Early Preclinical Stages Research Articles

Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease.

Alterations in locus coeruleus' (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown. We examined associations of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n=604). FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ42, but not in AD patients with cognitive impairment. Higher locus coeruleus [18F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration. LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.

Reactive microglia partially envelop viable neurons in prion diseases.

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrated that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occured in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrPSc in the brain. Microglia that enveloped neurons exhibited hypertrophic, cathepsin D-positive lysosomal compartments. However, most neurons undergoing envelopment were only partially encircled by microglia. Despite up to 40% of cortical neurons being partially enveloped at clinical stages, only a small percentage of envelopment proceeded to full engulfment. Partially enveloped neurons lacked apoptotic markers but showed signs of functional decline. Neuronal envelopment was independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. This phenomenon of partial envelopment was consistently observed across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.

Tracking the pre-clinical progression of transthyretin amyloid cardiomyopathy using artificial intelligence-enabled electrocardiography and echocardiography.

Diagnosing transthyretin amyloid cardiomyopathy (ATTR-CM) requires advanced imaging, precluding large-scale testing for pre-clinical disease. We examined the application of artificial intelligence (AI) to echocardiography (TTE) and electrocardiography (ECG) as a scalable strategy to quantify pre-clinical trends in ATTR-CM. Across age/sex-matched case-control datasets in the Yale-New Haven Health System (YNHHS) we trained deep learning models to identify ATTR-CM-specific signatures on TTE videos and ECG images (area under the curve of 0.93 and 0.91, respectively). We deployed these across all studies of individuals referred for cardiac nuclear amyloid imaging in an independent population at YNHHS and an external population from the Houston Methodist Hospitals (HMH) to define longitudinal trends in AI-defined probabilities for ATTR-CM using age/sex-adjusted linear mixed models, and describe discrimination metrics during the early pre-clinical stage. Among 984 participants referred for cardiac nuclear amyloid imaging at YNHHS (median age 74 years, 44.3% female) and 806 at HMH (69 years, 34.5% female), 112 (11.4%) and 174 (21.6%) tested positive for ATTR-CM, respectively. Across both cohorts and modalities, AI-defined ATTR-CM probabilities derived from 7,423 TTEs and 32,205 ECGs showed significantly faster progression rates in the years before clinical diagnosis in cases versus controls (p time × group interaction ≤0.004). In the one-to-three-year window before cardiac nuclear amyloid imaging sensitivity/specificity metrics were estimated at 86.2%/44.2% [YNHHS] vs 65.7%/65.5% [HMH] for AI-Echo, and 89.8%/40.6% [YNHHS] vs 88.5%/35.1% [HMH] for AI-ECG. We demonstrate that AI tools for echocardiographic videos and ECG images can enable scalable identification of pre-clinical ATTR-CM, flagging individuals who may benefit from risk-modifying therapies.

Cross Talk between β Cells and Immune Cells: What We Know, What We Think We Know, and What We Should Learn.

Type 1 diabetes (T1D) is a disease whose pathogenesis is driven by both immune dysregulation and β-cell dysfunction. While the specialized structure and function of β cells make them vulnerable to autoimmunity, several surface receptor/ligand pairs underlie the cross talk engaged with T lymphocytes and other immune subsets. The expression of these ligands on β cells is coordinately up-regulated by the exposure to interferons, notably the type I interferons that represent the signature cytokines since the early preclinical stages of T1D. Yet, their interaction with receptors expressed on T lymphocytes can favor either β-cell vulnerability or protection. Despite several knowledge gaps, this novel holistic view of autoimmunity that incorporates both immune and β-cell-derived pathogenic drivers is starting to translate into novel therapeutic strategies aimed at decreasing vulnerability and/or increasing these protective mechanisms. This review summarizes the current knowledge in this evolving field, the assumptions that are often taken for granted but lack formal evidence, and the blind spots in this landscape that may hide further therapeutic opportunities.

