The immune and microbial homeostasis determines the Candida-mast cells cross-talk in celiac disease.

Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans-MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms.

Technologies for frailty, comorbidity, and multimorbidity in older adults: a systematic review of research designs.

BACKGROUND: Frailty, neurodegeneration and geriatric syndromes cause a significant impact at the clinical, social, and economic level, mainly in the context of the aging world. Recently, Information and Communication Technologies (ICTs), virtual reality tools, and machine learning models have been increasingly applied to the care of older patients to improve diagnosis, prognosis, and interventions. However, so far, the methodological limitations of studies in this field have prevented to generalize data to real-word. This review systematically overviews the research designs used by studies applying technologies for the assessment and treatment of aging-related syndromes in older people. METHODS: Following the PRISMA guidelines, records from PubMed, EMBASE, and Web of Science were systematically screened to select original articles in which interventional or observational designs were used to study technologies' applications in samples of frail, comorbid, or multimorbid patients. RESULTS: Thirty-four articles met the inclusion criteria. Most of the studies used diagnostic accuracy designs to test assessment procedures or retrospective cohort designs to build predictive models. A minority were randomized or non-randomized interventional studies. Quality evaluation revealed a high risk of bias for observational studies, while a low risk of bias for interventional studies. CONCLUSIONS: The majority of the reviewed articles use an observational design mainly to study diagnostic procedures and suffer from a high risk of bias. The scarce presence of methodologically robust interventional studies may suggest that the field is in its infancy. Methodological considerations will be presented on how to standardize procedures and research quality in this field.

The Adult Neurogenesis Theory of Alzheimer's Disease.

Alzheimer's disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-ß deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this "reactive" pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.

The STING/TBK1/IRF3/IFN type I pathway is defective in cystic fibrosis.

Cystic fibrosis (CF) is a rare autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation is F508del-CFTR (ΔF) which leads the encoded ion channel towards misfolding and premature degradation. The disease is characterized by chronic bronchopulmonary obstruction, inflammation and airways colonization by bacteria, which are the major cause of morbidity and mortality. The STING pathway is the main signaling route activated in the presence of both self and pathogen DNA, leading to Type I Interferon (IFN I) production and the innate immune response. In this study, we show for the first time the relationship existing in CF between resistant and recurrent opportunistic infections by Pseudomonas aeruginosa and the innate immunity impairment. We demonstrate through ex vivo and in vivo experiments that the pathway is inadequately activated in ΔF condition and the use of direct STING agonists, as 2',3'-cyclic GMP-AMP (2', 3' cGAMP), is able to restore the immune response against bacterial colonization. Indeed, upon treatment with the STING pathway agonists, we found a reduction of colony forming units (CFUs) consequent to IFN-ß enhanced production in Pseudomonas aeruginosa infected bone marrow derived macrophages and lung tissues from mice affected by Cystic Fibrosis. Importantly, we also verified that the impairment detected in the primary PBMCs obtained from ΔF patients can be corrected by 2', 3' cGAMP. Our work indicates that the cGAS/STING pathway integrity is crucial in the Cystic Fibrosis response against pathogens and that the restoration of the pathway by 2', 3' cGAMP could be exploited as a possible new target for the symptomatic treatment of the disease.

Signs and symptoms method in neuropsychology: A standardized observational examination of cognitive functions can be effective in detecting mild cognitive impairment.

OBJECTIVE: The present study aimed at investigating the sensitivity and specificity of the NeuroPsychological Examination (NPE), a systematic collection of cognitive signs and symptoms based on the observation of the patient's behavior during a clinical interview, in detecting Mild Cognitive Impairment (MCI). METHOD: 475 participants, 208 suffering from MCI, 188 suffering from dementia and 79 subjective cognitive decline (SCD), have been assessed using NPE for the presence of signs and symptoms of cognitive impairment. Receiver operating characteristic (ROC) curve analysis and the Youden's test were used to determine the more appropriate cutoff points for the number of neuropsychological signs at the NPE that enabled to discriminate SCD from MCI, SCD from dementia and MCI from dementia. A sensitivity and specificity analysis and comparisons among the three groups were conducted. RESULTS: The mean number of signs at the NPE were 1.73 for SCD, 7.98 for MCI and 12.82 for dementia. Pairwise comparisons among the three group of participants showed significant differences (SCD vs. MCI, p < .001, r = -0.66; SCD vs. dementia, p < .001, r = -0.76; MCI vs. dementia, p < .001, r = -0.44). The criterion of 3 signs at the NPE showed a sensitivity of 0.95 (95% CI [0.91, 0.97]) and a specificity of 0.76 (95% CI [0.65, 0.84]) in discriminating SCD from MCI participants. CONCLUSIONS: A signs and symptoms approach could be a useful tool for clinical neuropsychologists working in the field of MCI and dementia assessment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Diencephalic versus Hippocampal Amnesia in Alzheimer's Disease: The Possible Confabulation-Misidentification Phenotype.

