MR elastography detection of early viscoelastic response of the murine hippocampus to amyloid ß accumulation and neuronal cell loss due to Alzheimer's disease.

PURPOSE: To investigate in vivo viscoelastic parameters related to early histopathological changes in the hippocampus and the cortex in early, preclinical Alzheimer's disease (AD) stages. MATERIALS AND METHODS: Magnetic resonance elastography (MRE) was applied to female APP23 mice, an established transgenic mouse model of AD, at three different stages early in disease progression. To investigate the potential therapeutic effects of physical, cognitive, and social stimulation on brain viscoelasticity and histopathological characteristics, MRE was also applied after exposing young APP23 mice to environmentally enriched cage conditions (ENR), for 1, 12, or 24 weeks, which corresponds to adolescent, young-adult, and adult age at the time of analysis. RESULTS: Viscosity in the hippocampus of APP23 mice is lower than in controls (CTR) (P = 0.005) and does not increase with age, as in CTR mice (adolescent vs. young-adult: P = 1.000, vs. adult: P = 0.493, young-adult vs. adult: P = 1.000). Hippocampal cell numbers decrease with disease progression in APP23 mice (P < 0.001). Elasticity in the hippocampus is also reduced in APP23 mice (P = 0.024) but increases (P = 0.027) with disease progression. ENR in APP23 mice transiently increased hippocampal cell numbers (P = 0.002) but not viscosity (P = 0.838). CONCLUSION: MRE detects alterations in viscoelasticity in the hippocampus related to early histopathological changes in the APP23 mouse model of AD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:105-114.

One Health Education Nexus: enhancing synergy among science-, school-, and teacher education beyond academic silos.

Introduction: The fact that the daily lives of billions of people were affected by the medical, social, and political aspects of the SARS-CoV-2 pandemic shows the need to anchor the understanding of One Health in society. Hence, promoting awareness and deepening the understanding of the interrelation between human health, animal health, and ecosystems must be accomplished through quality education, as advocated by UN Sustainable Development Goal 4. The often-questioned and discussed measures taken by governments to control the global pandemic between 2020 and 2023 can be seen as an opportunity to meet the educational needs of civil society solutions in multi-stakeholder settings between public, universities, and schools. Methods: This paper focuses on the integration of One Health principles in educational frameworks, particularly within the context of the higher education teaching framework "Teaching Clinic." This master-level course in the domain of pre-service teacher education serves as a potent vehicle for facilitating One Health Education, bridging the gap between research, higher education, and schools. Through the presentation of two case studies, this article demonstrates how the Teaching Clinic approach fosters interdisciplinary perspectives and provides a dynamic learning environment for pre-service teachers, as well as for pupils involved in the educational process. Results: In both cases, the integration of educational One Health school teaching-learning settings effectively enhanced pupils' understanding of complex topics and engaged them in active learning experiences. Pre-service teachers played a crucial role in developing, implementing, and evaluating these interventions. In Case I, pupils demonstrated proficiency in analyzing data and evaluating mathematical models, while in Case II, the chosen instructional approach facilitated One Health knowledge acquisition and enjoyment among pupils. These results underscore the potential of the One Health Teaching Clinic as a valuable educational framework for enhancing teaching and learning outcomes for pre-service teachers and fostering pupil engagement in socio-scientific One Health-related topics. Discussion: The discussion delves into the significance of breaking down disciplinary silos and the crucial role of teacher education in promoting a holistic approach to education, emphasizing the intersectionality of One Health Education and Education for Sustainable Development. This article underpins the significance of collaborative efforts across multiple (scientific) disciplines and across secondary and tertiary education levels to reach a nexus. Moreover, it emphasizes the alignment of this approach with the 2030 Agenda, Education for Sustainable Development, and Sustainable Development Goals, highlighting the potential for collective action toward a more sustainable future.

Transposon-mediated glial cell line-derived neurotrophic factor overexpression in human adipose tissue-derived mesenchymal stromal cells: A potential approach for neuroregenerative medicine?

Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects and may be a promising candidate for regenerative strategies focusing on neurodegenerative diseases. As GDNF cannot cross the blood-brain barrier to potentially regenerate damaged brain areas, continuous in situ delivery with host cells is desired. Here, a non-viral Sleeping Beauty transposon was used to achieve continuous in vitro overexpression of GDNF in immune-privileged human adipose tissue-derived mesenchymal stromal cells (GDNF-tASCs). In addition, in vivo survival, tolerance, and effectiveness of transfected cells were tested in a very mild 6-hydroxydopamine (6-OHDA)-induced dopamine depletion rat model by means of intrastriatal injection on a sample basis up to 6 months after treatment. GDNF-tASCs showed vast in vitro gene overexpression up to 13 weeks post-transfection. In vivo, GDNF was detectable 4 days following transplantation, but no longer after 1 month, although adipose tissue-derived mesenchymal stromal cells (ASCs) could be visualized histologically even after 6 months. Despite successful long-term in vitro GDNF overexpression and its in vivo detection shortly after cell transplantation, the 6-OHDA model was too mild to enable sufficient evaluation of in vivo disease improvement. Still, in vivo immunocompatibility could be further examined. ASCs initially induced a pronounced microglial accumulation at transplantation site, particularly prominent in GDNF-tASCs. However, 6-OHDA-induced pro-inflammatory immune response was attenuated by ASCs, although delayed in the GDNF-tASCs group. To further test the therapeutic potential of the generated GDNF-overexpressing cells in a disease-related context, a follow-up study using a more appropriate 6-OHDA model is needed.

Chia seeds as a potential cognitive booster in the APP23 Alzheimer's disease model.

Glucose hypometabolism potentially contributes to Alzheimer's disease (AD) and might even represent an underlying mechanism. Here, we investigate the relationship of diet-induced metabolic stress and AD as well as the therapeutic potential of chia seeds as a modulator of glucose metabolism in the APP23 mouse model. 4-6 (pre-plaque stage, PRE) and 28-32 (advanced-plaque stage, ADV) weeks old APP23 and wild type mice received pretreatment for 12 weeks with either sucrose-rich (SRD) or control diet, followed by 8 weeks of chia seed supplementation. Although ADV APP23 mice generally showed functioning glucose homeostasis, they were more prone to SRD-induced glucose intolerance. This was accompanied by elevated corticosterone levels and mild insulin insensitivity. Chia seeds improved spatial learning deficits but not impaired cognitive flexibility, potentially mediated by amelioration of glucose tolerance, attenuation of corticosterone levels and reversal of SRD-induced elevation of pro-inflammatory cytokine levels. Since cognitive symptoms and plaque load were not aggravated by SRD-induced metabolic stress, despite enhanced neuroinflammation in the PRE group, we conclude that impairments of glucose metabolism do not represent an underlying mechanism of AD in this mouse model. Nevertheless, chia seeds might provide therapeutic potential in AD as shown by the amelioration of cognitive symptoms.

Association between genetic and environmental factors and the risk of Alzheimer's disease.

The only well confirmed genetic risk factor for sporadic Alzheimer's disease (AD) is the possession of apolipoprotein E (APOE) epsilon4 allele. As it contributes to 40-70% of AD cases, a large proportion of genetic variance may be determined by additional loci. Our aim was to estimate how reported genetic factors (APOE, NOS3, MTHFR) interact to increase the risk for AD and combine them with environmental factors (homocysteine, vitamin B12, cholesterol). Genotyping was performed in 154 AD patients and 176 healthy controls. Levels of homocysteine, vitamin B12 and cholesterol were assessed in subgroups of 100 AD patients and 100 controls. We found a difference in APOE epsilon4 and NOS3 G/G distribution between groups (p<0.005). Plasma total homocysteine was increased and vitamin B12 decreased in AD patients (p<0.001). The influence of APOE epsilon4 and NOS3 G alleles on the risk of AD was independent of homocysteine, vitamin B12 levels and MTHFR status.

Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serve as early markers for Alzheimer's disease in the APP23 mouse model.

Recent research on Alzheimer's disease (AD) focuses on processes prior to amyloid-beta plaque deposition accounting for the progress of the disease. However, early mechanisms of AD are still poorly understood and predictors of the disease in the pre-plaque stage essential for initiating an early therapy are lacking. Behavioral and psychological symptoms of dementia (BPSD) and potentially impaired cognition may serve as predictors and early clinical diagnostic markers for AD. To investigate potential BPSD and cognitive impairments in association with neuronal cell development as such markers for AD in the pre-plaque stage, female APP23 mice at eight, 19 and 31 weeks of age and corresponding control animals were tested for BPSD (elevated zero maze; sucrose preference test), motor coordination (rotarod), spatial memory and reversal learning (Morris water maze) and hippocampal neurogenesis as a neuronal correlate for hippocampus-dependent behavior. To evaluate a potential therapeutic effect of physical, cognitive and social stimulation, animals were exposed to environmental enrichment (EE) for one, twelve or 24 weeks from five weeks of age. In APP23, decreased anxiety accompanied increased agitation from eight weeks of age. Impairment of spatial memory and learning flexibility prior to plaque deposition involved an insufficient use of spatial search strategies associated with an unsuccessful compensatory increase of neurogenesis. EE had an overall beneficial effect on behavior and neurogenesis and thus constitutes a therapeutic tool to slow disease progression. BPSD, cognition and associated impaired neurogenesis complement clinical diagnostic markers for pre-plaque AD and contribute to an early detection essential to halt disease progression.

