Severity of Dementia, Anosognosia, and Depression in Relation to the Quality of Life of Patients With Alzheimer Disease: Discrepancies Between Patients and Caregivers

Objective: To investigate the factors associated with discrepancies between patient and caregiver reports of the quality of life of patients (QoLp) with Alzheimer"s disease (AD). Methods: Cross-sectional analytic study of 141 patients and their caregivers. The instruments used were the Quality of Life in AD (QoL-AD), the Global Deterioration Scale (GDS), the Geriatric Depression Scale (GDS-d) and the Anosognosia Questionnaire Dementia (AQ-D). Differences were analyzed according to GDS stage. A linear regression analysis was conducted using the difference between the absolute QoLp scores of patients and caregivers. A cluster analysis involving the patient variables was then performed. Results: The discrepancy between patient and caregiver QoLp ratings increased in line with GDS stages (χ2 (2) = 8.7, p = 0.013). In the regression model (F [7,133] = 16.6, p <0.001; R2 = 0.477), discrepancies in QoLp reports were associated with greater anosognosia, less depression and a better cognitive status in patients, as well as with female gender among caregivers. The cluster analysis showed that patients with the lowest ratings of QoLp had a better cognitive status, more depression and less anosognosia. Conversely, the highest ratings were given by patients with a poorer cognitive status, less depression and greater anosognosia. Conclusions: The factors associated with greater discrepancies between patient and caregiver ratings of QoLp were severity of dementia, anosognosia, depression and cognitive status in patients, and female gender in caregivers. In patients with advanced dementia, greater anosognosia leads to more positive ratings in QoLp and complementary observations are required

C9ORF72 Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion' patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5-17% of patients (21-41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine 'expansion-positive' patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an 'intermediate' allele with a mean size of only similar to 65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of 'non-expansion' FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as similar to 65 repeats may be sufficient to cause disease

Discovering the 3′ UTR-mediated regulation of alpha-synuclein

Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration