Adriana Ruiz

Hippocampal Hyperactivation in Presymptomatic Familial Alzheimer's Disease

The examination of individuals who carry fully penetrant genetic alterations that result in familial Alzheimers disease (FAD) provides a unique model for studying the early presymptomatic disease stages. In AD, deficits in episodic and associative memory have been linked to structural and functional changes within the hippocampal system. This study used functional MRI (fMRI) to examine hippocampal function in a group of healthy, young, cognitively‐intact presymptomatic individuals (average age 33.7 years) who carry the E280A presenilin‐1 (PS1) genetic mutation for FAD. These PS1 subjects will go on to develop the first symptoms of the disease around the age of 45 years. Our objective was to examine hippocampal function years before the onset of clinical symptoms.

Cortical atrophy in presymptomatic Alzheimer's disease presenilin 1 mutation carriers

Background Sporadic late-onset Alzheimers disease (AD) dementia has been associated with a ‘signature’ of cortical atrophy in paralimbic and heteromodal association regions measured with MRI. Objective To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset. Methods 40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions. Results Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe. Conclusion Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.

An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers

Alzheimers disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1H‐MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD.

Reduced regional gray matter in cognitively normal young adults at genetic risk for early-onset Alzheimer's disease

Background: The neural mechanisms by which genetic variation increases risk for a disease have long been elusive, as there is a pathway between genes, cognitive performance, and clinical disease manifestations. We conducted a candidate gene study exploring genetic variation in brain volumes and cognitive performance measures that have been used to define heritable intermediate phenotypes related to the risk for dementia. These possible genetic bases of brain magnetic resonance imaging (MRI) measures and performance on cognitive tests were investigated in a large sample of older, community-dwelling individuals. Methods: We employed data from 997 non-demented participants (M 1⁄4 528, F 1⁄4 469; age range 1⁄4 50-92) who were prospectively followed through the Baltimore Longitudinal Study of Aging (BLSA). 119 of them also underwent annual MRI assessments. We performed both cross sectional and longitudinal analyses with APOE, a known AD risk gene, and four other putative genes for cognitive impairment and dementia (COMT, BDNF, SORL1, and KIBRA) as predictors. We used linear mixed effects models, adjusting for sex and education, to relate single nucleotide polymorphisms (SNPs; Illumina 550K Human Gene Chip) to 16 global and regional brain volumes and to performance on 12 standard cognitive tests spanning five cognitive domains (memory, word knowledge, attention, executive function, and visuo-spatial abilities). Results: Our findings provide evidence for gene associations with both cross-sectional and longitudinal cognitive performance, with the most persistent and selective associations observed between the decline in executive function (Trails B) and SORL1 and KIBRA respectively (p‘ s< 0.05). Polymorphisms in BDNF and COMT showed evidence for cross-sectional associations with white matter volume, while SORL1 polymorphisms were related to both cross-sectional and longitudinal differences specific to whole brain and white matter volume (p’ s< 0.05). Conclusions: Our results suggest that putative genes for cognitive impairment and dementia also have detectable effects on cognition and brain volume in non-demented older adults. This approach may not only aid in the discovery of novel pathways involved in structural and functional brain aging, but may also lead to better understanding of individual differences in brain structure and function.