The Mixed Role of Sleep and Time of Day in Working Memory Performance of Older Adults with Mild Cognitive Impairment.

The importance of night sleep for maintaining good physical and cognitive health is well documented as well as its negative changes during aging. Since Mild Cognitive Impairment (MCI) patients bear additional disturbances in their sleep, this study aimed at examining whether there are potential mixed effects of sleep and afternoon time of day (ToD) on the storage, processing, and updating components of working memory (WM) capacity in older adults with MCI. In particular, the study compared patients' performance in the three working memory components, in two-time conditions: "early in the morning and after night sleep", and "in the afternoon and after many hours since night sleep". The Working Memory Capacity & Updating Task from the R4Alz battery was administered twice to 50 older adults diagnosed with MCI. The repeated measures analysis showed statistically significant higher performance in the morning condition for the working memory updating component (p < 0.001). Based on the findings, it seems that the afternoon ToD condition negatively affects tasks with high cognitive demands such as the WM updating task in MCI patients. These findings could determine the optimal timing for cognitive rehabilitation programs for MCI patients and the necessary sleep duration when they are engaged in cognitively demanding daily activities.

Surgicogenomics: The Role of Genetics in Deep Brain Stimulation in Parkinson's Disease Patients.

Parkinson's disease (PD) is the second-most common neurodegenerative disease, affecting 1% of people aged over 60. Currently, there is only symptomatic relief for PD patients, with levodopa being the gold standard of PD treatment. Deep brain stimulation (DBS) is a surgical option to treat PD patients. DBS improves motor functions and may also allow a significant reduction in dopaminergic medication. Important parameters for DBS outcomes are the disease duration, the age of disease onset, responsiveness to levodopa and cognitive or psychiatric comorbidities. Emerging data also highlight the need to carefully consider the genetic background in the preoperative assessment of PD patients who are candidates for DBS, as genetic factors may affect the effectiveness of DBS in these patients. This review article discusses the role of genetics in DBS for PD patients, in an attempt to better understand inter-individual variability in DBS response, control of motor PD symptoms and appearance of non-motor symptoms, especially cognitive decline.

The Reproductive Lifespan of Ovarian Follicle.

The functional unit within mammalian ovaries is the ovarian follicle. The development of the ovarian follicle is a lengthy process beginning from the time of embryogenesis, passing through multiple different stages of maturation. The purpose of this review is to describe the most basic events in the journey of ovarian follicle development, discussing the importance of ovarian reserve and highlighting the role of several factors that affect oocyte quality and quantity during aging including hormonal, genetic and epigenetic factors. Novel, promising anti-aging strategies are also discussed.

GLP-1 Receptor Agonists: A New Treatment in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases, including PD and type 2 diabetes mellitus (T2DM), suggesting a crucial interplay between the gut-brain axis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies is also very promising, enhancing the possibility of adding GLP1-R agonists to the current armamentarium of drugs available for PD treatment.

Cognitive Impairment in Neurological Diseases.

The complex link between cognitive impairment and neurological disorders underscores the intricacies of neurological sciences [...].

An Examination of the Motives for Attributing and Interpreting Deception in People with Amnestic Mild Cognitive Impairment.

The aim of the present study was to examine how a person with amnestic mild cognitive impairment perceives the phenomenon of deception. Amnestic mild cognitive impairment (aMCI) usually represents the prodromal phase of Alzheimer's disease (AD), with patients showing memory impairment but with normal activities of daily living. It was expected that aMCI patients would face difficulties in the attribution and interpretation of deceptive behavior due to deficits regarding their diagnosis. The main sample of the study consisted of 76 older adults who were patients of a daycare center diagnosed with aMCI. A sample of 55 highly educated young adults was also examined in the same experiment to qualitatively compare their performance with that of aMCI patients. Participants were assigned a scenario where a hypothetical partner (either a friend or a stranger) was engaged in a task in which the partner could lie to boost their earnings at the expense of the participant. The results showed that aMCI patients, even if they understood that something was going wrong, did not invest in interpretations of potential deception and tended to avoid searching for confirmative information related to the hypothetical lie of their partner compared to highly educated young adults. It seems that aMCI patients become somehow "innocent", and this is discussed in terms of cognitive impairment and/or socioemotional selectivity.

