brief mindfulness training de-couples the anxiogenic effects of distress intolerance on reactivity to and recovery from stress among deprived smokers.

OBJECTIVE: We tested whether mindfulness de-couples the expected anxiogenic effects of distress intolerance on psychological and physiological reactivity to and recovery from an anxiogenic stressor among participants experimentally sensitized to experience distress. METHOD: N = 104 daily smokers underwent 18-hours of biochemically-verified smoking deprivation. Participants were then randomized to a 7-min analogue mindfulness intervention (present moment attention and awareness training; PMAA) or a cope-as-usual control condition; and subsequently exposed to a 2.5-min paced over breathing (hyperventilation) stressor designed to elicit acute anxious arousal. Psychological and physiological indices of anxious arousal (Skin Conductance Levels; SCL) as well as emotion (dys)regulation (Respiratory Sinus Arrhythmia; RSA) were measured before, during and following the stressor. RESULTS: We found that PMAA reduced psycho-physiological dysregulation in response to an anxiogenic stressor, as well as moderated the anxiogenic effect of distress intolerance on psychological but not physiological responding to the stressor among smokers pre-disposed to experience distress via deprivation. CONCLUSIONS: The present study findings have a number of theoretical and clinical implications for work on mindfulness mechanisms, distress tolerance, emotion regulation, and smoking cessation interventions.

Early Age-Related Functional Connectivity Decline in High-Order Cognitive Networks.

As the world ages, it becomes urgent to unravel the mechanisms underlying brain aging and find ways of intervening with them. While for decades cognitive aging has been related to localized brain changes, growing attention is now being paid to alterations in distributed brain networks. Functional connectivity magnetic resonance imaging (fcMRI) has become a particularly useful tool to explore large-scale brain networks; yet, the temporal course of connectivity lifetime changes has not been established. Here, an extensive cross-sectional sample (21-85 years old, N = 887) from a public fcMRI database was used to characterize adult lifespan connectivity dynamics within and between seven brain networks: the default mode, salience, dorsal attention, fronto-parietal control, auditory, visual and motor networks. The entire cohort was divided into young (21-40 years, mean ± SD: 25.5 ± 4.8, n = 543); middle-aged (41-60 years, 50.6 ± 5.4, n = 238); and old (61 years and above, 69.0 ± 6.3, n = 106) subgroups. Correlation matrices as well as a mixed model analysis of covariance indicated that within high-order cognitive networks a considerable connectivity decline is already evident by middle adulthood. In contrast, a motor network shows increased connectivity in middle adulthood and a subsequent decline. Additionally, alterations in inter-network interactions are noticeable primarily in the transition between young and middle adulthood. These results provide evidence that aging-related neural changes start early in adult life.