BACKGROUND: Alzheimer's disease (AD) is clinically heterogeneous, including the classical-amnesic (CA-) phenotype and some variants. OBJECTIVE: We aim to describe a further presentation we (re)named confabulation-misidentification (CM-) phenotype. METHODS: We performed a retrospective longitudinal case-series study of 17 AD outpatients with the possible CM-phenotype (CM-ADs). Then, in a cross-sectional study, we compared the CM-ADs to a sample of 30 AD patients with the CA-phenotype (CA-ADs). The primary outcome was the frequency of cognitive and behavioral features. Data were analyzed as differences in percentage by non-parametric Chi Square and mean differences by parametric T-test. RESULTS: Anterograde amnesia (100%) with early confabulation (88.2%), disorientation (88.2%) and non-infrequently retrograde amnesia (64.7%) associated with reduced insight (88.2%), moderate prefrontal executive impairment (94.1%) and attention deficits (82.3%) dominated the CM-phenotype. Neuropsychiatric features with striking misidentification (52.9%), other less-structured delusions (70.6%), and brief hallucinations (64.7%) were present. Marked behavioral disturbances were present early in some patients and very common at later stages. At the baseline, the CM-ADs showed more confabulation (p < 0.001), temporal disorientation (p < 0.02), misidentification (p = 0.013), other delusions (p = 0.002), and logorrhea (p = 0.004) than the CA-ADs. In addition, more social disinhibition (p = 0.018), reduction of insight (p = 0.029), and hallucination (p = 0.03) persisted at 12 months from baseline. Both the CA- and CM-ADs showed anterior and medial temporal atrophy. Compared to HCs, the CM-ADs showed more right fronto-insular atrophy, while the CA-ADs showed more dorsal parietal, precuneus, and right parietal atrophy. CONCLUSION: We described an AD phenotype resembling diencephalic rather than hippocampal amnesia and overlapping the past-century description of presbyophrenia.

Autonomic function predicts cognitive decline in mild cognitive impairment: Evidence from power spectral analysis of heart rate variability in a longitudinal study.

Background: Despite the emerging clinical relevance of heart rate variability (HRV) as a potential biomarker of cognitive decline and as a candidate target for intervention, there is a dearth of research on the prospective relationship between HRV and cognitive change. In particular, no study has addressed this issue in subjects with a diagnosis of cognitive status including cognitive impairment. Objective: To investigate HRV as a predictor of cognitive decline in subjects with normal cognition (NC) or Mild Cognitive Impairment (MCI). Specifically, we tested the literature-based hypothesis that the HRV response to different physical challenges would predict decline in different cognitive domains. Methods: This longitudinal study represents the approximately 3-year follow-up of a previous cross-sectional study enrolling 80 older outpatients (aged ≥ 65). At baseline, power spectral analysis of HRV was performed on five-minute electrocardiographic recordings at rest and during a sympathetic (active standing) and a parasympathetic (paced breathing) challenge. We focused on normalized HRV measures [normalized low frequency power (LFn) and the low frequency to high frequency power ratio (LF/HF)] and on their dynamic response from rest to challenge (Δ HRV). Extensive neuropsychological testing was used to diagnose cognitive status at baseline and to evaluate cognitive change over the follow-up via annualized changes in cognitive Z-scores. The association between Δ HRV and cognitive change was explored by means of linear regression, unadjusted and adjusted for potential confounders. Results: In subjects diagnosed with MCI at baseline a greater response to a sympathetic challenge predicted a greater decline in episodic memory [adjusted model: Δ LFn, standardized regression coefficient (ß) = -0.528, p = 0.019; Δ LF/HF, ß = -0.643, p = 0.001] whereas a greater response to a parasympathetic challenge predicted a lesser decline in executive functioning (adjusted model: Δ LFn, ß = -0.716, p < 0.001; Δ LF/HF, ß = -0.935, p < 0.001). Conclusion: Our findings provide novel insight into the link between HRV and cognition in MCI. They contribute to a better understanding of the heart-brain connection, but will require replication in larger cohorts.

