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.

Clinical Efficacy of Cerebrolysin and Cerebrolysin plus Nootropics in the Treatment of Patients with Acute Ischemic Stroke in Vietnam.

AIMS: To investigate the efficacy and safety of Cerebrolysin and Cerebrolysin plus nootropics in the routine treatment of patients with acute ischemic stroke (AIS). BACKGROUND: Acute ischemic stroke (AIS) is a leading cause of disability with unmet treatment needs lacking effective drug therapy. Multimodal drugs modulating stroke pathophysiology as Cerebrolysin constitute a good therapeutic option. OBJECTIVE: In this study, we assessed the effects of Cerebrolysin and Cerebrolysin plus nootropics, in comparison with other nootropic drugs alone, on functional, neurological and cognitive recovery of patients with AIS in Vietnam. METHODS: This non-interventional, controlled, open-label, prospective and multicenter study included 398 AIS patients (234 males) treated with Cerebrolysin (n=190; 20 i.v. infusions of 10 ml), other nootropics (comparator group; n=86), or a combination of both (n=122). The study primary endpoint was the modified Ranking Scale (mRS) score on day 90. Secondary endpoints included study-period change in NIHSS score; percentage of well-recovered (mRS 0-2) patients, the proportion of good NIHSS response (≥6 points) cases, and MoCA scores at day 90; and safety indicators. RESULTS: Compared with other nootropics, both Cerebrolysin and combined therapy induced significant improvements (p<0.001) in: Functional recovery (mRS scores); percentage of well-recovered patients (Cerebrolysin: 81.6%; combination: 93.4%; comparator: 43.0%); neurological recovery (study- period NIHSS change); proportion of good NIHSS responders (Cerebrolysin: 77.5%; combination: 92.5%; comparator: 47.6%); and MoCA scores (Cerebrolysin: 23.3±4.8; combination: 23.7±4.1; comparator: 15.9±7.7). Compared to Cerebrolysin, combined therapy improved (p<0.01) mRS outcomes and NIHSS change, but not MoCA scores, in moderate-severe stroke (NIHSS>11) cases only. No drug-related adverse events were reported. CONCLUSION: Cerebrolysin alone or combined with other nootropics was effective and safe in routine AIS treatment, during both acute and recovery phases, which supports its use in daily clinical practice. Others: According to the results of this multicenter study, the importance of reducing differences in the treatment regimens of AIS in Vietnam should be further emphasized.

Serum VEGF Predicts Clinical Improvement Induced by Cerebrolysin Plus Donepezil in Patients With Advanced Alzheimer's Disease.

Serum vascular endothelial growth factor (VEGF) increases with Alzheimer's disease (AD) severity and may prevent cognitive decline. However, information on the influence of AD drug therapy on circulating VEGF is limited. This study assessed changes in serum VEGF levels and its association with clinical and functional responses in mild to moderate AD patients who were treated with Cerebrolysin, donepezil, or the combined therapy in a randomized, controlled trial. Treatment with Cerebrolysin plus donepezil reduced elevated serum VEGF levels and improved functioning and cognition significantly compared with donepezil alone in patients with advanced AD, and treatment differences were more pronounced in patients with higher VEGF levels. Our results indicate that the combined therapy reversed the increase of serum VEGF in advanced AD, which was associated with cognitive and functional responses, particularly in patients with high baseline VEGF.

Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers.

Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

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.

Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease.

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long-lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin treatment (washout effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice. We demonstrate that, in APP tg mice, Cerebrolysin-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption; however, these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin-treated APP tg mice immediately after treatment was no longer apparent at 3 months after treatment interruption, indicating that the beneficial effects of Cerebrolysin at this time point were independent of its effect on amyloid-ß deposition. In conclusion, the results demonstrate that the effects of Cerebrolysin persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin.

Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil.

Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: -2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.

Persistence of the effects of Cerebrolysin on cognition and qEEG slowing in vascular dementia patients: results of a 3-month extension study.