Association of Christian Orthodox Fasting with Sociodemographic, Anthropometric and Lifestyle Factors and Serum Biochemical Indices: A Cross-Sectional Study on Patients with Metabolic Diseases.

Christian Orthodox fasting, a type of time-restricted diet, which presents some similarities to the Mediterranean Diet, also including certain similarities with periodic vegetarianism or other time-restricted diets (e.g., intermittent diet and Ramadan fasting), may cumulatively be related to the same or even better beneficial healthy effects as these well-recognized dietary patterns. The present study aimed to explore the potential beneficial impact of Christian Orthodox fasting in patients with metabolic disorders, such as diabetes mellitus type 2, excessive obesity, hypothyroidism and osteoporosis. This was a cross-sectional study, including 135 patients with metabolic disorders (67 fasters and 68 non-fasters). The enrolled fasters had adapted Christian Orthodox fasting recommendations for at least twelve consecutive years or even from childhood. Relevant questionnaires were used to record sociodemographic, anthropometric and lifestyle data of the study population through face-to-face interviews between the enrolled individuals and qualified personnel during a non-fasting period. Christian Orthodox fasting patients showed a significantly and independently lower prevalence of overweight/obesity and abdominal obesity, which is highly associated with cardiometabolic disease risks, as well as a significantly and independently lower incidence of hypertension, including separately lower systolic and diastolic pressure, than non-fasting patients. Fasters also had a significantly and independently increased prevalence of an advanced educational level and no smoking history, as well as a lower incidence of sedentary behavior, and a trend of a correlation with reduced c-reactive protein (CRP), an indicator of inflammation, compared to non-fasters. Fasters also exhibited higher serum albumin and high-density lipoprotein (HDL) levels, as well as lower glucose levels, than non-fasters. This is one of the few cross-sectional studies demonstrating that Christian Orthodox fasting may promote metabolic health by improving several aspects of metabolic disorders, being associated with specific sociodemographic, anthropometric and lifestyle factors. Further studies conducted on larger sample sizes from different countries and different ethnicities that include Christian Orthodox fasters are recommended to evaluate the impact of long-term religious fasting effects on human health, either as a preventative factor reducing the risk of chronic diseases and especially cardiometabolic disorders or as a nutritional intervention to ameliorate symptom severity.

The Genetic Landscape of Sleep Disorders in Parkinson's Disease.

Parknson's disease (PD) is the second most common neurodegenerative disease, affecting 1% of people aged over 60. PD is characterized by a wide range of motor symptoms, however the clinical spectrum of PD covers a wide range of non-motor symptoms, as well. Sleep disorders are among the most common non-motor symptoms of PD, can occur at any stage of the disease and significantly affect quality of life. These include rapid eye movement sleep behavior disorder (RBD), restless legs syndrome (RLS), excessive daytime sleepiness (EDS), insomnia, obstructive sleep apnea (OSA) and circadian rhythm disturbances. One of the main challenges in PD research is identifying individuals during the prodromal phase of the disease. Combining genetic and prodromal data may aid the early identification of individuals susceptible to PD. This review highlights current data regarding the genetic component of sleep disorders in PD patients, focusing on genes that have currently been associated with this PD co-morbidity.

Current genetic data on depression and anxiety in Parkinson's disease patients.

Parkinson's disease (PD) is a common neurodegenerative disorder affecting about 1 % of the population over the age of 60 years. PD is characterized by a wide spectrum of symptomatology including not only motor symptoms but non-motor symptoms, as well. Depression is one of the most common non-motor manifestations, and the most frequent neuropsychiatric comorbidity in PD. Neuropsychiatric symptoms like depression and anxiety may precede the appearance of motor features, highlighting their importance in the early detection of the disease and its strategic management. This review discusses the possible genetic background of the development of these neuropsychiatric symptoms in PD patients analyzing current genetic data associated with this clinical entity.

Resilience in Mild Cognitive Impairment (MCI): Examining the Level and the Associations of Resilience with Subjective Wellbeing and Negative Affect in Early and Late-Stage MCI.