Crystal Ball Health Policies: A Case Against Preventive Testing For Alzheimer's Disease.

After the recent approval of a new drug for the treatment of Alzheimer's disease, the first in almost twenty years, it is useful to consider what are the real possibilities to make a preclinical diagnosis of dementia and to treat its symptoms. The scientific community widely agrees that the drugs available today can only slow down the progression of the disease; it, therefore, seems helpful to warn against encouraging the spread of preventive testing. In fact, faced with the prospect of drugs that promise to act in the first stage of Alzheimer's, there might be an incentive to invest in the research on biomarkers and even healthy adults could be encouraged to increasingly resort to such prediction tests. Our claim, however, is that such massive use of biomarkers would eventually make things worse for many individuals and for society as well. A few examples are given to illustrate this risk. Therefore, our proposal is to limit access to prediction testing until truly effective treatments for Alzheimer's are available.

Socially desirable responding in geriatric outpatients with and without mild cognitive impairment and its association with the assessment of self-reported mental health.

BACKGROUND: Socially desirable responding is a potentially relevant issue in older adults and can be evaluated with the Marlowe-Crowne Social Desirability Scale (MCSDS). However, the eight-item MCSDS has never been specifically administered to geriatric subjects, and there is a dearth of literature on the relationship between social desirability and cognitive impairment. Also, the connection between social desirability and subjective measures of psychological well-being is a matter of controversy. This study has three main aims. First, to determine the psychometric properties of the eight-item MCSDS in geriatric outpatients without dementia (i.e. with normal cognition (NC) or mild cognitive impairment (MCI)). Second, to investigate the link between social desirability and cognitive functioning. Third, to determine the association between social desirability and the assessment of self-reported mental health. METHODS: Community-dwelling outpatients (aged ≥ 65) were consecutively recruited and neuropsychologically tested to diagnose NC or MCI (n = 299). Social desirability was assessed with the eight-item MCSDS. Depressive and anxiety symptoms were measured with the short Geriatric Depression (GDS-s) and the State-Trait Personality Inventory Trait Anxiety (STPI-TA) scales. RESULTS: On principal components analysis, the eight-item MCSDS was found to have a multidimensional structure. Of the initial three-component solution, only two subscales had acceptable internal consistency (Cronbach's alpha > 0.6): "Acceptance of responsibility" and "Integrity". The third subscale ("Kindness towards others") appeared to gauge two distinct constructs of formal (i.e. politeness) versus substantive (i.e. forgiveness) compassion. On binary logistic regression, only higher income was a significant predictor of formal compassion. Test-retest reliability was substantial to excellent (Gwet's AC2 ≥ 0.8). There were no meaningful differences in social desirability between the NC and MCI groups. Likewise, negative Spearman's correlations between social desirability and cognitive Z-scores across the whole sample were weak (rs < |0.3|) and confined to one MCSDS item. Although social desirability was an independent predictor of the STPI-TA score in multiple linear regression, it explained only a marginal amount of incremental variance in anxiety symptoms (less than 2%). CONCLUSIONS: Our results suggest that social desirability need not be a major concern when using questionnaires to assess mental health in geriatric outpatients without dementia.

Signs and symptoms method in neuropsychology: A preliminary investigation of a standardized clinical interview for assessment of cognitive decline in dementia.