Prediction of deterioration of mild cognitive impairment with CT and SPECT.

BACKGROUND: Mild cognitive impairment (MCI) is a condition referring to persons with significant memory impairment, often accompanied by functional deficits in the attention, language, visuospatial, and psychomotor domains, who do not fulfill the criteria for dementia. Individuals with MCI are at an increased risk of developing dementia. The objective of this study was to examine baseline differences between MCI subjects who did or did not deteriorate at follow-up on measures of cognition and neuroimaging. MATERIAL/METHODS: MCI individuals (n=105) enrolled in a longitudinal study at the Alzheimer's Day Clinic in Warsaw received annual clinical and psychometric examinations for up to a mean of three years. At baseline, all patients received temporal lobe-oriented CT and 99mTc HMPAO SPECT. The diagnosis of MCI according to Mayo Clinic Petersen's Criteria was conducted by a panel of specialists and neuropsychological testing was completed on all subjects. RESULTS: After three years of follow-up, 42 subjects remained stable or had improved (8) and 63 had progressive cognitive disturbances, including 23 who converted to dementia. Compared with stable MCI patients, decliners have significantly higher radial width of the temporal horn bilaterally and width of the lateral part of the transverse fissure on the right, dilated third ventricle, and smaller oblique thickness of the anterior part of the hippocampal formation bilaterally at the baseline. No significant differences in SPECT perfusion were found between the two groups. CONCLUSIONS: The proposed linear measurements of atrophy in CT may constitute a predictor for those MCI patients who are more likely to deteriorate.

CYP46: a risk factor for Alzheimer's disease or a coincidence?

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46). Although serum and cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol are altered during the progress of Alzheimer's disease, studies carried out to date in different populations on the association of CYP46 gene polymorphisms and risk of AD have been inconclusive. In this report, we analyzed CYP46 polymorphisms in 215 Polish AD cases and 173 healthy individuals. A fragment of CYP46 intron 2 was amplified by PCR reaction and sequenced. We discovered a new single nucleotide substitution in CYP46 intron 2, but found no difference in particular genotype or allele frequencies between AD patients and controls. However, the GG genotype of the known rs754203 polymorphic site might be a risk factor for AD, especially in APOE varepsilon4 carriers. Interestingly, in AD patients the rs754203 G allele was more frequent in males than in females. However, considering the extreme divergence of results obtained by different authors, a clear connection between the CYP46 gene and AD is questionable.

Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer's disease.

As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), alpha 2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE epsilon 4 distribution between groups (P<0.005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE epsilon 4 allele is the only known genetic risk factor for late-onset, sporadic AD.

Strong association between Saitohin gene polymorphism and tau haplotype in the Polish population.

The saitohin (STH) gene is located in intron 9 of the tau protein gene. It has been postulated that the R allele of Q7R polymorphism at the Saitohin gene is over-represented in the homozygous state in sporadic Alzheimer's disease (AD). Tau protein was implicated in AD pathophysiology and the tau gene haplotype is probably connected with sporadic late-onset Parkinson's disease (PD). We analyzed the STH polymorphism and tau gene haplotype in 100 clinically diagnosed AD cases, 100 PD cases and 100 age-matched healthy controls. We found that the R allele of the STH gene is associated with the H2 haplotype of tau in all cases. Additionally we observed no correlation between R allele frequency and AD or PD.

The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort.

Mutations in the presenilin 1 (PSEN1) gene are known to cause nearly 50% of early-onset, familial Alzheimer's disease (AD) cases. To determine whether E318G mutation is related causally to AD in the Polish population E318G mutation frequency was assessed using PCR-RFLP method in a total of 659 subjects: 256 AD patients, 210 healthy, age-matched control subjects, 100 Parkinson's disease patients and 93 centenarians. When the mutation frequencies were compared to healthy controls, no significant differences between the groups were found. It could be concluded that E318G mutation is not related causally to AD in the Polish population, either as a risk factor or a disease causing mutation.

The prion protein M129V polymorphism: longevity and cognitive impairment among Polish centenarians.

