Current and emerging avenues for Alzheimer's disease drug targets.

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aß) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aß and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

The economic impact of dementia in Europe in 2008-cost estimates from the Eurocode project.

OBJECTIVE: Care for demented people is very resource demanding, the prevalence is increasing and there is so far no cure. Cost of illness (CoI) studies are important by identifying the distribution of costs between different payers of care. The European Union (EU) funded the European Collaboration on Dementia (Eurocode) as part of the EU's 2005 work plan of the Community public health programme. Eurocode was administered by Alzheimer Europe. The aim was to describe the economic impact of dementia in Europe in 2008. METHODS: Eurocode's new estimates for dementia prevalence were included in a cost model based on published European CoI papers. For countries where no CoI figures were available, imputation was used. RESULTS: The total CoI of dementia in the EU27 in 2008 was estimated to be €160 billion (€22 000 per demented per year), of which 56% were costs of informal care. The corresponding costs for the whole Europe was €177 billion. In northern Europe, the direct costs are estimated to be considerabe, while the cost of informal care is the major cost component in southern Europe. The sensitivity analysis showed a range for total EU27 costs between €111 and 168 billion. CONCLUSIONS: The estimated CoI in this study is higher than in previous studies. There are also large differences in different European regions. Notwithstanding the methodological challenges, the societal costs of dementia in Europe are very high which in turn have substantial resource impacts on the social and health care systems in Europe.

Costs of dementia in Hungary.

OBJECTIVE: The main aim of this paper is to give an overview on the quality of life, health care utilisation and costs of dementia in Hungary. METHOD: A cross-sectional non-population based study of 88 consecutive dementia patients and their caregivers was conducted in three GP practices and one outpatient setting in 2008. Resource Utilization in Dementia (RUD), Mini Mental State Examination (MMSE) and quality of life (EQ-5D) were surveyed and cost calculations were performed. Costs of patients living at home were estimated by the current bottom-up cost-of-illness calculations, while costs of nursing home patients were considered by official reimbursement to determine the disease burden from a societal viewpoint. RESULTS: The mean age of the patients was 77.4 years (SD=9.2), 59% of them were female. The mean MMSE score was 16.70 (SD=7.24), and the mean EQ-5D score was 0.40 (SD=0.34). The average annual cost of dementia was 6,432 Euros per patient living at home and 6,086 Euros per patient living in nursing homes. For the whole demented population (based on EuroCoDe data) we estimated total annual costs of 846.8 million Euros; of which 55% are direct costs, 9% indirect costs and 36% informal care cost. Compared to acute myocardial infarction the total disease burden of dementia is 26.3 times greater. CONCLUSIONS: This is the first study investigating resource utilisation, costs, and quality of life of dementia patients in the Central and Eastern European region. Compared to the general population of Hungary EQ-5D values of the demented patients are lower in all age groups. Dementia related costs are much lower in Hungary compared to Western European countries. There is no remarkable difference between the costs of demented patients living at home and in nursing homes, from the societal point of view.

Changes in medical and surgical treatments of glaucoma between 1997 and 2003 in France.

PURPOSE: To analyze quantitative changes in glaucoma treatment strategies between 1997 and 2003 in France. METHODS: Numbers of ab externo trabeculectomies and other glaucoma surgeries were extracted from the national database of the French Diagnosis Related Group system, which includes data for both public and private hospitals. Numbers of patients treated per year were estimated from drug unit sales using defined daily doses for each drug. RESULTS: New medical treatments of glaucoma and ocular hypertension, introduced in France between 1997 and 2003, allowed treatment of 557,000 patients. In 2003, 63% of patients treated with these new medicines were receiving prostaglandins (39% latanoprost, 9% travoprost, 8% the fixed combination of latanoprost + timolol, and 7% bimatoprost), 13% brinzolamide, 13% the fixed combination of dorzolamide + timolol, and 11% brimonidine. During the same period, trabeculectomies declined by 38% (-48% in public hospitals and -32% in private clinics), while the total number of glaucoma surgeries declined by 22% (-34% in public hospitals and -14% in private clinics). Hospital days related to open-angle glaucoma surgery declined by 51%. There is a strong correlation (r2=-0.97) between the reduction of glaucoma surgery and the increase in the number of patients treated with prostaglandins during the study period. CONCLUSIONS: Between 1997 and 2003, new glaucoma drugs, primarily prostaglandins, improved intraocular pressure control and delayed surgery, reducing glaucoma surgery by 22%.

