BACKGROUND: Insulin-degrading enzyme (IDE) is a widely distributed Zn2+-binding metalloprotease that cleaves multiple short and medium-sized peptides prone to form β-structures. These include insulin and amyloid-β peptides. Accumulation and fibrillation of amyloid-β peptides leading to the formation of amyloid plaques is a characteristic sign of Alzheimer's disease (AD) pathology. OBJECTIVE: The study investigated the rs2421943 single nucleotide polymorphism (SNP) of the IDE gene as a risk factor for MCI (mild cognitive impairment) and AD. METHODS: Two independent groups of 1670 patients and controls were included. The AD group consisted of 595 patients and 400 controls; the MCI group involved 135 patients and 540 matched controls. PCR and restriction fragment length analysis were used to analyze the rs2421943 polymorphism. Using the miRBase and RNA22 prediction tools in silico indicated that the rs2421943 polymorphism is a potential target for a specific miRNA (hsa-miR-7110-5p). RESULTS: AG and GG genotypes of rs2421943 significantly increased the risk of AD, and the AG genotype increased the risk of MCI. It seems the G allele both increases the risk of AD and accelerates the transition through the MCI phase. In silico study revealed that rs2421943 is inside the sequence binding miRNA hsa-miR-7110-5p. The polymorphism could affect the rate of IDE pre-RNA (heterogeneous nuclear RNA, hnRNA) processing, resulting in slower translation, lower levels of IDE, deficient removal of amyloid-β fragments, and greater risk of and/or accelerated progression of AD. CONCLUSION: GG and AG genotypes of the single nucleotide polymorphism rs2421943 of insulindegrading enzyme gene increase the risk of AD and MCI.

• Klíčová slova
• Alzheimer’s disease, amyloid-β peptide, insulin-degrading enzyme, mild cognitive impairment, single nucleotide polymorphisms, type-2 diabetes mellitus,
• MeSH
• Alzheimerova nemoc * genetika   MeSH
• amyloidní beta-protein metabolismus   MeSH
• insulinasa * genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• mikro RNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• insulinasa * MeSH
• mikro RNA * MeSH

INTRODUCTION: Dementia becomes a major public health challenge in both the Czech Republic and worldwide. The most common form of dementia is Alzheimer's disease (AD). OBJECTIVE: We conducted two successive epidemiological projects in 2012-2015 and 2016-2019. Their aim was to study the effect of selected potential genetic, vascular and psychosocial risk factors on the development of AD by comparing their frequencies in AD patients and controls. METHODS: Epidemiological case-control studies were conducted. In total, data from 2106 participants (1096 cases, 1010 controls) were analyzed. RESULTS: Three times more females than males suffered from AD. The highest proportion of cases were those with primary education, unlike controls. There were statistically significantly more manual workers among cases than among controls. Of selected vascular risk factors, coronary heart disease was found to be statistically significantly more frequent in cases than in controls. The onset of hypertension and diabetes mellitus was earlier in controls than in cases. As for hobbies and interests, there were statistically significant differences in physical activity, reading and solving crosswords between the groups, with these activities being more common in controls. CONCLUSION: The prevalence of chronic neurodegenerative diseases, in particular AD, is currently increasing. Given the aging of the population, these conditions may be expected to rise in prevalence. Potential risk of AD needs to be studied, analyzed and confirmed; a detailed knowledge of the risks of AD and early detection of the pathology may therefore be very beneficial for prevention and early treatment of this condition.

• Klíčová slova
• Alzheimer's disease, Dementia, epidemiology, neurodegenerative diseases., risk factors,
• MeSH
• Alzheimerova nemoc * epidemiologie   genetika   MeSH
• epidemiologické studie * MeSH
• koronární nemoc epidemiologie   MeSH
• lidé MeSH
• prevalence MeSH
• rizikové faktory MeSH
• senioři MeSH
• stárnutí fyziologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments available for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initiation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mitochondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mitochondrial systems biology. We review evidence for mitochondrial impairments ranging from mitochondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expression, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dynamics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could potentially alter the course of this progressive, heterogeneous Disease while being cognizant that successful future therapeutics may require a combinatorial approach.