Novel Leptin-Based Therapeutic Strategies to Limit Synaptic Dysfunction in Alzheimer's Disease.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aβ) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid β. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

Natural polymer hydrogel based 3D printed bioreactor testing platform for cancer cell culture

Although two-dimensional cell cultures provide a time- and cost-effective method for testing drugs at the preclinical level, they do not capture the three-dimensional cellular interactions or tumor penetration that must occur in vivo. Therefore, these drugs often fail as they transition from two-dimensional culture models to more complex ones, including animal models or even human clinical trials. The goal of this research was to develop a three-dimensional bioprinted pancreatic cancer drug testing platform that could increase the effectiveness of drug testing during the early preclinical stages. Specifically, different natural polymer hydrogel formulations of cellulose, alginate, and gelatin were tested to find the optimal printability and cell viability. It was determined that a cellulose nanocrystal and alginate hydrogel provided the best printability because of its superior shear thinning properties. In addition, BxPC-3 cells, that were printed and then cultured within this hydrogel for four days, exhibited a range of cell viability between 80 % and 60 %. To simulate vasculature around the bioprinted cultures, a spinning bioreactor was manufactured; however, it disturbed the cells, leading to a decrease in cell viability compared to stagnant cultures. Overall, the platform demonstrated good printability and cell viability for future use in pancreatic cancer drug testing.

CSF Aβ42/40 is associated with neurodegeneration independently of CSF p‐tau in the earliest AD continuum

AbstractBackgroundSoluble Aβ dyshomeostasis is thought to be the earliest detectable alteration in AD, but is believed to have little impact on neurodegeneration. Conversely, the onset of tau pathology in the presence of Aβ drives subsequent neurodegeneration. Here, we aimed to assess the independent contribution of soluble Aβ and tau dyshomeostasis to neurodegeneration, in the earliest stages of the AD continuum.MethodThe first 330 consecutive participants of the ALFA+ study with available longitudinal (3.45±0.24 y) MRI, CSF Aβ42, Aβ40, p‐tau181, and NfL at baseline were included. CSF biomarkers were assessed with the Roche NeuroToolKit robust prototype immunoassays and p‐tau181 with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Gray matter volume (GMv) changes were computed voxelwise using SPM12 on T1w scans. Hippocampal subfields were segmented using ASHS on high‐resolution acquisitions. To detect regions showing early neurodegeneration, correlations between CSF NfL and GMv changes were sought. Then, GMv and hippocampal subfields changes were sought in association with CSF Aβ42/40 and CSF p‐tau181, both alone and after controlling for the other biomarkers. The interactive effect of CSF p‐tau181 and Aβ status (CSF Aβ42/40 < 0.071) on brain structure was determined.ResultTable 1 shows sample’s characteristics. CSF NfL concentrations were associated with longitudinal GMv atrophy in the medial and inferior temporal areas (Fig. 1A). CSF Aβ42/40 significantly predicted GMv atrophy in the hippocampus bilaterally, alone and when controlling for CSF p‐tau181 and NfL (Fig. 1B‐C). CSF p‐tau181 interacted with Aβ status to predict GMv atrophy in the posterior hippocampus bilaterally (Fig. 1D). Longitudinal GMv atrophy in the hippocampal subfields were confirmed in association with CSF Aβ42/40 in the bilateral CA1, dentate gyrus and BA35 (Table 2).ConclusionIndependently of p‐tau, early Aβ dyshomeostasis is associated with longitudinal GMv atrophy in AD‐sensitive brain areas in the early AD continuum. As expected, tau levels were associated with additional atrophy in these regions in Aβ+ individuals. Pathophysiological alterations other than Aβ, but correlated with CSF Aβ levels, might contribute to the observed atrophy patterns. Control of the earliest pathophysiological alterations in AD may have a relevant impact on neurodegeneration, even at the earliest preclinical stages.

Functional Connectivity and White Matter integrity of intercommunity hub nodes in Subjective Cognitive Decline