The current study examines the relationship between the cognitive state of participants [healthy-early mild cognitive impairment (MCI)-late MCI], some subjective wellbeing factors (positive emotions, engagement, positive relationships, meaning in life, accomplishment, and negative emotions), and negative psychological outcomes (depression, anxiety, stress), as well as psychological resilience. We expected that people with advanced MCI would perceive increased negative psychological outcomes, poorer psychological resilience, and lower levels of subjective wellbeing in contrast to early MCI and healthy participants. The study involved 30 healthy, 31 early, and 28 late MCI individuals. A series of questionnaires have been applied to assess the aforementioned constructs. To examine the hypotheses of the study, path analysis (EQS program) was applied. Results showed that early MCI persons maintain the same levels of positive emotions and feelings of accomplishment with healthy peers. Late-stage patients present those feelings in a diminished form, which adversely impacts psychological resilience. Individuals with early and late MCI exhibit negative emotions and stress that impact their resilience; however, those with early MCI experience greater stress, negative emotions, depression, and anxiety. These findings may be utilized to design psychological interventions for resilience enhancement and support brain health in elderly adults who are at risk of neurodegeneration.

Cognitive Impairment in MRI-Negative Epilepsy: Relationship between Neurophysiological and Neuropsychological Measures.

BACKGROUND: Epileptic patients frequently encounter cognitive impairment. Functions that are mostly affected involve memory, attention, and executive function; however, this is mainly dependent on the location of the epileptic activity. The aim of the present study is to assess cognitive functions in MRI-negative epilepsy patients by means of neurophysiological and neuropsychological measures, as well as study the concept of transient cognitive impairment in patients with epileptiform discharges during EEG acquisition. METHODS: The patients were enrolled from an outpatient Epilepsy/Clinical Neurophysiology clinic over a time period of 6 months. The study sample comprised 20 MRI-negative epilepsy patients (mean age ± standard deviation (SD), 30.3 ± 12.56 years; age range, 16-60 years; average disease duration, 13.95 years) and 10 age-matched controls (mean age ± SD, 24.22 ± 15.39 years), who were also education-matched (p > 0.05). Patients with epileptogenic lesions were excluded from the study. Informed consent was obtained from all subjects involved in the study. Auditory ERPs and the cognitive screening tool EpiTrack were administered to all subjects. RESULTS: Latencies of P300 and slow waves were prolonged in patients compared to controls (p < 0.05). The ASM load and patients' performance in the EpiTrack maze subtest were the most significant predictors of P300 latency. A decline in the memory, attention, and speed of information processing was observed in patients with cryptogenic epilepsy compared to age-matched controls, as reflected by P300 latency and EpiTrack scores.

Correlates of Functional Impairment in Patients with the Behavioral Variant of Frontotemporal Dementia: A PRISMA-Compliant Systematic Review.

The behavioral variant of frontotemporal dementia (bvFTD) has a devastating effect on multiple domains of daily living. The purpose of this PRISMA-compliant systematic review is to summarize the most important factors associated with functional impairment in this clinical group by critically analyzing the existing literature spanning the period from 2000 to 2023. To be included in the review, a study had to investigate any kind of correlates of functional status in bvFTD patients, using a previously validated instrument of functional assessment. Out of 40 articles assessed for eligibility, 18 met the inclusion criteria. The anatomical pattern of cerebral atrophy at baseline appeared to be the strongest predictor of the rate of functional decline over time, with the frontal-dominant anatomical subtype being associated with a faster rate of functional impairment. Additionally, executive dysfunction as well as apathy appeared to contribute significantly to functional disability in bvFTD patients. A comparative examination of bvFTD in relation to other clinical subtypes of FTD and other types of dementia in general suggests that it is the predominant atrophy of the frontal lobes along with the subsequent unique combination of cognitive and neuropsychiatric manifestations that account for the pronounced functional limitations observed in these individuals, even from the early stages of the disease.

