The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan.

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.

Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory.

Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of COMT Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample (n = 208, age 20-79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50-79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20-49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan.

Designing a Multicenter Registry of COVID-19 and Other Respiratory Infections in Fars, Iran.

OBJECTIVE: A year after the emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as a new crisis in respiratory infections, there remain many uncertainties and unknowns about SARS-CoV-2 and the disease it causes, called coronavirus disease (COVID-19). Although COVID-19 is known as a respiratory disease, some atypical manifestations have been seen, different from those seen in other types of viral respiratory infections. This paper aims to describe designing, launching, and implementing a data collection system for all respiratory diseases, with a focus on SARS-CoV-2 from the onset of this pandemic. METHOD: The current registry is designed in compliance with the standard Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, along with the declaration of Helsinki principles. RESULTS: A respiratory disease registry, with an emphasis on COVID-19 and other co-infections, was developed. Data consisted of demographic, clinical, and supporting information about SARS-CoV-2 and other respiratory viral diseases. CONCLUSION: It is hoped that the current data registry will facilitate patient evaluation and improve the outcomes of cases of respiratory infection defined by a particular condition, disease, or exposure. Moreover, the registry can harmonize data about the treatment, outcomes, and well-being of patients who receive care over time, and identify best practices.

Contributions of HFE polymorphisms to brain and blood iron load, and their links to cognitive and motor function in healthy adults.

BACKGROUND: Brain iron overload is linked to brain deterioration, and cognitive and motor impairment in neurodegenerative disorders and normal aging. Mutations in the HFE gene are associated with iron dyshomeostasis and are risk factors for peripheral iron overload. However, links to brain iron load and cognition are less consistent and data are scarce. AIMS AND METHODS: Using quantitative susceptibility mapping with magnetic resonance imaging, we investigated whether C282Y and H63D contributed to aging-related increases in brain iron load and lower cognitive and motor performance in 208 healthy individuals aged 20-79 years. We also assessed the modulatory effects of HFE mutations on associations between performance and brain iron load, as well as peripheral iron metabolism. RESULTS: Independent of age, carriers of either C282Y and/or H63D (HFE-pos group, n = 66) showed a higher load of iron in putamen than non-carriers (HFE-neg group, n = 142), as well as higher transferrin saturation and lower transferrin and transferrin receptors in blood. In the HFE-neg group, higher putaminal iron was associated with lower working memory. In the HFE-pos group, higher putaminal iron was instead linked to higher executive function, and lower plasma transferrin was related to higher episodic memory. Iron-performance associations were modest albeit reliable. CONCLUSION: Our findings suggest that HFE status is characterized by higher regional brain iron load across adulthood, and support the presence of a modulatory effect of HFE status on the relationships between iron load and cognition. Future studies in healthy individuals are needed to confirm the reported patterns.

The role of comorbidities on mortality of COVID-19 in patients with diabetes.

BACKGROUND: Patients with diabetes are one of the most high-risk group to become infected with SARS-CoV-2. Current study was designed to evaluate the risk of other complications in COVID-19 patients with diabetes. METHODS: In this cross-sectional study (25 February to July 10, 2020), 458 patients with diabetes were enrolled based on their characteristics, symptoms and signs, laboratory data and presence of other underlying diseases. Multiple logistic regression and Chi-square test analysis were used to check the effectiveness of other comorbidities on the mortality outcome among patients with diabetes. RESULTS: Of 458 patients with diabetes, 306 (67%) had other underlying diseases, such as 200 (65.4%) hypertension, 103 (33.7%) cardiovascular diseases and 29 (9.5%) kidney diseases. The rate of fatality was significantly high in patients with chronic kidney and liver diseases. The odds of mortality were increased 3.1-fold for patients over 55 years as compared to those under 55 years (P = 0.011), and the odds of mortality outcome were more than 5.1-fold for those who had chronic kidney disease (P < 0.001). CONCLUSIONS: The presentation of SARS-CoV-2 in older patients with diabetes with other comorbidities such as chronic kidney and liver diseases is more severe in risk of mortality.

Comparing different approaches for operationalizing subjective cognitive decline: impact on syndromic and biomarker profiles.

Subjective cognitive decline (SCD) has been proposed as a risk factor for future cognitive decline and dementia. Given the heterogeneity of SCD and the lack of consensus about how to classify this condition, different operationalization approaches still need to be compared. In this study, we used the same sample of individuals to compare  different SCD operationalization approaches. We included 399 cognitively healthy individuals from a community-based cohort. SCD was assessed through nine questions about memory and non-memory subjective complaints. We applied four approaches to operationalize SCD: two hypothesis-driven approaches and two data-driven approaches. We characterized the resulting groups from each operationalization approach using multivariate methods on comprehensive demographic, clinical, cognitive, and neuroimaging data. We identified two main phenotypes: an amnestic phenotype characterized by an Alzheimer's Disease (AD) signature pattern of brain atrophy; and an anomic phenotype, which was mainly related to cerebrovascular pathology. Furthermore, language complaints other than naming helped to identify a subgroup with subclinical cognitive impairment and difficulties in activities of daily living. This subgroup also showed an AD signature pattern of atrophy. The identification of SCD phenotypes, characterized by different syndromic and biomarker profiles, varies depending on the operationalization approach used. In this study we discuss how these findings may be used in clinical practice and research.

Survival rate in hypertensive patients with COVID-19.

INTRODUCTION: A life-threatening respiratory disease, coronavirus 2019 (COVID-19), has spread across the globe since December 2019. Many prognostic factors have already been put forward to predict the risk of death and other outcomes. The current study is evaluating the survival rate between hypertensive and non-hypertensive infected patients. METHODS: Patients who were included in this study were admitted between 20 February to 1 March 2020 in Fars (southwest of Iran) province hospitals. Data were collected from the electronic base registry which contained demographic information, medical symptoms, and signs, underlying diseases, CT scan results, and final outcome. RESULTS: Of all 1239 positive cases, 159 (12.83%) had known with hypertension ant this group was significantly older than non-hypertensive patients (66.1 years Vs 48.95 years, p < .001). According to Kaplan-Meier survival curve and log-rank test, it was seen hypertensive patients deteriorated more rapidly than non-hypertensive group (p = .032). Moreover, HIV, cardiovascular, and kidney disease were diagnosed as factors that increase the risk of death in hypertensive patients. CONCLUSION: The current study about the survival rate of COVID-19 patients had shown hypertensive patents are in danger of disease severity, although it may be related to their age. Moreover, the probability of other complications like diabetes, smoking, asthma, kidney, and cardiovascular diseases, and either some other infections such as HIV can make the condition complicated and need more consideration to prevent noxious outcomes.

Characteristics of deceased patients with CoVID-19 after the first peak of the epidemic in Fars province, Iran.

Emergence of a new coronavirus causes a serious concern whether this can be stopped at all. The ongoing coronavirus disease created a substantial variation in the fatality rate over the world. The current report brought an explore about the epidemiological characteristics of deceased patients and the fatality rate after the first peak in Fars province which is the fourth most populous and large province in Iran. Of the 3702 confirmed cases with coVID-19, 87 patients passed away and so the fatality rate estimated 2.35. Also, it was derived that male sex, old age and underlying diseases especially diabetes were common characteristics of these victims.

Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?

Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

Monitoring disease progression in mild cognitive impairment: Associations between atrophy patterns, cognition, APOE and amyloid.

BACKGROUND: A disease severity index (SI) for Alzheimer's disease (AD) has been proposed that summarizes MRI-derived structural measures into a single score using multivariate data analysis. OBJECTIVES: To longitudinally evaluate the use of the SI to monitor disease progression and predict future progression to AD in mild cognitive impairment (MCI). Further, to investigate the association between longitudinal change in the SI and cognitive impairment, Apolipoprotein E (APOE) genotype as well as the levels of cerebrospinal fluid amyloid-beta 1-42 (Aß) peptide. METHODS: The dataset included 195 AD, 145 MCI and 228 control subjects with annual follow-up for three years, where 70 MCI subjects progressed to AD (MCI-p). For each subject the SI was generated at baseline and follow-ups using 55 regional cortical thickness and subcortical volumes measures that extracted by the FreeSurfer longitudinal stream. RESULTS: MCI-p subjects had a faster increase of the SI over time (p < 0.001). A higher SI at baseline in MCI-p was related to progression to AD at earlier follow-ups (p < 0.001) and worse cognitive impairment (p < 0.001). AD-like MCI patients with the APOE ε4 allele and abnormal Aß levels had a faster increase of the SI, independently (p = 0.003 and p = 0.004). CONCLUSIONS: Longitudinal changes in the SI reflect structural brain changes and can identify MCI patients at risk of progression to AD. Disease-related brain structural changes are influenced independently by APOE genotype and amyloid pathology. The SI has the potential to be used as a sensitive tool to predict future dementia, monitor disease progression as well as an outcome measure for clinical trials.

Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid.

BACKGROUND: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF). OBJECTIVE: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aß1-42, and Aß42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS. METHODS: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks. RESULTS: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aß1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aß1-42, Aß42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aß1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03). CONCLUSIONS: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

A 'Disease Severity Index' to identify individuals with Subjective Memory Decline who will progress to mild cognitive impairment or dementia.

Subjective memory decline (SMD) is a heterogeneous condition. While SMD might be the earliest sign of Alzheimer's disease (AD), it also occurs in aging and various neurological, medical, and psychiatric conditions. Identifying those with higher risk to develop dementia is thus a major challenge. We tested a novel disease severity index generated by multivariate data analysis with numerous structural MRI measures as input. The index was used to identify SMD individuals with high risk of progression to mild cognitive impairment (MCI) or AD. A total of 69 healthy controls, 86 SMD, 45 MCI, and 38 AD patients were included. Subjects were followed up for 7.5 years. Clinical, cognitive, PET amyloid imaging and APOE ε4 data were used as outcome variables. The results showed that SMD evidenced cognitive performance intermediate between healthy controls and MCI. The disease severity index identified eleven (13%) SMD individuals with an AD-like pattern of brain atrophy. These individuals showed lower cognitive performance, increased CDR-SOB, higher amyloid burden and worse clinical progression (6.2 times higher likelihood to develop MCI, dementia or die than healthy controls). The current disease severity index may have relevance for clinical practice, as well as for selecting appropriate individuals for clinical trials.

The Effect of Age Correction on Multivariate Classification in Alzheimer's Disease, with a Focus on the Characteristics of Incorrectly and Correctly Classified Subjects.

The similarity of atrophy patterns in Alzheimer's disease (AD) and in normal aging suggests age as a confounding factor in multivariate models that use structural magnetic resonance imaging (MRI) data. To study the effect and compare different age correction approaches on AD diagnosis and prediction of mild cognitive impairment (MCI) progression as well as investigate the characteristics of correctly and incorrectly classified subjects. Data from two multi-center cohorts were included in the study [AD = 297, MCI = 445, controls (CTL) = 340]. 34 cortical thickness and 21 subcortical volumetric measures were extracted from MRI. The age correction approaches involved: using age as a covariate to MRI-derived measures and linear detrending of age-related changes based on CTL measures. Orthogonal projections to latent structures was used to discriminate between AD and CTL subjects, and to predict MCI progression to AD, up to 36-months follow-up. Both age correction approaches improved models' quality in terms of goodness of fit and goodness of prediction, as well as classification and prediction accuracies. The observed age associations in classification and prediction results were effectively eliminated after age correction. A detailed analysis of correctly and incorrectly classified subjects highlighted age associations in other factors: ApoE genotype, global cognitive impairment and gender. The two methods for age correction gave similar results and show that age can partially masks the influence of other aspects such as cognitive impairment, ApoE-e4 genotype and gender. Age-related brain atrophy may have a more important association with these factors than previously believed.

Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study.

BACKGROUND: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known. OBJECTIVE: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study. METHODS: 174 AD patients (74 ± 9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender. RESULTS: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight. CONCLUSIONS: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.

Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease.

Several studies support the relation between leptin and Alzheimer's disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Aß1₋42. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Aß accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time.

The use of MRI, CT and lumbar puncture in dementia diagnostics: data from the SveDem Registry.

BACKGROUND/AIMS: The use of structural brain imaging [computed tomography (CT)/magnetic resonance imaging (MRI)] and the analysis of cerebrospinal fluid biomarkers are included in the guidelines for the diagnosis of dementia. The influence of variables such as age, gender and disease severity on the use of MRI, CT and lumbar puncture (LP) for the differential diagnosis of dementia and the consonance with the recommendations of the Swedish national guidelines were investigated. METHODS: From the National Swedish Dementia Registry (SveDem), 17,057 newly diagnosed dementia patients were included in our study, with the majority from specialist care units (90%). RESULTS: In the diagnostic workup, a CT was performed in 87%, MRI in 16% and LP in 40% of the cases. Age (p < 0.001) and cognitive status (p < 0.001) significantly influenced the use of MRI, CT or LP. Older patients with severe dementia were often investigated with CT. LP and MRI were used more often when less common dementia disorders were suspected. CONCLUSION: Our findings indicate that age, severity of cognitive impairment and the type of dementia disorder suspected are determinants for the choice of CT, MRI or LP. The majority of the dementia workups in specialist care units follow the recommendations of the Swedish national guidelines where CT is performed as a basic workup, and MRI and LP are chosen when extended workup is needed. .