AbstractBackgroundSubjective Cognitive Decline (SCD) is considered an early preclinical stage of Alzheimer’s Disease and related dementias (ADRD) which may show promise for targeted preventative treatments. Subtle changes in functional connectivity and white matter integrity (WMI) may occur in SCD. Few studies have applied both functional graph theory (GT) and diffusional kurtosis imaging (DKI) techniques in tandem to identify differences in vulnerable network hubs. We addressed these issues by applying GT and DKI to study differences in intercommunity brain hubs. The hypothesis was that in hubs identified in healthy controls, SCD subjects’ hubs would show decreased GT diversity coefficient (DC) and DKI mean kurtosis (MK).MethodImages were acquired on a Siemens PRISMA scanner. Matlab was used to calculate DC and identify 5 hubs in 107 healthy controls (HC) and DC in 30 SCD (93 females, mean age = 67.51). SCD classification was determined by a comprehensive clinician evaluation or Everyday Cognition average item score>1.6, with objectively healthy cognitive performance (Montreal Cognitive Assessment score>22). Hub DC was the target in GLMM analysis, with diagnosis as predictor. Mean Kurtosis (MK) was analyzed in DSI Studio’s cross‐sectional connectometry using the hubs as seeds. Only the covariate of gray matter volume approached significance (p = .059), and was included in analysis. Mean age, education, head motion, and sex balance did not significantly differ between groups.ResultAll hubs had lower DC in SCD compared to HC (p ≤ .006). Connectometry identified positive correlation between MK and diagnosis in Left hemisphere tracts associated with two hubs: Inferior Fronto‐Occipital, Extreme capsule, and Uncinate tracts from Insular cortex, and Superior Longitudinal, Superior Corticalstriatal, Arcuate, Frontal Aslant, and Corticalspinal tracts from Middle Frontal gyrus.Conclusion Conclusion Rs‐fMRI findings show that intercommunity functional hubs are weaker in SCD compared to healthy individuals. Furthermore, the study identified a relationship of higher MK values in SCD for hubs located in insular cortex and middle frontal gyrus, all left hemisphere biased. Higher MK in SCD also runs counter to our hypothesis but is supported by recent paradoxical increase theories of decline. WMI differences between groups may be subtler than functional changes, warranting examination of the 2 modalities’ relationship.

SPDGFRβ and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. Adults (45-65 years) with a parental history of AD were enrolled (n=82). CSF and blood biomarkers were collected at baseline and year 2. CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW. Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

Leptin prevents aberrant targeting of tau to hippocampal synapses via PI 3 kinase driven inhibition of GSK3β.

Amyloid-β (Aβ) and hyper-phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis-localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau-driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto-toxic effects of tau may prevent AD-related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ-induced toxicity. However, it is unclear if leptin protects against tau-related synaptic dysfunction. Here we show that Aβ1-42 significantly increases dendritic and synaptic levels of tau and p-tau in hippocampal neurons, and these effects were blocked by leptin. In accordance with GSK-3β being involved in tau phosphorylation, the protective effects of leptin involve PI 3-kinase (PI3K) activation and inhibition of GSK-3β. Aβ1-42 -driven synaptic targeting of tau was associated with the removal of GluA1-containing AMPARs from synapses, which was also inhibited by leptin-driven inhibition of GSK-3β. Direct application of oligomeric tau to hippocampal neurons caused internalisation of GluA1-containing AMPARs and this effect was blocked by prior application of leptin. Similarly, leptin prevented the ability of tau to block induction of activity-dependent long-term potentiation (LTP) at hippocampal SC-CA1 synapses. These findings increase our understanding of the neuroprotective actions of leptin in the early pre-clinical stages of AD and further validate the leptin system as a therapeutic target in AD.

Aquaporin 3 inhibition suppresses the mitochondrial respiration rate and viability of multiple myeloma cells

Aquaporin 3 (AQP3) is a member of the aquaporin water channel family expressed by numerous cell types, including some cancer cells. Accumulating evidence suggests that AQP3 inhibition may impede cancer progression, but drugs targeting AQP3 are still in the early pre-clinical stage of development. Here, we examined the effect of AQP3 inhibition on multiple myeloma (MM), an incurable plasma cell malignancy. Four MM cell lines were cultured in the presence of an anti-AQP3 monoclonal antibody (mAb), the AQP3 inhibitor DFP00173, or corresponding controls, and the effects on cell viability, proliferation, apoptosis, and mitochondrial respiration capacity were compared. Both anti-AQP3 mAb and DFP00173 reduced cell growth, mitochondrial respiration rate, and electron transport chain complex I activity. Both agents also potentiated the antiproliferative efficacy of the anticancer drug venetoclax. Administration of the anti-AQP3 mAb to immunodeficient mice inoculated with RPMI8226 or KMS-11 MM cells significantly suppressed tumor growth. These data provide evidence that AQP3 blockade can suppress MM cell growth in vitro and tumor growth in mice. Thus, AQP3 inhibition may be an effective therapeutic strategy for MM.

