Alzheimer Disease: Moessler H

Alvarez XA, Cacabelos R, Laredo M, Couceiro V, Sampedro C, Varela M, Corzo L, Fernandez-Novoa L, Vargas M, Aleixandre M, Linares C, Granizo E, Muresanu D, Moessler H. · Euroespes Biomedical Research Centre, Santa Maria de Babio, Bergondo, La Coruna, Spain. · Eur J Neurol. · Pubmed #16420392 No free full text.

Abstract: Cerebrolysin (Cere) is a compound with neurotrophic activity shown to be effective in Alzheimer's disease in earlier trials. The efficacy and safety of three dosages of Cere were investigated in this randomized, double-blind, placebo-controlled, study. Two hundred and seventy-nine patients were enrolled (69 Cere 10 ml; 70 Cere 30 ml; 71 Cere 60 ml and 69 placebo). Patients received iv infusions of 10, 30, 60 ml Cere or placebo 5 days/week for the first 4 weeks and thereafter, two iv infusions per week for 8 weeks. Effects on cognition and clinical global impressions were evaluated 4, 12 and 24 weeks after the beginning of the infusions using the CIBIC+ and the modified Alzheimer's Disease Assessment Scale (ADAS)-cog. At week 24, significant improvement of cognitive performance on the ADAS-cog (P=0.038) and global function (CIBIC+; P>0.001) was observed for the 10 ml dose. The 30 and 60 ml doses showed significant improvement of the global outcome but failed to show significant improvement of cognition. The results are consistent with a reversed U-shaped dose-response relationship for Cere. The percentage of patients reporting adverse events was similar across all study groups. Cere treatment was well tolerated and led to significant, dose-dependent improvement of cognition and global clinical impression.

Muresanu DF, Rainer M, Moessler H. · Neurology Department, University of Cluj-Napoca, Cluj-Napoca, Romania. · J Neural Transm Suppl. · Pubmed #12456070 No free full text.

Abstract: BACKGROUND: Cerebrolysin (Cere) is a peptidergic, neurotrophic drug which has been shown to improve cognitive performance and global function of Alzheimer's disease (AD) patients in earlier trials. In this study, we have attempted to replicate this findings with particular emphasis on functional improvement of the patients. PATIENTS AND METHODS: Patients received infusions of 30 ml Cere or placebo five days/week for six consecutive weeks. Patients had to have a diagnosis of AD and a MMSE score of 14-25 inclusive. Effects on cognition, global function, and activities of daily living were evaluated 3, 6, and 18 weeks after the beginning of the infusions. RESULTS: Significant improvement of cognitive function, clinical global impression and activities of daily living were seen after the end of the therapy. The effects were most pronounced in the DAD score, a measure for the capability to perform activities of daily living. Interestingly, and in line with the findings of earlier studies, the treatment effect of Cere was maintained after cessation of treatment up to the week 18 assessment. CONCLUSION: The data confirm the findings of earlier trials and clearly demonstrates that Cere leads to functional improvement of patients with AD. The sustained treatment effect of Cere after withdrawal has been confirmed.

Ruether E, Alvarez XA, Rainer M, Moessler H. · Göttingen University Clinic for Psychiatry, Göttingen, Federal Republic of Germany. · J Neural Transm Suppl. · Pubmed #12456069 No free full text.

Abstract: BACKGROUND: In a recent study, Cerebrolysin (Cere), a compound with neurotrophic activity, has been shown to be effective in the treatment of mild to moderate Alzheimer's disease (AD). A subgroup analysis of this double-blind, placebo-controlled study was performed to assess the effects of Cere in cases with more advanced forms of AD. PATIENTS AND METHODS: Patients received infusions of 30 ml Cere or placebo five days/week for four weeks. This treatment was repeated after a two-months therapy-free interval. Effects on cognition, global function, behavioural symptoms and activities of daily living were evaluated 4, 12, 16, and 28 weeks after the beginning of the infusions. 109 patients with MMSE scores <20 were included in this analysis. RESULTS: The responder rate of the Cere group was 65% on the CGI, compared to 24.5% in the placebo group (p < 0.004). In the ADAS-cog, a score difference of 4.1 points in favour of Cere was observed (p < 0.0001). Notably, improvements were largely maintained in the Cere group up to the week 28 visit. CONCLUSION: The data clearly demonstrate the efficacy of Cere treatment in moderate to severe forms of AD with sustained treatment effects on cognition and global function even after discontinuation of treatment.

Panisset M, Gauthier S, Moessler H, Windisch M, Anonymous00105. · McGill Centre for Studies in Ageing, Montreal, Quebec, Canada. · J Neural Transm. · Pubmed #12111446 No free full text.

