Modulation of Amyloid-ß and Tau in Alzheimer's Disease Plasma Neuronal-Derived Extracellular Vesicles by Cerebrolysin® and Donepezil.

BACKGROUND: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. OBJECTIVE: We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. METHODS: Plasma NDEV levels of Aß42, total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. RESULTS: NDEV levels of Aß42, total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aß42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aß42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05). CONCLUSION: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.

Three-dimensional fluoroscopic navigation versus fluoroscopy-guided placement of pedicle screws in L4-L5-S1 fixation: single-centre experience of pedicular accuracy and S1 cortical fixation of 810 screws.

BACKGROUND: Three-dimensional (3D) navigation techniques can theoretically provide higher accuracy rates and increased safety for pedicle screw (PS) placement than traditional fluoroscopy (FL) guided methods. In this study, we compare the pedicular accuracy of 3D isocentric fluoroscopic navigation (3DFL) versus FL guidance in PS L4-L5-S1 fixation and evaluate the differential cortical purchase and safety of fixation of the S1 PS. METHODS: This is a single-centre retrospective study of 810 PSs placed in open L4-L5-S1 fixation between 2012 and 2017 in 39 patients using standard FL and in 96 patients under 3DFL. Pedicular screw accuracy was determined by postoperative computed tomography (CT) and graded on a 4-tiered classification system according to Gertzbein and Robbins. In addition, sacral screws were evaluated depending on the degree of cortical fixation: monocortical, bicortical or tricortical, and the degree of safety with respect to retroperitoneal structures. RESULTS: Grade 0 perfect pedicular screw placement was 95% for 3DFL screws compared to 85% for screws placed under fluoroscopy (P<0.05). The number of grade 0 versus grade 1 and higher (breached screws) was statistically significant (P<0.05). Higher S1 cortical screw accuracy [77% versus 51% (P<0.05)] for bi- and tricortical fixation and a lower percentage of "at risk" PSs (P<0.05) were achieved with placement under 3DFL versus FL. CONCLUSIONS: 3DFL enhances the accuracy and safety of PS placement in L4-L5-S1 fixation, reducing the rate of misplaced screws and improving S1 cortical fixation.

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases.

BACKGROUND: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer's disease. METHODS: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer's disease patients. RESULTS: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. CONCLUSION: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer's disease cases with apolipoprotein E epsilon-4 allele.

Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent cerebrolysin.

According to current scientific knowledge, excess tumour necrosis factor-α (TNF-α) and low insulin-like growth factor-I (IGF-I) are pathogenic-risk factors that constitute therapeutic targets for Alzheimer's disease (AD). Changes in serum TNF-α, total and dissociable IGF-I levels were determined by ELISA in 207 AD patients completing a 24-wk, double-blind, placebo-controlled trial to evaluate the effects of the neurotrophic compound Cerebrolysin (Cere: 10, 30 or 60 ml for 12 wk). At week 24, Cere reduced TNF-α and enhanced dissociable IGF-I with respect to placebo in a dose-related manner. TNF-α decreased in parallel with behavioural disturbances. Increases in total IGF-I were induced by 60 ml Cere and correlated significantly with improvements in global function, disabilities and behaviour in late-onset AD patients. These results showing for the first time the opposite influence of one anti-dementia treatment on serum TNF-α and IGF-I suggest the contribution of both factors to the clinical effects of Cere, and probably other drugs.

Reductions in qEEG slowing over 1 year and after treatment with Cerebrolysin in patients with moderate-severe traumatic brain injury.

Changes in quantitative EEG (qEEG) recordings over a 1-year period and the effects of Cerebrolysin (Cere) on qEEG slowing and cognitive performance were investigated in postacute moderate-severe traumatic brain injury (TBI) patients. Time-related changes in qEEG activity frequency bands (increases of alpha and beta, and reductions of theta and delta relative power) and in qEEG slowing (reduction of EEG power ratio) were statistically significant in patients with a disease progress of less than 2 years at baseline, but not in those patients having a longer disease progress time. Slowing of qEEG activity was also found to be significantly reduced in TBI patients after 1 month of treatment with Cere and 3 months later. Therefore, Cere seems to accelerate the time-related reduction of qEEG slowing occurring in untreated patients. The decrease of qEEG slowing induced by Cere correlated with the improvement of attention and working memory. Results of this exploratory study suggest that Cere might improve the functional recovery after brain injury and encourage the conduction of further controlled clinical trials.

Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease.

Tumor necrosis factor-alpha (TNF-alpha) and insulin-like growth factor-I (IGF-I) have been involved in the pathogenesis of Alzheimer's disease (AD) as neurotoxic and survival factors, respectively. Recent experimental studies suggest that the signalling pathways of TNF-alpha and IGF-I are functionally interrelated. In order to investigate the possible interaction of TNF-alpha and IGF-I in AD and mild cognitive impairment (MCI), the serum levels of total IGF-I, free IGF-I and TNF-alpha were determined in 141 AD patients, 56 MCI cases and 30 controls. As compared with controls, AD patients showed increased TNF-alpha and decreased IGF-I levels in serum, as well as a significant negative correlation between TNF-alpha and free IGF-I values. MCI patients also exhibited significantly higher TNF-alpha levels than controls. The present results suggest that increased TNF-alpha levels are involved in the pathogenesis of AD and MCI, and might antagonize the neurotrophic activity of IGF-I in these medical conditions. In addition, the combined determination of TNF-alpha and IGF-I might be useful to monitor anti-inflammatory and/or neurotrophic drug effects in AD.