Metacognitive Strategy Training Improves Decision-Making Abilities in Amnestic Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is associated with deficits in decision-making, which is of utmost importance for daily functioning. Despite evidence of declined decision-making abilities, research on decision-making interventions for MCI is scarce. As metacognition seems to play an important role in decision-making, the present study's aim was to examine whether a metacognitive strategy training can improve MCI patients' decision-making abilities. Older adults-patients of a day care center, diagnosed with amnestic MCI (n = 55) were randomly allocated in two groups, which were matched in gender, age and educational level. Τhe experimental group (n = 27, 18 women, mean age = 70.63, mean years of education = 13.44) received the metacognitive strategy training in parallel with the cognitive and physical training programs of the day care center, and the active control group (n = 28, 21 women, mean age = 70.86, mean years of education = 13.71) received only the cognitive and physical training of the center. The metacognitive strategy training included three online meeting sessions that took place once per week. The basis of the intervention was using analytical thinking, by answering four metacognitive-strategic questions, to make decisions about everyday situations. To examine the efficacy of the training, the ability to make decisions about everyday decision-making situations and the ability to apply decision rules were measured. Both groups participated in a pre-test session and a post-test session, while the experimental group also participated in a follow-up session, one month after the post-test session. The results showed that the experimental group improved its ability to decide, based on analytical thinking, about economic and healthcare-related everyday decision-making situations after they received the metacognitive strategy training. This improvement was maintained one month later. However, the ability to apply decision rules, which requires high cognitive effort, did not improve. In conclusion, it is important that some aspects of the analytical decision-making ability of amnestic MCI patients were improved due to the present metacognitive intervention.

Metacognitive Differences in Amnestic Mild Cognitive Impairment and Healthy Cognition: A Cross-Sectional Study Employing Online Measures.

This study aimed to examine metacognitive abilities in individuals diagnosed with amnestic mild cognitive impairment (aMCI) by using online metacognitive measures during cognitive tasks. A total of 100 participants were enrolled, all aged 50 or older (mean age = 61.98; SD = 6.27), and with a minimum of six years of education (mean = 14.95; SD = 2.94). The sample included 50 individuals with aMCI (34 females) and 50 healthy controls (HC) (33 females). Both groups underwent metacognitive versions of memory tasks (Doors and People) and executive functions tasks (Wisconsin Card Sorting Test). Metacognition was assessed through confidence ratings given after each answer (referred to as metacognitive monitoring) and the accuracy of the participants' decisions to include or exclude answers from their final scores (known as metacognitive control). The results showed that although individuals with aMCI were aware of their cognitive limitations-evidenced by their lower confidence ratings across all tasks-they still exhibited overconfidence relative to their actual performance. Moreover, they included a greater number of incorrect answers in their final scores compared to the healthy control group. These findings suggest that while individuals with aMCI retain some level of awareness, their self-evaluations appear to lack precision. This observation was consistent across both types of cognitive tasks. The results underscore the need for additional research to better understand metacognition in MCI as well as the interplay between metacognitive monitoring and control.

CSF Biomarkers in the Early Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is a rapidly growing disease that affects millions of people worldwide, therefore there is an urgent need for its early diagnosis and treatment. A huge amount of research studies are performed on possible accurate and reliable diagnostic biomarkers of AD. Due to its direct contact with extracellular space of the brain, cerebrospinal fluid (CSF) is the most useful biological fluid reflecting molecular events in the brain. Proteins and molecules that reflect the pathogenesis of the disease, e.g., neurodegeneration, accumulation of Abeta, hyperphosphorylation of tau protein and apoptosis may be used as biomarkers. The aim of the current manuscript is to present the most commonly used CSF biomarkers for AD as well as novel biomarkers. Three CSF biomarkers, namely total tau, phospho-tau and Abeta42, are believed to have the highest diagnostic accuracy for early AD diagnosis and the ability to predict AD development in mild cognitive impairment (MCI) patients. Moreover, other biomarkers such as soluble amyloid precursor protein (APP), apoptotic proteins, secretases and inflammatory and oxidation markers are believed to have increased future prospects.

Stress, Anxiety, and Depression Levels among University Students: Three Years from the Beginning of the Pandemic.