Psychologists usually perform a preliminary assessment of the person's cognitive status through a brief interview conducted before the formal testing. However, this exam has not yet been standardized with ad hoc recommendations in psychology literature. In this work, a standard observational NeuroPsychological Examination (NPE) designed for psychologists was proposed, and its clinical effectiveness evaluated. The NPE was administered to patients referred to a neuropsychological service in a memory clinic over a 2-year period. The NPEs of the patients with Alzheimer dementia (AD), vascular dementia (VaD), and healthy controls (HC) were retrospectively retrieved. Comparisons among the three groups were conducted. Abnormalities/signs identified during the NPE in the AD and VaD groups are more numerous compared to those reported in the HC group. About 80% of HCs show none or only one abnormal sign. Vice versa, 87.5% of both AD and VaD patients show three or more abnormalities. Accordingly, the NPE has 0.88 (95%CI = 0.81-0.95) sensitivity and 0.95 (95%CI = 0.88-1.02) specificity for detecting cognitive decline when a cut-point of three or more signs is applied. Some significant differences also emerge on the number of pathological signs between AD and VaD patients. NPE is a promising tool with demonstrated diagnostic utility in dementia patients.

ICT technologies as new promising tools for the managing of frailty: a systematic review.

OBJECTIVES: Frailty is a major health issue as it encompasses functional decline, physical dependence, and increased mortality risk. Recent studies explored Information and Communication Technology (ICT) interventions as alternatives to manage frailty in older persons. The aim of the present systematic review was to synthesize current evidence on ICT application within the complex models of frailty care in older people. METHODS: Data sources included PubMed, PsycINFO, EMBASE and Web of Science, considering eligible those reviews on ICT application in samples of older persons formally assessed as frail. Records were screened by two independent researchers, who extracted data and appraised methodological quality of reviews and studies. RESULTS: Among the 764 retrieved papers, two systematic reviews were included. Most of the studies analyzed defined frailty considering only few components of the phenotype and used ICT to stratify different levels of frailty or to support traditional screening strategies. Assessment of frailty was the context in which ICT has been mostly tested as compared to intervention. Cost effectiveness evaluations of the ICT technologies were not reported. CONCLUSIONS: The research investigating the use of ICT in the context of frailty is still at the very beginning. Few studies strictly focused on the assessment of frailty, while intervention on frailty using ICT was rarely reported. The lack of a proper characterization of the frail condition along with the methodological limitations prevented the investigation of ICT within complex care models. Future studies are needed to effectively integrate ICT in the care of frailty in orders.

Different dimensions of social support differentially predict psychological well-being in late life: opposite effects of perceived emotional support and marital status on symptoms of anxiety and of depression in older outpatients in Italy.

BACKGROUND: Social support is important to psychological well-being in late life. However, findings in the literature regarding its effects are mixed, less information is available for anxiety than for depressive symptoms, and few studies have been carried out in Italy. Therefore, the aim of this study was to investigate the influence of social support on symptoms of anxiety and of depression in a sample of geriatric outpatients in Italy. METHODS: This cross-sectional study consecutively enrolled 299 outpatients without dementia (age ≥ 65, all neuropsychologically tested). Social support was assessed with the ENRICHD Social Support Instrument and by interview. Symptoms of anxiety and of depression were evaluated with short versions of the State-Trait Personality Inventory Trait Anxiety and Geriatric Depression scales. The relationship between social support and psychological well-being was examined by multiple linear regression models with socio-demographic and clinical variables, including cognitive performance, as potential confounders. RESULTS: Perceived emotional support was a negative predictor of symptoms of anxiety (standardised beta coefficient (ß) -0.288, standard error (SE) 0.074, P < 0.001) and symptoms of depression (ß -0.196, SE 0.040, P < 0.001). On the contrary, marital status (i.e. being married) was a positive predictor of symptoms of anxiety (ß 0.199, SE 0.728, P = 0.003) and symptoms of depression (ß 0.142, SE 0.384, P = 0.035). CONCLUSIONS: Different dimensions of social support differentially affect psychological well-being. The protective effect of perceived emotional support is consistent with social cognitive models of health. The harmful effect of being married may be capturing the distress of the pre-bereavement period. Alternatively, it may reflect oppression by gender roles within marriage in a predominantly female sample in a traditional society. Our findings provide insight into the relationship between social support and psychological well-being, and identify potential targets for psychosocial interventions promoting mental health in late life.

Supervised Digital Neuropsychological Tests for Cognitive Decline in Older Adults: Usability and Clinical Validity Study.