Abstract: Cerebrolysin (Cere) is a compound with neurotrophic activity. It has been shown to be effective in the treatment of Alzheimer's disease (AD) in earlier trials. In this multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients were injected intravenously with placebo or 30 mL Cere five days per week for four weeks. Effects on cognition and global function were evaluated with the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinicians Interview-based Impression of Change with Caregiver Input scale (CIBIC+) 4, 12, 24 weeks after the beginning of the injections. 192 patients were enrolled, 95 were randomized to placebo, and 97 to Cere. At baseline, there was a significant difference between groups for age, age of onset of dementia, and the number of patients with hallucinations. At week 12 there was a significant difference on the CIBIC+ (p = 0.033) in favor of Cere. The number of CIBIC+ responders (score < or = 4), was significantly higher (p = 0.007), with 68 (76%) in the Cere group and 51 (57%) in the placebo group. Trends were noted in the Disability Assessment in Dementia scale and the Cornell Depression Scale. Adverse events were recorded in 73% of placebo and 64% of Cere patients. Most common adverse events were headaches, dizziness, weight loss and anxiety. CONCLUSIONS: Cere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatment.

Ruether E, Husmann R, Kinzler E, Diabl E, Klingler D, Spatt J, Ritter R, Schmidt R, Taneri Z, Winterer W, Koper D, Kasper S, Rainer M, Moessler H. · Goettingen University Clinic for Psychiatry, Germany. · Int Clin Psychopharmacol. · Pubmed #11552768 No free full text.

Abstract: Cerebrolysin (Cere) is a compound with neurotrophic activity which has been shown to be effective in the treatment of Alzheimer's disease (AD) in earlier trials. The efficacy and safety of repeated treatments with Cere were investigated in this randomized, double-blind, placebo-controlled, parallel-group study. One hundred and forty-nine patients were enrolled (76 Cere; 73 placebo). Patients received i.v. infusions of 30 ml Cere or placebo 5 days per week for 4 weeks. This treatment was repeated after a 2-month therapy-free interval. Effects on cognition and clinical global impressions were evaluated 4, 12, 16, and 28 weeks after the beginning of the infusions using the Clinical Global Impression (CGI) and the Alzheimer's Disease Assessment Scale-cognitive subpart (ADAS-cog). All assessments, including the 28-week follow-up visit were performed under double-blind conditions. At week 16, the responder rate of the Cere group was 63.5% on the CGI, compared to 41.4% in the placebo group (P < 0.004). In the ADAS-cog, an efficacy difference of 3.2 points in favour of Cere was observed (P < 0.0001). Notably, improvements were largely maintained in the Cere group until week 28, 3 months after the end of treatment. Adverse events were recorded in 43% of Cere and 38% of placebo patients. Cere treatment was well tolerated and led to significant improvement in cognition and global clinical impression. A sustained benefit was still evident 3 months after drug withdrawal.

Rockenstein E, Mante M, Adame A, Crews L, Moessler H, Masliah E. · Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, 92093-0624, USA. · Acta Neuropathol. · Pubmed #17131129 No free full text.

Abstract: Cerebrolysin (CBL) is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative alterations in Alzheimer's disease (AD). We have previously shown that in the amyloid precursor protein (APP) transgenic (tg) mouse model of AD, CBL improves synaptic plasticity and behavioral performance. However, the mechanisms are not completely clear. The neuroprotective effects of CBL might be related to its ability to promote neurogenesis in the hippocampal subgranular zone (SGZ) of the dentate gyrus (DG). To study this possibility, tg mice expressing mutant APP under the Thy-1 promoter were injected with BrdU and treated with CBL for 1 and 3 months. Compared to non-tg controls, vehicle-treated APP tg mice showed decreased numbers of BrdU-positive (+) and doublecortin+ (DCX) neural progenitor cells (NPC) in the SGZ. In contrast, APP tg mice treated with CBL showed a significant increase in BrdU+ cells, DCX+ neuroblasts and a decrease in TUNEL+ and activated caspase-3 immunoreactive NPC. CBL did not change the number of proliferating cell nuclear antigen+ (PCNA) NPC or the ratio of BrdU+ cells converting to neurons and astroglia in the SGZ cells in the APP tg mice. Taken together, these studies suggest that CBL might rescue the alterations in neurogenesis in APP tg mice by protecting NPC and decreasing the rate of apoptosis. The improved neurogenesis in the hippocampus of CBL-treated APP tg mice might play an important role in enhancing synaptic formation and memory acquisition.