BACKGROUND: Three years after the outbreak of the COVID-19 pandemic, psychological distress among college students remains increased. This study assesses stress, anxiety, and depression levels among students of the Aristotle University of Thessaloniki by the end of the third year of the pandemic (November 2022), revealing demographic characteristics and probable stressors. METHODS: A questionnaire was distributed in November 2022 via the academic students' e-mails. The evaluation was performed with the DASS21 survey tool. The correlation analysis and the effect size calculation were performed with the t-test. RESULTS: The majority of participants were undergraduates, on their first or second academic year, female students (67%), age of 18 to 21, unmarried or single (91%), and vaccinated against COVID-19 infection (83.4%). Severely increased levels of stress, anxiety, and depression (21.3%, 23.3%, and 25.1%, respectively) were measured. The normal and mild levels of stress, anxiety, and depression were 64.0%, 66.5%, and 57.2%, respectively. Female and younger students were at a higher risk of extremely severe stress, anxiety and depression prevalence (ORs up to 2.07, p-Values < 0.00001). Participants who were receiving psychological or psychiatric treatment exhibited severe stress, anxiety, and depression levels (ORs above 2.9, p-Values < 0.00001). CONCLUSIONS: Despite the undeniable withdrawal of the COVID-19 pandemic, the community of the Aristotle University of Thessaloniki presents high stress, anxiety, and depression levels, similar to those reported during the first year of the pandemic (November 2020). Stressors and risk factors were according to the reported literature and previous studies on Greek students. Academic psychological support offices should consider the students' "profile" in order to evaluate properly the potential risk for emotional and psychological distress. Evidence suggest that new technology (virtual reality, tele-psychiatry or tele-support apps and sessions) should also be implemented in universities.

R4Alz-Revised: A Tool Able to Strongly Discriminate 'Subjective Cognitive Decline' from Healthy Cognition and 'Minor Neurocognitive Disorder'.

BACKGROUND: The diagnosis of the minor neurocognitive diseases in the clinical course of dementia before the clinical symptoms' appearance is the holy grail of neuropsychological research. The R4Alz battery is a novel and valid tool that was designed to assess cognitive control in people with minor cognitive disorders. The aim of the current study is the R4Alz battery's extension (namely R4Alz-R), enhanced by the design and administration of extra episodic memory tasks, as well as extra cognitive control tasks, towards improving the overall R4Alz discriminant validity. METHODS: The study comprised 80 people: (a) 20 Healthy adults (HC), (b) 29 people with Subjective Cognitive Decline (SCD), and (c) 31 people with Mild Cognitive Impairment (MCI). The groups differed in age and educational level. RESULTS: Updating, inhibition, attention switching, and cognitive flexibility tasks discriminated SCD from HC (p ≤ 0.003). Updating, switching, cognitive flexibility, and episodic memory tasks discriminated SCD from MCI (p ≤ 0.001). All the R4Alz-R's tasks discriminated HC from MCI (p ≤ 0.001). The R4Alz-R was free of age and educational level effects. The battery discriminated perfectly SCD from HC and HC from MCI (100% sensitivity-95% specificity and 100% sensitivity-90% specificity, respectively), whilst it discriminated excellently SCD from MCI (90.3% sensitivity-82.8% specificity). CONCLUSION: SCD seems to be stage a of neurodegeneration since it can be objectively evaluated via the R4Alz-R battery, which seems to be a useful tool for early diagnosis.

Biomarkers of therapeutic efficacy in adolescents and adults with 5q spinal muscular atrophy: a systematic review.

BACKGROUND: The therapeutic landscape of spinal muscular atrophy (SMA) was dramatically transformed with the introduction of three disease-modifying therapies (DMTs). A systematic review was performed to assess available evidence regarding quantitative therapeutic biomarkers used in SMA patients older than 11 years under treatment with DMTs. METHODS: Latest literature search in MEDLINE, EMBASE, Cochrane databases and gray literature resources was performed in June 2021. Studies reporting only motor function or muscle strength scales or pulmonary function tests were excluded. Primary outcome was the change from baseline score of any serum, cerebrospinal fluid (CSF) or neurophysiologic biomarker examined. RESULTS: Database and gray literature search yielded a total of 8050 records. We identified 14 records published from 2019 until 2021 examining 18 putative serum, CSF or neurophysiologic biomarkers along with routine CSF parameters in 295 SMA nusinersen-treated type 2-4 patients older than 11 years of age. There is evidence based on real-world observational studies suggesting that serum creatinine, creatine kinase activity levels along with CSF Αß42, glial fibrillary acidic protein concentration as well as ulnar compound motor action potential amplitude and single motor unit potential amplitude changes may depict therapeutic response in this population. CONCLUSION: This systematic review explored for the first-time biomarkers used to monitor therapeutic efficacy in SMA adolescents and adults treated with DMTs. Research in this area is in its early stages, and our systematic review can facilitate selection of quantitative therapeutic biomarkers that may be used as surrogate measures of treatment efficacy in future trials. PROTOCOL REGISTRATION: PROSPERO CRD42021245516.