Naturalistic, prospective study of glaucoma and ocular hypertension treatment in France: Strategies, clinical outcomes, and costs at 2 years.

PURPOSE: To prospectively observe second-line treatment strategies, their clinical outcomes, and treatment costs in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH) in France. METHODS: Second-line patients were recruited from September 14, 1998, to December 20, 2000, in 37 centers and were followed for up to 2 years. Outcomes were numbers of and reasons for treatment changes, changes in clinical parameters (intraocular pressure (IOP) levels, visual field defects, and optic nerve excavation), and direct medical costs associated with glaucoma management. This article reports results of the final analysis of 2-year follow-up data for patients with at least two contacts with a study ophthalmologist. RESULTS: Data were analyzed for 346 patients and 672 treated eyes. Monotherapy was used as first-line therapy in 92.0% of eyes. Second-line treatment was initiated an average of 2.8+/-0.2 years after diagnosis, primarily due to insufficient IOP control (60.3%) and adverse drug reactions (18.3%). Relative risk (RR) (95% CI) for adverse drug reactions (ADR) under monotherapy was 1.00 (1.00-1.00) under beta blockers (n = 116) versus 0.40 (0.16-0.64) under latanoprost (n = 21), 2.30 under carbonic anhydrase inhibitors (n = 29), and 2.90 under adrenergics (n = 38); RR for ADR under combination therapy was 1.00 (1.00-1.00) for unfixed combinations without latanoprost (n = 66) versus 0.11 (0.00-0.22) for unfixed combinations of latanoprost + timolol (n = 3). Cardiac or pulmonary problems have been reported in 26.9% of patients. Persistency on initial therapy was 62.5% (95% CI 53.0-72.0) for latanoprost monotherapy versus 41.1% (34.8-47.4) for beta-blocker monotherapy and 43.6% (26.6-60.6) for the latanoprost + timolol combination versus 29.8% (15.2-44.4) for combination therapies that did not include latanoprost. Average daily cost for latanoprost monotherapy was similar to that for patients who failed beta-blocker monotherapy: latanoprost + timolol did not cost more than therapeutic combinations without latanoprost. CONCLUSIONS: Insufficient IOP control and adverse drug reactions are the two main reasons for changing first-line treatment in patients with POAG or OH. After 2 years, second-line treatment with latanoprost, as monotherapy or combined with timolol, provides superior safety and persistency to treatment at an acceptable cost.

Naturalistic, prospective study of glaucoma and ocular hypertension treatment in France: Strategies, clinical outcomes, and costs at 2 years.

PURPOSE: To prospectively observe second-line treatment strategies, their clinical outcomes, and treatment costs in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH) in France. METHODS: Second-line patients were recruited from September 14, 1998, to December 20, 2000, in 37 centers and were followed for up to 2 years. Outcomes were numbers of and reasons for treatment changes, changes in clinical parameters (intraocular pressure (IOP) levels, visual field defects, and optic nerve excavation), and direct medical costs associated with glaucoma management. This article reports results of the final analysis of 2-year follow-up data for patients with at least two contacts with a study ophthalmologist. RESULTS: Data were analyzed for 346 patients and 672 treated eyes. Monotherapy was used as first-line therapy in 92.0% of eyes. Second-line treatment was initiated an average of 2.8+/-0.2 years after diagnosis, primarily due to insufficient IOP control (60.3%) and adverse drug reactions (18.3%). Relative risk (RR) (95% CI) for adverse drug reactions (ADR) under monotherapy was 1.00 (1.00-1.00) under beta blockers (n=116) versus 0.40 (0.16-0.64) under latanoprost (n=21), 2.30 under carbonic anhydrase inhibitors (n=29), and 2.90 under adrenergics (n=38); RR for ADR under combination therapy was 1.00 (1.00-1.00) for unfixed combinations without latanoprost (n=66) versus 0.11 (0.00-0.22) for unfixed combinations of latanoprost + timolol (n=3). Cardiac or pulmonary problems have been reported in 26.9% of patients. Persistency on initial therapy was 62.5% (95% CI 53.0-72.0) for latanoprost monotherapy versus 41.1% (34.8-47.4) for beta-blocker monotherapy and 43.6% (26.6-60.6) for the latanoprost + timolol combination versus 29.8% (15.2-44.4) for combination therapies that did not include latanoprost. Average daily cost for latanoprost monotherapy was similar to that for patients who failed beta-blocker monotherapy: latanoprost + timolol did not cost more than therapeutic combinations without latanoprost. CONCLUSIONS: Insufficient IOP control and adverse drug reactions are the two main reasons for changing first-line treatment in patients with POAG or OH. After 2 years, second-line treatment with latanoprost, as monotherapy or combined with timolol, provides superior safety and persistency to treatment at an acceptable cost. (Eur J Ophthalmol 2005; 15: 562-80).