Rockenstein E, Torrance M, Mante M, Adame A, Paulino A, Rose JB, Crews L, Moessler H, Masliah E. · Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California 92093-0624, USA. · J Neurosci Res. · Pubmed #16511867 No free full text.

Abstract: Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.

Rockenstein E, Adame A, Mante M, Larrea G, Crews L, Windisch M, Moessler H, Masliah E. · Department of Neurosciences, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA. · J Neural Transm. · Pubmed #15657642 No free full text.

Abstract: Increased production and reduced clearance of amyloid beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). We have recently shown that the neurotrophic peptide mixture Cerebrolysin (Cbl) has the ability of improving synaptic functioning and reducing amyloid deposition in a transgenic (tg) animal model of Alzheimer's disease (AD). Since in AD, potentially toxic Abeta aggregates accumulate not only around neurons but also in the blood vessels, then it is important to investigate whether bioactive compounds such as Cbl might have the capacity to ameliorate the age-related cerebral amyloid angiopathy (CAA) in tg models. To this end, tg mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cbl or saline alone starting at 7 or 12 months of age for a total of three months. Neuropathological analysis with an antibody against Abeta showed that Cbl decreased amyloid deposition around the blood vessels in a time dependent manner. These effects were accompanied by a reduction in perivascular microgliosis and astrogliosis and increased expression of markers of vascular fitness such as CD31 and ZO-1. No lymphocytic infiltration was observed associated with Abeta in the vessels. Consistent with these findings, ultrastructural analysis showed that while in tg mice treated with saline alone there was an abundant accumulation of amyloid fibers in the vascular wall accompanied by thickening of the basal membrane and endothelial cell damage, in Cbl-treated mice there was considerable reduction in the subcellular alterations of endothelial and smooth muscle cells with preservation of basal membranes and intercellular junctions. Taken together, these results suggest that Cbl treatment might have beneficial effects in patients with cognitive impairment due to cerebrovascular amyloidosis by reducing Abeta accumulation and promoting the preservation of the cerebrovasculature.

Rockenstein E, Adame A, Mante M, Moessler H, Windisch M, Masliah E. · Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA. · J Neural Transm. · Pubmed #14628195 No free full text.

Abstract: Cerebrolysin is a peptide mixture with neurotrophic effects that might have the ability of both reducing amyloid burden and improving synaptic plasticity in Alzheimer's disease (AD). In order to determine if Cerebrolysin is capable of ameliorating the neurodegenerative and behavioral alterations associated with amyloid beta (A beta) production; transgenic (tg) mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cerebrolysin or saline alone starting at 3 or 6 months of age for a total of three months. Animals were then tested behaviorally (at 6 and 9 months of age respectively) in the water maze and then analyzed neuropathologically for amyloid burden, synaptic density, astrogliosis and apoptosis. Performance analysis in the water maze showed that in the younger tg mice cohort, Cerebrolysin treatment significantly ameliorated the performance deficits. In the older cohort, there was a trend toward improved performance in the learning curve. Neuropathological examination showed that in both age/treatment groups, Cerebrolysin promoted synaptic regeneration, and reduced the proportion of neurons displaying DNA fragmentation by the (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method. Moreover, Cerebrolysin treatment reduced A beta burden by 43% in the young group and by 27% in the older group. Taken together, these results suggest that Cerebrolysin treatment might have beneficial effects in patients with cognitive impairment by reducing A beta accumulation and promoting the preservation of synaptic terminals.

Rockenstein E, Mallory M, Mante M, Alford M, Windisch M, Moessler H, Masliah E. · Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093-0624, USA. · J Neural Transm Suppl. · Pubmed #12456076 No free full text.

Abstract: We investigated the potential mechanisms through which Cerebrolysin, a neuroprotective noothropic agent, might affect Alzheimer's disease pathology. Transgenic (tg) mice expressing mutant human (h) amyloid precursor protein 751 (APP751) cDNA under the Thy-1 promoter (mThy1-hAPP751) were treated for four weeks with this compound and analyzed by confocal microscopy to asses its effects on amyloid plaque formation and neurodegeneration. In this model, amyloid plaques in the brain are found much earlier (beginning at 3 months) than in other tg models. Quantitative computer-aided analysis with anti-amyloid-beta protein (A beta) antibodies, revealed that Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice. Furthermore, Cerebrolysin treatment reduced the levels of A beta(1-42). This was accompanied by amelioration of the synaptic alterations in the frontal cortex of mThy1-hAPP751 tg mice. In conclusion, the present study supports the possibility that Cerebrolysin might have neuroprotective effects by decreasing the production of A beta(1-42) and reducing amyloid deposition.