Diabesity and Dietary Interventions: Evaluating the Impact of Mediterranean Diet and Other Types of Diets on Obesity and Type 2 Diabetes Management.

BACKGROUND: Diabesity, the intersection of obesity and diabetes, presents a global health crisis with profound implications. Addressing diabesity requires multifaceted strategies, with diet playing a pivotal role. Over the last 15 years, clinical studies have intensified their exploration of various dietary approaches in diabesity management. This literature review aims to synthesize findings from clinical studies conducted in the last 15 years, shedding light on the efficacy, mechanisms, and nuances of different diet types in diabesity management with special focus on the Mediterranean diet (MD). METHODS: Thorough research of academic databases yielded a collection of relevant clinical studies. These studies encompassed a range of dietary strategies, including the MD, low-carbohydrate diets, plant-based diets, high-protein diets, low-fat regimens, and intermittent fasting. Key findings, methodologies, and outcomes were thoroughly extracted and analyzed. RESULTS: The last 15 years have witnessed considerable improvements in recognizing the role of human nutritional habits in diabesity management. The MD appears to be the most well-recognized diet, exerting favorable effects against both obesity and diabetes. Low-carbohydrate diets were found to enhance glycemic regulation and decrease insulin resistance. Plant-based diets demonstrated potential benefits in weight management and cardiometabolic health. High-protein, low-fat dietary models exhibited positive effects on satiety and body weight decline. Intermittent fasting regimens also exerted metabolic improvements and body weight decline. Personalization emerged as a crucial factor in dietary recommendations. CONCLUSIONS: Clinical studies from the last 15 years underscore the intricate relationship between diet types and diabesity management. The above results contribute to an increasing body of evidence, emphasizing the need for tailored dietary approaches and especially the MD. Healthcare providers can utilize this knowledge to offer personalized dietary recommendations for individuals with diabesity, potentially curbing the rise of these twin epidemics and improving the well-being of affected populations.

Trajectories of Cognitive Impairment in Adults Bearing Vascular Risk Factors, with or without Diagnosis of Mild Cognitive Impairment: Findings from a Longitudinal Study Assessing Executive Functions, Memory, and Social Cognition.

With the aging of the population, a key concern of both societies and health services is to keep the population cognitively healthy until the maximum age limit. It is a well-known fact that vascular aging has a negative effect on the cognitive skills of adults, putting them at greater risk of developing dementia. The present longitudinal study aimed to evaluate the main dimensions of cognition in two pathological groups with different health profiles: a group of adults with vascular risk factors (VRF) (n = 35) and a group of adults with vascular risk factors and mild cognitive impairment (VRF + MCI) (n = 35). The two groups were matched in age, education, and gender. They were assessed with extensive neuropsychological testing at three different times with a distance of about 8 months between them; the assessment regarded executive functions, memory capacity, and Theory of Mind abilities. The analyses carried out were (a) mixed-measures ANOVA, (b) repeated measures ANOVA, and (c) ANOVA. The findings showed that global cognitive status and short-term memory are the main cognitive abilities that decline in community dwelling people bearing VRF. Hence, this group of adults should be examined at least every 2 years for this decline. As regards people with both VRF and MCI, it seems that the assessment of Theory of Mind abilities can better capture their further impairment. Global cognitive status, task/rule switching function, and long-term memory (delayed verbal recall) were revealed as the abilities that clearly and steadily differentiate VRF people with and without MCI.