The maintenance of the effects of Cerebrolysin, a peptidergic compound with neurotrophic activity, on cognitive performance and qEEG activity was investigated through a 12-week, open-label extension of a 4-week, randomised, placebo-controlled pilot study. Thirty-three out of 41 patients with mild-to-moderate severe probable vascular dementia (VaD) according to NINDS-AIREN participating in the double-blind phase of the study were also assessed at the follow-up visit at week 16. Patients received i.v. infusions of Cerebrolysin (10 or 30 mL) or placebo (saline) 5 days/week for 4 weeks. Neuropsychological evaluations and qEEG recordings were done at baseline, week 4 and week 16. The mean change in score from baseline in the ADAS-cog+ and the slow-to-fast qEEG power ratio (PR), used as an index of qEEG slowing, were the two primary endpoints. Correlations between changes in cognition and qEEG induced by the treatment were also assessed. At the week 16 follow-up visit, Cerebrolysin improved (p<0.05) cognitive performance at the 10-mL and 30-mL doses and reduced qEEG slowing significantly (p<0.05) at the 30-mL dose with respect to the placebo. In addition, a significant (p<0.05) positive correlation between the change from the baseline qEEG PR and ADAS-cog+ variables was observed at week 16. These results indicate a persistence of the beneficial effects of Cerebrolysin on cognition and qEEG activity in VaD patients for at least 12 weeks after treatment cessation, and they suggest the potential utility of qEEG parameters as biomarkers for VaD clinical trials.

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.

A pilot study to evaluate the effects of Cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration.

The effects of the neurotrophic compound Cerebrolysin (Cere) on cognitive performance, evaluated with the ADAS-cog, and on qEEG activity were investigated in forty one patients with mild to moderate severe probable vascular dementia (VaD) according to NINDS-AIREN criteria, included in a placebo-controlled pilot study. Patients received i.v. infusions of Cere (10 or 30 ml) or placebo (normal saline) 5 days/week for 4 weeks. Mean score of change from baseline in the ADAS-cog and percent change from baseline in slow to fast EEG power ratio (PR) scores were the two primary endpoints. Correlations between cognition and qEEG were also evaluated for both baseline scores and for scores of change from baseline in ADAS-cog and in qEEG parameters, including EEG power ratio (PR) as an index of EEG slowing. Baseline ADAS-cog scores showed significant positive correlations with delta power, theta power and PR scores, and correlated negatively with alpha activity. These correlations indicating that an increased EEG slowing is associated with a worst cognitive performance in VaD patients. Cere treatment improved cognitive performance significantly at the 10 ml dose and reduced EEG slowing with both 10 and 30 ml dosages. A significant positive correlation between PR and ADAS-cog scores of change from baseline was observed in Cere-treated patients. According to results of this pilot study, it is concluded that Cere improves cognitive performance and reduces EEG slowing in patients with VaD, and that there is a positive relationship between changes in cognition and qEEG activity induced by Cere. The conduction of further regular clinical trials is required to confirm the potential utility of Cere in the treatment of VaD suggested by the present results.

Effects of N-PEP-12 on memory among older adults.

N-PEP-12 is a derivative of cerebrolysin, a brain-derived neuropeptide compound that has been approved for the treatment of Alzheimer's disease (AD) in more than 30 countries. N-PEP-12 is much less potent than cerebrolysin but it can be administered orally whereas the parent compound must be administered through multiple intravenous infusions. This study was undertaken to determine whether N-PEP-12 is effective in improving memory and other cognitive abilities among healthy older adults who have experienced 'normal' age-related memory loss. Subjects were 54 males and females, aged 50 years and older, who presented both subjective and objective evidence of memory loss since early adulthood. The study was a fully randomized, double-blind comparison of N-PEP-12 and placebo. Cognitive assessments were performed at baseline and following 30 days of treatment. The primary outcome measure was the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) Memory score, with the Syndrom Kurz Test (SKT) test, digit cancellation, digit span, verbal fluency and clinical ratings as secondary outcomes. N-PEP-12 treated subjects performed better than placebo-treated subjects on the ADAS-cog Memory score, the SKT, clinical ratings and some, but not other tests. N-PEP-12 may be an effective treatment for memory loss in healthy older adults.

Positive effects of cerebrolysin on electroencephalogram slowing, cognition and clinical outcome in patients with postacute traumatic brain injury: an exploratory study.

The potential effects of Cerebrolysin (EBEWE Pharma, Unterach, Austria), a peptide preparation with neurotrophic activity, on brain bioelectrical activity, cognitive performance and clinical outcome in postacute traumatic brain injury (TBI) patients, were investigated in an exploratory study. A decrease in slow electroencephalogram (EEG) activity and an increase in fast frequencies were observed after the administration of Cerebrolysin. This EEG-activating effect was not influenced by TBI time course or severity, nor by the chronic treatment with nootropic compounds. Cognitive performance, evaluated with the Syndrome Kurztest test, improved in TBI patients after Cerebrolysin treatment, independent of disease severity, time course or disability. A significant improvement in the patients' clinical outcome, only evident during the first year after brain trauma, was also found following Cerebrolysin infusions. No relevant changes in biological parameters nor drug-related adverse events were observed. These promising preliminary results suggest that Cerebrolysin might be a useful treatment to improve the recovery of patients with traumatic brain damage, and encourage the conduction of confirmatory clinical trials.