• Klíčová slova
• Alzheimer's disease, bioenergetics, epigenetic modifiers, lifestyle changes, mitochondria, mtDNA, repurposed drugs., β-amyloid,
• MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• lidé MeSH
• mitochondriální DNA metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• neurodegenerativní nemoci * metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• mitochondriální DNA MeSH

BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex. OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD. METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice. RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice. CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.

• Klíčová slova
• APP/PS1 mice, Alzheimer's disease, amyloid-β plaques, cerebellum, hippocampus, neuroinflammation, palm11-PrRP31, synaptogenesis.,
• MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidní plaky patologie   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• diabetes mellitus 2. typu * MeSH
• hormon uvolňující prolaktin metabolismus   farmakologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozeček MeSH
• myši transgenní MeSH
• myši MeSH
• presenilin-1 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• amyloidový prekurzorový protein beta MeSH
• hormon uvolňující prolaktin MeSH
• presenilin-1 MeSH

BACKGROUND: Bulbous neuritic changes in neuritic plaques have already been described, and their possible effect on the clinical course of the disease has been discussed. OBJECTIVE: In our study, we focused on the location and density of these structures in patients with only Alzheimer's disease (AD) and patients with AD in comorbidity with synucleinopathies. METHODS: Utilizing immunohistochemistry and confocal microscopy, we evaluated differences of neocortical and archicortical neuritic plaques and the frequency of bulbous changes in the archicortex of 14 subjects with Alzheimer's disease (AD), 10 subjects with the Lewy body variant of Alzheimer's disease (AD/DLB), and 4 subjects with Alzheimer's disease with amygdala Lewy bodies (AD/ALB). Also, the progression and density of neuritic changes over the time course of the disease were evaluated. RESULTS: We found structural differences in bulbous dystrophic neurites more often in AD/DLB and AD/ALB than in pure AD cases. The bulbous neuritic changes were more prominent in the initial and progressive phases and were reduced in cases with a long clinical course. CONCLUSION: Our results indicate that there is a prominent difference in the shape and composition of neocortical and archicortical neuritic plaques and, moreover, that bulbous neuritic changes can be observed at a higher rate in AD/DLB and AD/ALB subjects compared to pure AD subjects. This observation probably reflects that these subacute changes are more easily seen in the faster clinical course of AD patients with comorbidities.

• Klíčová slova
• Alzheimer`s disease, archicortex, bulbous neuritic changes, neocortex, neuritic plaques, synucleinopathy,
• MeSH
• Alzheimerova nemoc patologie   MeSH
• amyloidní plaky patologie   MeSH
• hipokampus patologie   MeSH
• imunohistochemie MeSH
• lidé MeSH
• neurity patologie   MeSH
• pilotní projekty MeSH
• senioři MeSH
• synukleinopatie patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: The purpose of the study was to evaluate the reliability of our new visual scale for a quick atrophy assessment of parietal lobes on brain Magnetic Resonance Imaging (MRI) among different professionals. A good agreement would justify its use for differential diagnosis of neurodegenerative dementias, especially early-onset Alzheimer's Disease (AD), in clinical settings. METHODS: The visual scale named the Parietal Atrophy Score (PAS) is based on a semi-quantitative assessment ranging from 0 (no atrophy) to 2 (prominent atrophy) in three parietal structures (sulcus cingularis posterior, precuneus, parietal gyri) on T1-weighted MRI coronal slices through the whole parietal lobes. We used kappa statistics to evaluate intra-rater and inter-rater agreement among four raters who independently scored parietal atrophy using PAS. Rater 1 was a neuroanatomist (JM), rater 2 was an expert in MRI acquisition and analysis (II), rater 3 was a medical student (OP) and rater 4 was a neurologist (DS) who evaluated parietal atrophy twice in a 3-month interval to assess intra-rater agreement. All raters evaluated the same 50 parietal lobes on brain MRI of 25 cognitively normal individuals with even distribution across all atrophy degrees from none to prominent according to the neurologist's rating. RESULTS: Intra-rater agreement was almost perfect with the kappa value of 0.90. Inter-rater agreement was moderate to substantial with kappa values ranging from 0.43-0.86. CONCLUSION: The Parietal Atrophy Score is the reliable visual scale among raters of different professions for a quick evaluation of parietal lobes on brain MRI within 1-2 minutes. We believe it could be used as an adjunct measure in differential diagnosis of dementias, especially early-onset AD.

