Laura Núñez

Posttranslational Nitro-Glycative Modifications of Albumin in Alzheimer's Disease: Implications in Cytotoxicity and Amyloid-β Peptide Aggregation

Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimers disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD.

Efficacy and Safety of Plasma Exchange with 5% Albumin to Modify Cerebrospinal Fluid and Plasma Amyloid-β Concentrations and Cognition Outcomes in Alzheimer’s Disease Patients: A Multicenter, Randomized, Controlled Clinical Trial

Background: Studies conducted in animal models and humans suggest the presence of a dynamic equilibrium of amyloid-β (Aβ) peptide between cerebrospinal fluid (CSF) and plasma compartments. Objective: To determine whether plasma exchange (PE) with albumin replacement was able to modify Aβ concentrations in CSF and plasma as well as to improve cognition in patients with mild-moderate Alzheimer’s disease (AD). Methods: In a multicenter, randomized, patient- and rater-blind, controlled, parallel-group, phase II study, 42 AD patients were assigned (1 : 1) to PE treatment or control (sham) groups. Treated patients received a maximum of 18 PE with 5% albumin (Albutein®, Grifols) with three different schedules: two PE/weekly (three weeks), one PE/weekly (six weeks), and one PE/bi- weekly (12 weeks), plus a six-month follow-up period. Plasma and CSF Aβ1–40 and Aβ1–42 levels, as well as cognitive, functional, and behavioral measures were determined. Results: CSF Aβ1–42 levels after the last PE compared to baseline were marginally higher in PE-treated group versus controls (adjusted means of variation: 75.3 versus –45.5 pg/mL; 95% CI: –19.8, 170.5 versus 135.1, 44.2; p = 0.072). Plasma Aβ1–42 levels were lower in the PE-treated group after each treatment period (p < 0.05). Plasma Aβ1–40 levels showed a saw-tooth pattern variation associated with PE. PE-treated patients scored better in the Boston Naming Test and Semantic Verbal Fluency (p < 0.05) throughout the study. Neuropsychiatric Inventory scores were higher in controls during the PE phase (p < 0.05). Conclusion: PE with human albumin modified CSF and plasma Aβ1–42 levels. Patients treated with PE showed improvement in memory and language functions, which persisted after PE was discontinued.

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer’s Disease Patients Treated with Plasma Exchange with 5% Human Albumin

Background: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer’s disease (AD) treated with plasma exchange (PE) with albumin replacement. Objective: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Methods: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. Results: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Conclusions: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

APOE STATUS MODULATES BRAIN PATTERNS OF AMYLOID DISTRIBUTION IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE (SCD) FROM THE FACEHBI STUDY

MMSE 29.21 6 0.94 29 6 0.89 29.22 6 0.96 29.29 6 0.88 Merc e Boada, Octavio Rodriguez-Gomez, Silvia Gil, Angela Sanabria, Montserrat Alegret, Sonia Moreno-Grau, Alba Perez, Francisco Lome~na, Javier Pav ıa, Rossella Gismondi, Santiago Bullich, Assumpta Vivas, Marta G omez Chiari, Antonio P aez, Laura N u~nez, Bego~na Hern andez-Olasagarre, Adelina Orellana, Sergi Valero, Agust ın Ruiz Ruiz, Lluis Tarraga, Gemma Mont e-Rubio, Fundaci o ACE, Barcelona Alzheimer Treatment & Research Center, Barcelona, Spain; Neuroscience Center, Fundaci o ACE, Institut Catal a de Neuroci encies Aplicades, Barcelona, Spain; Hospital Clinic, Barcelona, Spain; Nuclear Medicine Department, Hospital Clinic, Barcelona, Spain; Piramal Imaging GmbH, Berlin, Germany; Cl ınica Corachan, Barcelona, Spain; Grifols S.A., Barcelona, Spain. Contact e-mail: mboada@ fundacioace.com

AN ACTIVE ANTI-AB40 VACCINE (ABVAC40) PROVED TO BE SAFE AND IMMUNOGENIC IN THE PHASE I CLINICAL TRIAL

cebo were studied. Comprehensive neuropathological assessments were performed ranging from 4 months to 14 years after the trial. Large coronal paraffin sections of cerebral hemisphere were immunostained for Ab, scanned, then (i) the entire neocortical ribbon was scored for plaques in a CERAD-like manner (frequent1⁄43, moderate1⁄42, sparse1⁄41, none1⁄40) and (ii) false coloured to permit visualisation of staining patterns at low power. Results: 16/21 had a distribution of tangles and at least some residual Ab pathology indicating the cause of dementia had been AD, whereas 5/21 had alternative causes for dementia (PSP1⁄41, DLB1⁄41, VaD1⁄41and FTDTDP431⁄42). 18/21 had received the active agent and 3/21 the placebo. Scanning and false colouration of large Ab immunostained sections generated images suitable for comparison with amyloid PET scans as used in current immunotherapy trials. 13/15 AD subjects receiving the active agent had evidence of plaque removal (almost complete removal1⁄45, extensive patches of removal1⁄44, small patches of removal1⁄44, no plaque removal1⁄42). In the immunised AD group the mean plaque score was 1.46 (range1⁄40.05-2.9) vs. 2.4 for the single placebo AD case. There was a significant inverse correlation between peripheral blood anti-Ab titres and plaque scores. Conclusions: AD patients actively immunised against Ab can remain virtually plaque–free for up to 14 years. Nearly a quarter of the patients examined in this study did not have neuropathologically verified AD. Neuropathology follow up of patients in therapeutic trials for AD provides valuable information on the cause of dementia and effects of treatment.

Neuroimage in Alzheimer's disease: Results after plasma exchange with Human Albumin Grifols®

Further, MCI patients also showed decreased BOLD signal in the hippocampus during the delay period when compared to controls. Although MCI patients had diminished neural activity, they performed similarly to controls on the delayed yes/no recognition task. However, in a surprise, incidental longterm memory task, MCI patients reported less familiarity with the previously viewed pictures than controls. Conclusions: Taken together, these findings suggest that MCI patients were unable to adequately modulate neural activity in critical task-specific brain regions for attention and memory, and thereafter demonstrated impaired long-term memory recognition. In summary, the DLPFC and the hippocampus may be sites of early selective vulnerability in MCI patients, and that differences in neural modulation may be a potential biomarker of mild cognitive impairment.