Life Experience Matters: Enrichment and Stress Can Influence the Likelihood of Developing Alzheimer's Disease via Gut Microbiome.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) formed from abnormally phosphorylated tau proteins (ptau). To date, there is no cure for AD. Earlier therapeutic efforts have focused on the clinical stages of AD. Despite paramount efforts and costs, pharmaceutical interventions including antibody therapies targeting Aβ have largely failed. This highlights the need to alternate treatment strategies and a shift of focus to early pre-clinical stages. Approximately 25-40% of AD cases can be attributed to environmental factors including chronic stress. Gut dysbiosis has been associated with stress and the pathogenesis of AD and can increase both Aβ and NFTs in animal models of the disease. Both stress and enrichment have been shown to alter AD progression and gut health. Targeting stress-induced gut dysbiosis through probiotic supplementation could provide a promising intervention to delay disease progression. In this review, we discuss the effects of stress, enrichment, and gut dysbiosis in AD models and the promising evidence from probiotic intervention studies.

PENSA study for the prevention of cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline: Description of baseline demographic and neuropsychological data of the study population

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disorder likely caused by a complex interplay of different pathological processes that are influenced by internal and external determinants. In the absence of effective treatments to reverse cognitive deterioration related to AD, there is a need to develop novel non‐pharmacological prevention interventions that may delay or prevent these pathological processes at early preclinical stages of AD. The PENSA study, framed within the WW‐FINGERS consortium, is a randomized clinical trial involving cognitively normal elderly individuals with an increased risk of developing AD (meeting subjective cognitive decline, SCD‐plus criteria and being APOE‐ɛ4 carriers). The aim of the study is to evaluate the efficacy of a multimodal personalized lifestyle intervention (dietary and physical activity counseling and cognitive training) combined with a dietary supplement, epigallocatechin gallate (EGCG) in slowing down cognitive decline.MethodBaseline sociodemographic, mood and cognitive characteristics of the entire study sample participants is presented. Cognitive function was measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC) and adding to this original version the interference score from the Stroop Color and Word Test and the Five Digit Test (ADCS‐PACC‐Plus‐exe). Additionally, the Digit Span, the Boston Naming Test and the Animal Fluency Test were administered. Psychological distress was measured with the Hospital Anxiety and Depression Scale.ResultOn Desember 2021 the study had enrolled 128 individuals (64.8% women) with a mean (SD) age of 67.3 (4.73) years and the following APOE genotype: 87% ɛ3/ɛ4, 7% ɛ4/ɛ4 and 6% ɛ2/ɛ4. Most had higher education (44.1%) and 81.9% were retired (Table 1). 11% of participants exhibited relevant anxiety and depressive symptoms measured by the Hospital Anxiety and Depression Scale. According to an ad‐hoc SCD questionnaire, 65.8% of participants referred memory centered complaints. Considering the different domains, participants reported alterations on memory (97.6%), concentration (62.6%), language (69.9%) and visuospatial skills (10.6%). Table 2 shows the ADCS‐PACC‐Plus‐exe scoresConclusionThe PENSA study will help shed light on the effectiveness of lifestyle interventions supplemented with EGCG to prevent cognitive decline in people at risk of developing AD.

Intestinal epithelial transcription factor HNF4A protects against microbiota dependent colitis and expansion of Akkermansia muciniphila