The PRNP gene encodes the cellular isoform of prion protein (PrP (c) ). The M129V polymorphism influences the risk of prion diseases and may modulate the rate of neurodegeneration with age. We present the first study of the polymorphism among Polish centenarians. In the control group (n = 165, ages 18 to 56 years) the observed M129V genotype frequencies agreed with those expected according to the Hardy-Weinberg equilibrium (MM, MV, VV): 43%, 44%, 13% (HWE p > 0.05). Among centenarians (n = 150, ages 100 to 107) both homozygotes were more common than expected and HWE was rejected: 46%, 37%, 17% (expected 42%, 46%, 13%; HWE p = 0.025). This finding is consistent with a higher mortality rate among heterozygotes. However, the observed allele and genotype frequencies did not differ significantly between the oldest-old and the young controls. The genotypic frequencies were not related to severe cognitive impairment among the centenarians.

APBB2 genetic polymorphisms are associated with severe cognitive impairment in centenarians.

APBB2 gene encodes for ß-amyloid precursor protein-binding family B member 2, (APBB2, FE65-like, FE65L1), an adaptor protein binding to the cytoplasmatic domain of ß-amyloid precursor protein (ßAPP). Over-expression of APBB2 promotes formation of ß-amyloid (Aß), the main constituent of senile plaques. Polymorphisms within APBB2 gene have been proposed as candidate risk factors for Alzheimer's disease. However, their association with longevity has never been investigated. Here we present the first attempt to analyze APBB2 polymorphisms in centenarians. We used a PCR-RFLP method to analyze two intronic nucleotide substitutions: hCV1558625 (rs17443013) and rs13133980. We found no differences in genotype or allele distribution between centenarians and young controls. After stratification of centenarians upon their cognitive performance, the APBB2 rs13133980 G allele was over-represented in centenarians with severe cognitive impairment compared to individuals without this disability. Also the hCV1558625-rs13133980 AG haplotype increased relative risk for severe cognitive impairment in centenarians. Our results support the concept of APBB2 polymorphism association with cognitive performance in the oldest age.

Cognitive deficits and polymorphism of apolipoprotein E in Alzheimer's disease.

The aim of this study was to test the relationship between apolipoprotein E (ApoE) genotypes and patterns of cognitive deficits in Alzheimer's disease (AD). All subjects were diagnosed as probable AD patients on the basis of the DSM-IV and NINCDS-ADRDA criteria. Each subject was examined for (1) ApoE genotype, (2) general level of mental activity (Global Deterioration Scale and Mini-Mental State Examination) and (3) cognitive functions by means of a battery of neuropsychological tests. On the basis of ApoE genotype, patients were subdivided into two groups: the first group consisted of patients with at least one epsilon4 allele (epsilon4+ group), while the second one consisted of patients without the epsilon4 allele (epsilon4- group). Our results showed that several cognitive processes depended on the ApoE genotype. In early stages of AD, patients from the epsilon4+ group had greater deficits in delayed recall of new information. On the other hand, working memory appeared to be more impaired in the epsilon4- group of patients. Independent of the genotype, both groups showed similar impairment of learning ability without, however, deficits in remote memory.

An open-label study to evaluate the safety, tolerability and efficacy of rivastigmine in patients with mild to moderate probable Alzheimer's disease in the community setting.

BACKGROUND: Long-term safety and efficacy of Exelon (rivastigmine) was evaluated in a multi-center open-label study of 62 patients with probable mild to moderate Alzheimer's disease living in community setting. MATERIAL/METHODS: The patients started treatment with 1.5 mg bid (3 mg/day) Exelon and were scheduled to receive doses of 1.5 mg bid Exelon escalating on a biweekly basis. The patients were maintained on the highest tolerated dose within the assigned dose range 1.5-6.0 mg bid (3-12 mg/day) for the rest of the study. Evaluations were scheduled at biweekly intervals for the first 8 weeks and subsequently at study weeks 12, 18 and 26. Effects of Exelon on cognition were evaluated using the mini-mental state examination (MMSE) and selected items of Alzheimer's disease assessment scale (ADAS-cog) and the staging of the disease was measured using the global deterioration scale (GDS). Safety was monitored by physical examinations, vital signs, laboratory tests, ECG recording and by the assessment of adverse events. RESULTS: 55 patients completed the study (89%). Patients treated for 26 weeks showed the mean MMSE, ADAS-cog and GDS scores close to baseline values (p=NS) with no improvement and no deterioration. Exelon was generally well tolerated with 11% of patients withdrawing due to adverse events. The most frequently reported adverse events related to the gastrointestinal tract. CONCLUSIONS: In conclusion, the study data indicate that treatment with Exelon is safe, generally well tolerated and inhibits the progression of cognitive decline in patients with mild to moderate Alzheimer's disease over 26 weeks of treatment.

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland.

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimer's disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.