Journal of Alzheimer's Disease - Volume 68, issue 3

Authors: Boomsma, Jooske M.F. | Exalto, Lieza G. | Barkhof, Frederik | van den Berg, Esther | de Bresser, Jeroen | Heinen, Rutger | Leeuwis, Anna E. | Prins, Niels D. | Scheltens, Philip | Weinstein, Henry C. | van der Flier, Wiesje M. | Biessels, Geert Jan | behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer’s disease (AD) pathology. Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n  = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n  = 398), microbleeds (n  = 368), …lacunar (n  = 188) and non-lacunar (n  = 96) infarct(s), macrobleeds (n  = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n  = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (β: – 0.26, p  = 0.05). Results were similar in the presence (n  = 300) or absence (n  = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (β: – 0.08, p  = 0.02) and working memory (β: – 0.08, p  = 0.04). Conclusion: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology. Show more

Keywords: Cerebral small vessel diseases, cerebrovascular disorders, cognitive disorders, neuropsychological test

DOI: 10.3233/JAD-180696

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1273-1286, 2019

Authors: Andrés-Benito, Pol | Gelpi, Ellen | Povedano, Mónica | Ausín, Karina | Fernández-Irigoyen, Joaquín | Santamaría, Enrique | Ferrer, Isidro

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD). Objective: Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions. Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls. Results: …Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD. Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted ‘-omics’ is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples. Show more

Keywords: C9ORF72, frontotemporal lobar degeneration, FTLD-TDP, gene expression, proteomics

DOI: 10.3233/JAD-181123

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1287-1307, 2019

Article Type: Correction

DOI: 10.3233/JAD-199001

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1309-1309, 2019