Development of the inflammatory bowel diseases (IBD) has been linked to altered homeostatic relationships between the intestine and the microbiota it harbors. However early preclinical stages of IBD remain poorly understood, especially with respect to host-microbiota interactions. The nuclear receptor transcription factor Hepatocyte nuclear factor 4 alpha (HNF4A) has important roles in intestinal epithelial cell (IEC) physiology, and our recent studies in zebrafish and mice revealed that HNF4A activity in IEC is suppressed by intestinal microbiota. Variants at HNF4A have been associated with human IBD, and IEC-specific knockout of Hnf4a in mice ( Hnf4a ΔIEC ) leads to spontaneous colonic inflammation by 6-12 months. We hypothesized that intestinal pathology in Hnf4a ΔIEC mice may begin earlier in life and that microbiota may contribute to that process. Longitudinal analysis revealed that Hnf4a ΔIEC mice reared in specific pathogen-free (SPF) conditions develop fecal lipocalin 2 (LCN2) flares and episodic loose stools beginning as early as 4-5 weeks of age. Lifetime cumulative LCN2 levels correlated with histopathological features of colitis at 12 months of age. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4a ΔIEC mice were dependent on the presence of microbiota. Fecal 16S rRNA gene sequencing in an SPF cohort of Hnf4a ΔIEC mice and controls at 12 months of age disclosed that genotype was a significant contributor to alterations in microbiota composition. Longitudinal analysis in a subset of inflamed Hnf4a ΔIEC and wild-type mice revealed that microbial community differences emerged at early life stages when fecal LCN2 flares first arose. These microbiota differences included a salient increase in the relative abundance of Akkermansia muciniphila in a subset of Hnf4a ΔIEC mice. We isolated an A. muciniphila strain from an aged, inflamed Hnf4a ΔIEC mouse, and its genome sequence revealed it to be a member of a new Akkermansia phylogroup with genetic features distinct from the known phylogroups. We conclude that HNF4A functions in IEC throughout the lifespan to protect against episodic flares of inflammation induced by microbiota while also shaping microbiota assembly. These results establish Hnf4a ΔIEC mice as a useful model for investigating preclinical pathology and host-microbiota interactions that precede overt IBD onset. NIH P01-DK094779 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Orthodontic correction in rodents and hare-like animals: principles and methods of treatment

The aim: Our particular interest in this study is not only the ability to extrapolate the experience of orthodontics of humane medicine for effective orthodontic correction in representatives of the animal world, but also the possibility of using teleroentgenometry and craniometry to study the skull of rodents and hare-like animals for the early preclinical diagnosis of dental disease.
 Materials and methods. The data of teleroentgenography (TRG), cranio- and gnatometry, biochemistry of connective tissue (GAG, GP, HST), fluoroscopy, densitometric parameters for early subclinical detection of dental disease in chinchillas (Chinchilla lanigera (n=20)), guinea pigs (Cavia porcellus (n=48)) and rabbits (Oryctolagus cuniculus(n=52)) are presented. All stages of the effective correction of mesial occlusion of incisors in rabbits (N=5) and dystropia of premolars in guinea pigs (N=5) are described. The camputation of efforts and points of their application that are necessary to move the tooth of the ellodont type is carried out. There are given the sequential stages of creating a dental imprint or 3D models, as well as the manufacture of fixed orthodontic structures, including an elastophore, orthodontic buttons with an Enlight Ormco fixation for incisors; and individual extraoral devices with expanding screws for premolars are presented.
 Results. Namely, among animals with dental disease, the following anatomical characteristics reliably took place. The basal angle of inclination of the base of the jaws to each other characterizing the vertical position of the jaws increased by 11 %; the body of the lower jaw shortened by 18 %; the height of the branches of the jaw increased by 17.5, and the mandibular angle, which is measured between the tangents to the lower edge of the lower jaw and the back surface of its branches, increased by 6 %. These data must be considered together with a reliable densitometric decrease in bone density and changes of biochemical components of the connective tissue in the blood serum. An analysis of bone strength of rabbits and guinea pigs is given in Tab. 2, which shows that the bone marrow of animals with dental history is statistically significantly different from the strength of animal bones without such among patients of rabbits and guinea pigs (p = 0.012 and p = 0.024, respectively). Thus, the method of program densitometry can be used to quantify the severity of metabolic disorders in the bone tissue to predict the further course of the reparative process, to appoint adequate pharmacological correction and to control the evaluation of therapeutic measures.
 Conclusions. The study of dental pathology of rodents and hare-like animals using densitometric, craniometric and biochemical methods allows detection of disorders in the early preclinical stage. And the extrapolation of the experience of humane orthodontics solves the issue of correcting the occlusion of these types of animals to restore the possibility of self-feeding

Peculiarities of brain structural changes in young patients with arterial hypertension