BACKGROUND: Dementia is a major and growing health problem, and early diagnosis is key to its management. OBJECTIVE: With the ultimate goal of providing a monitoring tool that could be used to support the screening for cognitive decline, this study aims to develop a supervised, digitized version of 2 neuropsychological tests: Trail Making Test and Bells Test. The system consists of a web app that implements a tablet-based version of the tests and consists of an innovative vocal assistant that acts as the virtual supervisor for the execution of the test. A replay functionality is added to allow inspection of the user's performance after test completion. METHODS: To deploy the system in a nonsupervised environment, extensive functional testing of the platform was conducted, together with a validation of the tablet-based tests. Such validation had the two-fold aim of evaluating system usability and acceptance and investigating the concurrent validity of computerized assessment compared with the corresponding paper-and-pencil counterparts. RESULTS: The results obtained from 83 older adults showed high system acceptance, despite the patients' low familiarity with technology. The system software was successfully validated. A concurrent validation of the system reported good ability of the digitized tests to retain the same predictive power of the corresponding paper-based tests. CONCLUSIONS: Altogether, the positive results pave the way for the deployment of the system to a nonsupervised environment, thus representing a potential efficacious and ecological solution to support clinicians in the identification of early signs of cognitive decline.

Autonomic function in amnestic and non-amnestic mild cognitive impairment: spectral heart rate variability analysis provides evidence for a brain-heart axis.

Mild cognitive impairment (MCI) is a heterogeneous syndrome with two main clinical subtypes, amnestic (aMCI) and non-amnestic (naMCI). The analysis of heart rate variability (HRV) is a tool to assess autonomic function. Cognitive and autonomic processes are linked via the central autonomic network. Autonomic dysfunction entails several adverse outcomes. However, very few studies have investigated autonomic function in MCI and none have considered MCI subtypes or the relationship of HRV indices with different cognitive domains and structural brain damage. We assessed autonomic function during an active orthostatic challenge in 253 oupatients aged ≥ 65, [n = 82 aMCI, n = 93 naMCI, n = 78 cognitively normal (CN), neuropsychologically tested] with power spectral analysis of HRV. We used visual rating scales to grade cerebrovascular burden and hippocampal/insular atrophy (HA/IA) on neuroimaging. Only aMCI showed a blunted response to orthostasis. Postural changes in normalised low frequency (LF) power and in the LF to high frequency ratio correlated with a memory test (positively) and HA/IA (negatively) in aMCI, and with attention/executive function tests (negatively) and cerebrovascular burden (positively) in naMCI. These results substantiate the view that the ANS is differentially impaired in aMCI and naMCI, consistently with the neuroanatomic substrate of Alzheimer's and small-vessel subcortical ischaemic disease.

Does the Right Focal Variant of Alzheimer's Disease Really Exist? A Literature Analysis.

BACKGROUND: Alzheimer's disease (AD) is a clinically heterogeneous disease. Multiple atypical syndromes, distinct from the usual amnesic phenotype, have been described. In this context, the existence of a right variant of AD (RAD), characterized by enduring visuospatial impairment associated with right-sided asymmetric brain damage, has been proposed. However, to date, this phenotype remains controversial. In particular, its peculiar characteristics and the independence from more prevalent cases (especially the posterior cortical atrophy syndrome) have to be demonstrated. OBJECTIVE: To explore the existence of focal RAD on the basis of existing literature. METHODS: We performed a literature search for the description of atypical AD presentations, potentially evoking cases of focal RAD. To be considered as affected by RAD, the described cases had to present: 1) well documented right-sided asymmetry at neuroimaging; 2) predominant cognitive deficits localizable on the right hemisphere; 3) no specific diagnosis of a known variant of AD. RESULTS: Twenty-one cases were found in the literature, but some of them were subsequently excluded because some features of a different clinical syndrome were overlapped with the clinical features of RAD. Thirteen positive cases, three of them with pathologically confirmed AD, remained. A common right clinical-radiological syndrome, characterized by memory and visuospatial impairment with temporal and parietal involvement, consistently emerged. However, the heterogeneity among the reports prevented a definitive and univocal description of the syndrome. CONCLUSION: Even if sporadic observations strongly support the existence of a focal RAD, no definitive conclusions can still be drawn about it as an independent condition.