Isolation and nucleotide sequence of the chloroperoxidase gene from Caldariomyces fumago.

The chloroperoxidase gene from the filamentous fungus Caldariomyces fumago has been isolated within a 16.3-kilobase insert in the vector lambda EMBL3. The DNA sequence of the gene and its immediate flanking regions has been determined, and the start site of transcription has been mapped by primer extension.

Post-translational modifications of chloroperoxidase from Caldariomyces fumago.

The secreted form of the halogenating glycoenzyme, chloroperoxidase, is processed from a precursor containing a 21-residue-long, moderately hydrophobic signal sequence, at an atypical Gln-Glu peptide bond. Following cleavage, the N-terminal glutamic acid readily cyclizes into pyroglutamic acid. Chloroperoxidase contains two high-mannose N-glycosylation sites, identified as Asn12 and Asn213. Other modifications include deamidation of residues Asn13, Asn198, and Gln183 into the corresponding acids. Finally, structural arguments suggest that Cys87 may be the axial heme ligand in the active site of chloroperoxidase.

Fructose induces and glucose represses chloroperoxidase mRNA levels.

The fungus Caldariomyces fumago can be induced to secrete the heme protein chloroperoxidase at levels of 500 mg/liter. Chloroperoxidase synthesis is controlled at the mRNA level. Glucose strongly represses production of chloroperoxidase mRNA and protein, whereas fructose induces both to high levels. Chloroperoxidase has been partially sequenced by automated Edman degradation of tryptic peptides. Based on this amino acid sequence data, a 2-fold degenerate, 29-base oligonucleotide (29-mer) complementary to chloroperoxidase mRNA was synthesized. Polyadenylated RNA, purified from C. fumago, was used as substrate for cDNA synthesis using the 29-mer as primer. cDNAs were made double-stranded and cloned into plasmid pBR322 by conventional methods. Screening the resultant cDNA bank by colony hybridization with the 29-mer as probe showed that 18% of the clones contained the 29-mer sequence. Dideoxy sequencing of one clone (pMA340) identified it as part of the coding region for chloroperoxidase by comparison with known amino acid sequences. In addition, the amino-terminal coding region of clone pMA340 reveals a putative signal peptide for chloroperoxidase. Clone pMA340 was then used in Northern analysis of chloroperoxidase mRNA levels under conditions which induce and repress enzyme secretion.

Cloning and sequencing of chloroperoxidase cDNA.

An oligod-d(T) 12-18 primed cDNA library has been prepared from Caldariomyces fumago mRNA. A clone containing a full-length insert was sequenced on the supercoiled plasmid, pBR322. The complete primary sequence of chloroperoxidase has been derived. We have also determined about 73% of the peptide sequence by amino acid sequencing. The DNA sequence data matches all of the available known peptide sequences. The mature polypeptide contains 300 amino acids having a combined molecular weight of 32,974 daltons. A putative signal peptide of 21 amino acids is proposed from DNA sequence data. The chloroperoxidase gene encodes three potential glycosylation sites recognized as Asn-X-Thr/Ser sequences. Three cysteine residues are found in the protein sequence. A small region around Cys87 bears a minimal homology to the active site of cytochrome P450cam. No other heme protein homologues can be detected. We propose that Cys87 serves as a thiolate ligand to the iron of heme prosthetic group. A rare arginine codon, AGG, is used three times out of twelve in contrast to the very infrequent use of this codon in E. coli or yeast.