Bryan M. Spann

Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease.

In Alzheimers disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAβ). To identify immediate molecular targets downstream of oAβ binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric Aβ (dAβ). These patients also showed increased expression of neuroplasticity related genes, many encoding 3′UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dAβ.

NON-FLUENT PRIMARY PROGRESSIVE APHASIA: PRION-LIKE BEHAVIOR OF MISFOLDED PROTEINS IN THE SYNTACTIC NETWORK

microtubule associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72). Pathophysiological processes induced by these mutations may differ and some FTD subtypes have been associated with damage to the white matter (WM). This damage is visible as hyperintense signal on T2-weighted magnetic resonance (MR) imaging. The Genetic FTD Initiative (GENFI) is a longitudinal cohort study aimed at furthering understanding of disease in individuals with these three mutations. Methods: T1 and T2-weighted MR sequences were acquired for 180 subjects within the GENFI cohort, divided into 76 non-carriers, 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 43 symptomatic carriers (7 GRN, 13 MAPT and 23 C9orf72). WM hyperintensities (WMH) were automatically segmented using an algorithm based on outlier modelling in a multivariate Gaussian mixture model. Location in the WM was coded according to 1) a relative distance between ventricles and the cortex, divided into four equidistant layers (1 layer periventricular, 4 layer juxtacortical), and 2) to the closest cortical lobe. WMH in the basal ganglia were also investigated. Infratentorial regions were excluded from the analysis. Log-transformed WMH volumes were adjusted for age, gender, total intracranial volume, scanner type and years before expected onset. Results:Symptomatic GRN carriers had significantly more WMH than all other groups, but no differences could be detected between other subgroups (table 1). Symptomatic GRN carriers appeared to have a larger volume of WMH in the frontal and occipital regions compared with other symptomatic groups and presymptomatic GRN cases. Differences were most noticeable in periventricular layers, with higher WMH volumes in GRN cases compared with other groups. Conclusions: WMH patterns differ across FTD genetic subtypes, with symptomatic GRN carriers displaying particularly predominant fronto-occipital periventricular WMH. Future research should explore the pathophysiological mechanisms of WMH within genetic FTD.