Actuality: Arterial hypertension (AH) is one of the most common diseases among diseases of the circulatory system and, together with other cardiovascular diseases, ranks first in the world and in Ukraine in terms of mortality rates. About 45% of patients do not know that they have hypertension. The scale of this problem in the world is evidenced by the fact that hypertension is found in every third adult. This disease occurs more often in the elderly, but its development often begins at a young age, and sometimes even in childhood. The intensive development of neuroimaging methods (CT and MRI) in recent decades makes it possible to detect various changes in the brain at early preclinical stages, which is of great importance for the implementation of adequate differentiated primary prevention of the development and progression of cerebrovascular disease and such unpleasant manifestations as cognitive deficits, dementia and ischemic stroke. The purpose of the study: to reveal the nature of structural changes in the brain in young patients with clinically confirmed hypertension. Material and methods: a study of structural changes in the brain was conducted based on the MRI examination data (1.5 T) of 54 young patients (18-44 years old) with hypertension of various degrees. Statistical analysis was carried out by the IBM SPSS Statistics 20 license program using the criterion of agreement with the test of static significance (Fisher's exact test -F). Results: Differences in brain structural changes were obtained in patients depending on the degree of hypertension. A significant difference according to the χ² criterion (р<0.05) was found in the frequency of occurrence of mixed, external and internal hydrocephalus in patients with hypertension of the first and second century. Differences in the incidence of external and internal hydrocephalus in patients with AH I and AH III, AH II and AH III not detected by the χ² criterion (p< 0.05). There are differences in the frequency of leukoaraiosis of the 0th, 1st, 2nd, and 3rd stages. according to the Fazekas scale between groups of patients with 1st stage hypertension, 2nd stage hypertension, and 3rd stage hypertension reliable according to the χ² criterion (р< 0.05). Differences in the frequency of lacunar foci at different degrees of hypertension were not reliably detected. The analysis of the results of the assessment of structural changes of the brain by age showed that the main differences in the occurrence of mixed and external hydrocephalus are characteristic of all age groups. There is no difference in the frequency of internal hydrocephalus, mild and moderate leukoaraiosis in the groups of men and women. The frequency of occurrence of mixed, external hydrocephalus, the absence of leukoaraiosis and the presence of severe draining leukoaraiosis (in men, the severity of these changes prevails) is significantly different. No difference in the frequency of lacunar foci was found in the groups of men and women. Conclusions: Thus, hypertension is an age-dependent disease. No differences were found in the frequency of complaints of noise in the head, decreased attention and cognitive activity, sleep disturbances, and gender differences in the examined patients with hypertension of various degrees of severity. The main structural changes of the brain in the examined patients are various types of hydrocephalic manifestations, signs of leukoaraiosis (characteristic for the older age of 36-44 years) of one degree or another. Some gender specific features of brain structural changes in the examined patients were revealed (increased manifestations of hydrocephalus syndrome in men and absence of leukoaraiosis in them compared to women).

Multifactor mid‐life risk for Alzheimer’s disease associated with alterations in navigation but not episodic memory: the PREVENT‐Dementia study

AbstractBackgroundThe entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a VR path integration task was highly sensitive and specific for prodromal AD (Howett et al., 2019 Brain), we tested the hypothesis that path integration may be affected in asymptomatic middle‐aged individuals at increased risk of AD.Method100 cognitively healthy adults (aged 43–66) from the PREVENT Dementia cohort performed an immersive VR path integration task in a simulated environment with distal boundary cues to generate allocentric spatial representations. We manipulated EC‐dependence by pseudo‐randomly removing supportive spatial cues from the virtual environment (Figure 1). Participants additionally performed a battery of cognitive tasks including the ACE‐R and COGNITO episodic memory. Linear mixed effects models and Tukey‐corrected post‐hoc contrasts were used to explore the contributions to task performance of parental family history, APOE‐e4 status, global amyloid PET uptake value (N = 46) and CAIDE lifestyle dementia risk score, adjusted for age, sex and education.ResultIndividuals with a positive family history, APOE‐e4 allele or higher CAIDE dementia risk score showed a selective impairment in path integration only when supportive boundary cues were removed. Significant sex interactions indicated that the family history effect (t = 2.31, pTukey = 0.022, Figure 2) and APOE‐e4 effect (t = 3.18, pTukey = 0.023) was specific to males. The effect of CAIDE risk score was specific to individuals with a family history (t = 2.45, pTukey = 0.038) (Figure 3). Conversely, these AD risk factors showed no effect on performance for the other cognitive tasks. Global amyloid PET uptake values showed no association to any task performance.ConclusionThese results suggest that navigation tests based on EC grid cell function may identify the earliest cognitive changes in individuals at greater risk of AD. The additional moderation by sex indicates a future need to consider male/female differences when using family history or APOE status to inform detection of initial stages of AD.

Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease.

Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n=700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n=534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n=558) or those with amyloid and tau pathologies (A+T+N±; n=259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages.

Results of Two-Years Mammographic Screening in the Kaluga Region

Objective: approbation of the project of mass breast cancer mammographic screening in the Kaluga Region.Material and methods. From April 2018 to December 2019, screening mammography was performed in 35,439 women aged from 38 to 93 years (mean age 57.33 ± 8.07 years). The study was carried out on mobile mammography complexes assembled on Russian KamAZ vehicles with Russian-made equipment from Amiko company. Mammography was performed in frontal and oblique projections. BI-RADS ACR international classification was used to standardize the identified changes and assess the sensitivity and specificity of the study method.Results. Out of the total number of women examined, pathological changes (BI-RADS IV–V) were assumed according to mammography data in 778 (2.2%) cases, of which 700 (1.98%) patients appealed to an oncological institution. Benign processes were found in 394 (1.11%) patients, breast cancer in 164 (0.46%). Without verification of the diagnosis, 137 (0.39%) patients remained under the supervision of oncologists. Distribution of detected tumors by stages for 2 years of observation: stage 0 – 7, stage 1 – 73, stage 2 – 56, stage 3 – 13, stage 4 – 3. The stage was not set in 4 cases. The total number of those examined with verification of the diagnosis in the oncological institution was 596. The proportion of correct diagnoses was 94%. The total number of diagnostic errors that would occur in the absence of a true double scan accounted for 36 (6%) cases.Conclusion. The proposed screening method makes it possible to increase the breast cancer detection in the early preclinical stages of the disease, to provide the available diagnostics for the population due to mobile mammography complexes, and to speed up the process of diagnostics and further hospitalization for examination and necessary treatment according to the disease stage in a specialized oncological institution.

Practice effects in cognitive assessments three years later in non-carriers but not in symptom-free mutation carriers of autosomal-dominant Alzheimer's disease: Exemplifying procedural learning and memory?

Practice effects (PEs) defined as an improvement of performance in cognition due to repeated assessments between sessions are well known in unimpaired individuals, while less is known about impaired cognition and particularly in latent brain disease as autosomal-dominant Alzheimer's disease. The purpose was to evaluate the general (across tests/domains) and domain-specific PE calculated as the annual rate of change (ARC) in relation to years to the estimated disease onset (YECO) and in four groups of AD: asymptomatic mutation carriers (aAD, n = 19), prodromal, i.e., symptomatic mutation carriers, criteria for AD diagnosis not fulfilled (pAD, n = 4) and mutation carriers diagnosed with AD (dAD, n = 6) as well as mutation non-carriers from the AD families serving as a healthy comparison group (HC, n = 35). Cognition was assessed at baseline and follow-up about 3 years later by 12 tests covering six domains. The aAD and HC groups were comparable at baseline in demographic characteristics (age, gender, and education), when they were in their early forties, while the pAD and dAD groups were older and cognitively impaired. The results on mean ARC for the four groups were significantly different, small, positive, and age-insensitive in the HC group, while ARC was negative and declined with time/disease advancement in AD. The differences between HC and aAD groups in mean ARC and domain-specific ARC were not significant, indicating a subtle PE in aAD in the early preclinical stage of AD. In the symptomatic stages of AD, there was no PE probably due to cognitive disease-related progression. PEs were the largest in the verbal domain in both the HC and aAD groups, indicating a relationship with cognitive vulnerability. The group-related difference in mean ARC was predominant in timekeeping tests. To conclude, the practice effect in over 3 years was suggested to be linked to procedural learning and memory.