Body Mass Index in Different Dementia Disorders: Results from the Swedish Dementia Quality Registry (SveDem).

BACKGROUND: Most patients with dementia lose body weight over the course of the disease and have a lower body mass index (BMI) than subjects with normal cognition. AIMS: To examine body mass index and how it correlates with cognitive status, age and gender in patients with different dementia disorders. MATERIALS AND METHODS: Data from newly diagnosed dementia patients in the Swedish Dementia Quality Registry (SveDem) and recorded information about age, gender, cognitive status and BMI was analyzed using independent samples t tests and one-way analysis of variance. RESULTS: A total of 12,015 patients, 7,121 females and 4,894 males were included in the study. The average BMI was 24. More than a quarter of the patients had a BMI of <22. Females were significantly older (p < 0.001) and males had a significantly higher BMI (p < 0.001) at the time of diagnosis. BMI differed significantly by gender in various dementia disorders and correlated significantly with cognitive status and age. CONCLUSION: At the time of diagnosis, patients with various dementia disorders had a BMI within the normal range. However, a significant number had a BMI in a lower, suboptimal range for older persons stressing the need for nutritional assessment as part of the dementia work up. Further analyses with longitudinal follow-up are needed to investigate BMI changes over time.

Multivariate data analysis and machine learning in Alzheimer's disease with a focus on structural magnetic resonance imaging.

Machine learning algorithms and multivariate data analysis methods have been widely utilized in the field of Alzheimer's disease (AD) research in recent years. Advances in medical imaging and medical image analysis have provided a means to generate and extract valuable neuroimaging information. Automatic classification techniques provide tools to analyze this information and observe inherent disease-related patterns in the data. In particular, these classifiers have been used to discriminate AD patients from healthy control subjects and to predict conversion from mild cognitive impairment to AD. In this paper, recent studies are reviewed that have used machine learning and multivariate analysis in the field of AD research. The main focus is on studies that used structural magnetic resonance imaging (MRI), but studies that included positron emission tomography and cerebrospinal fluid biomarkers in addition to MRI are also considered. A wide variety of materials and methods has been employed in different studies, resulting in a range of different outcomes. Influential factors such as classifiers, feature extraction algorithms, feature selection methods, validation approaches, and cohort properties are reviewed, as well as key MRI-based and multi-modal based studies. Current and future trends are discussed.

Differences in routine clinical practice between early and late onset Alzheimer's disease: data from the Swedish Dementia Registry (SveDem).

BACKGROUND: Due to age of onset, Alzheimer's disease (AD) is divided into early onset (EOAD) or late onset (LOAD), but emerging data also suggests that the underlying pathology may be different. Whether differences in clinical care exist is less well investigated. OBJECTIVES: To evaluate whether there are differences in demographics, diagnostic work-up, and pharmacological treatment between EOAD and LOAD. MATERIAL AND METHODS: Data on patients with newly diagnosed EOAD (n = 453) and LOAD (n = 4599) was obtained from the Swedish dementia registry (SveDem). Logistic regression models were used to adjust the comparisons for the baseline confounders including gender, cognitive decline, and co-morbidity. RESULTS: The majority of EOAD and LOAD were in the mild stage of the disease when diagnosed. The majority of patients with EOAD went through an extended diagnostic work-up including more technical investigations as well as assessments by neuropsychologists and speech therapists than patients with LOAD. EOAD patients were treated with overall fewer medications but obtained treatment with cholinesterase inhibitors to a higher extent than those with LOAD, while there were no differences between the groups in antidepressant and antipsychotics use. CONCLUSIONS: There are differences between EOAD and LOAD in demographics, diagnostic work-up, and pharmacological treatment. Based on our findings, an extensive work-up should be recommended when EOAD is suspected.