• Klíčová slova
• Alzheimer's disease, Parietal Atrophy Score, brain magnetic resonance imaging, dementia, reliability, visual scale,
• MeSH
• atrofie MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• neurozobrazování MeSH
• odchylka pozorovatele MeSH
• reprodukovatelnost výsledků MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• temenní lalok diagnostické zobrazování   patologie   MeSH
• testy pro posouzení mentálních funkcí a demence MeSH
• vizuální analogová stupnice MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

There is now a general attempt in developed countries to implement strategic plans to fight against Alzheimer's disease, for which treatment represents an increasing economic burden for the ageing society. At present, the costs of treatment and care for Alzheimer's Disease (AD) patients are not consistently tracked and logged, therefore, the economic burden is calculated based on the records kept by individual countries. The aim of this paper is to conduct a meta-analysis of the available data on the total costs of treatment and care for elderly AD patients with respect to the stage of the disease determined by the Mini Mental State Examination (MMSE). The Web of Science and PubMed databases were used for a systematic search. Two independent reviewers screened the identified records and selected relevant articles published in the period from 2007 to 2017. A meta-analysis of costs is performed in three categories related to the stages of Alzheimer's disease (mild, moderate, and severe). The resulting estimation of total costs per patient per year determined by the meta-analysis is 20,461$ total costs. The total costs in relation to the stage of the disease according to the MMSE scale are 14,675 $ for the mild stage, 19,975 $ for the moderate stage, and 29,708 $ for the severe stage. The meta- analysis confirms that the costs rise significantly with the severity of AD. These findings therefore, emphasize the severity of the economic burden carried out by the AD patients, their families, and the healthcare system, and this fact must be taken into account when planning health policy strategies for the years to come.

• Klíčová slova
• Alzheimer's disease, costs, developed countries, mental disorders, meta-analysis, mini mental state examination.,
• MeSH
• Alzheimerova nemoc ekonomika   terapie   MeSH
• lidé MeSH
• náklady na zdravotní péči MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH

Memory impairment has been considered as one of the earliest clinical hallmarks of Alzheimer's disease. This paper summarizes recent progress in the assessment of memory impairment in predementia stages. New promising approaches of memory assessment include evaluation of longitudinal cognitive changes, assessment of long-term memory loss, evaluation of subjective cognitive concerns and testing of other memory modalities, such as spatial memory. In addition, we describe new challenging memory tests based on memory binding paradigms that have been recently developed and are currently being validated.

• Klíčová slova
• Alzheimer's disease, Elderly, memory binding, memory impairment, mild cognitive impairment, neuropsychological assessment, spatial memory, subjective cognitive decline.,
• MeSH
• Alzheimerova nemoc komplikace   diagnóza   MeSH
• časná diagnóza * MeSH
• lidé MeSH
• poruchy paměti diagnóza   etiologie   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets. OBJECTIVE: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals. METHODS: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed. RESULTS: Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development. CONCLUSION: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.

• Klíčová slova
• Alzheimer disease, ORAC, antioxidants, cholinesterase, chromone, donepezil, passerini reaction.,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• chromony chemická syntéza   farmakologie   MeSH
• donepezil chemická syntéza   farmakologie   MeSH
• lidé MeSH
• preklinické hodnocení léčiv MeSH
• scavengery volných radikálů chemická syntéza   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• chromony MeSH
• donepezil MeSH
• scavengery volných radikálů MeSH

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

• Klíčová slova
• 6-Chlorotacrine, Alzheimer´s disease, NMDA receptor, acetylcholinesterase, ion channel, memantine, patch-clamp technique.,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• CHO buňky MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• Cricetulus MeSH
• HEK293 buňky MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• kapilární permeabilita MeSH
• kyselina glutamová metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• memantin chemická syntéza   farmakologie   MeSH
• neuroprotektivní látky chemická syntéza   farmakologie   MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• takrin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• techniky tkáňových kultur MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 6-chlorotacrine MeSH Prohlížeč
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• kyselina glutamová MeSH
• ligandy MeSH
• memantin MeSH
• neuroprotektivní látky MeSH
• receptory N-methyl-D-aspartátu MeSH
• takrin MeSH