The brain system for language in cognitively intact elderly individuals: right-hemispheric recruitment in relationship to in vivo measures of amyloid load.

In this thesis we focused on brain amyloid deposition in a cognitively intact older population: we described its dependence on the genetic polymorphisms and its functional consequences on language and semantic processing. Moreover, we compared the performance of different amyloid biomarkers. All participants included in this project were community recruited cognitively intact older adults (52-74 years old Chapter 3 and 4 or 65-80 years old Chapter 5 and 6) who underwent genetic stratification for APOE and BDNF, conventional neuropsychological testing, volumetric MRI, 18F-flutemetamol PET, and additionally for experiments in Chapter 3 and 4 associative-semantic fMRI and neurolinguistic assessment, or for experiments in Chapter 5 and 6 a second PET with 11C-PIB and lumbar puncture to collect cerebrospinal fluid. In the first part of this work (Chapter 3), we examined whether the BDNF codon 66 polymorphism affects β amyloid deposition and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Our study revealed two key novel findings. First, APOE ε4 carriers exhibited a higher β amyloid load in the presence of one or two BDNF met alleles compared to BDNF met non-carriers. This interaction was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. Second, an inverse relationship between Aβ load and episodic memory exists in BDNF met / APOE ε4 carriers but not in any of the other subgroups. This experiment highlights a potential role of the BDNF polymorphism in the preclinical phase of β amyloid deposition and also suggests that the BDNF codon 66 polymorphism may influence resilience against β amyloid-related effects on cognition. In the second part of this project (Chapter 4), we examined whether amyloid load affects the network for language and associative-semantic processing. We found that a higher activity during associative-semantic processing in the posterior left middle temporal gyrus, correlated positively with increased amyloid load. This finding was based on a whole-brain search without prior restriction of the search volume. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with amyloid levels. In a secondary analysis based on a binary approach, the amyloid-positive group exhibited a higher activity compared to the amyloid-negative group during associative-semantic processing in the same region: the posterior left middle temporal gyrus. We concluded that the left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden at the preclinical AD stage. In the third part of this project (Chapter 5), we compared two amyloid imaging markers within subjects: 18F-flutemetamol and 11C-PIB. We found that the concordance between binary classification based on 18F-flutemetamol versus 11C-PIB according to semiquantitative assessment (SUVR) was 94%. Concordance of blinded binary visual reads between tracers was 84%. The correlation between 18F-flutemetamol and 11C-PIB SUVR values with cerebellar grey matter as reference region, was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with pons as reference region. Partial volume correction improved the correlation in two out of 9 investigated regions: striatum and medial temporal cortex. This study provided evidence that for the definition of preclinical AD based on 18F-flutemetamol, concordance with 11C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region. In the last part of this work (Chapter 6), we compared the diagnostic accuracy of different cerebrospinal fluid Aβ isoforms, their ratios, total tau, and Aβ42/ttau for detecting amyloid-positive individuals. For this purpose we performed ROC analysis on cerebrospinal fluid analytes with 18F-flutemetamol amyloid PET as classifier. Seven out of 38 subjects (18%) were assigned to the amyloid-positive category based on the PET cut-off. Aβ42/ttau, Aβ42/Aβ40, Aβ42/Aβ38, and Aβ42 had the highest accuracy to identify amyloid-positive subjects (AUC ≥ 0.908). Aβ40 and Aβ38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90% and 95% Aβ42/ttau had the highest sensitivity, 85.71% and 71.43%, respectively. This experiment showed that for the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aβ 42 over total tau rather than using Aβ42 in isolation.