COVID-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study.

Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in ECdelta (i.e., the difference in EC values pre- and post-COVID-19) and Volumetricdelta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that ECdelta significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetricdelta between groups (p = 0.041). The reduced ECdelta in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.

Brain Iron in signature regions relating to cognitive aging in older adults: the Taizhou Imaging Study.

BACKGROUND: Recent magnetic resonance imaging (MRI) studies have established that brain iron accumulation might accelerate cognitive decline in Alzheimer's disease (AD) patients. Both normal aging and AD are associated with cerebral atrophy in specific regions. However, no studies have investigated aging- and AD-selective iron deposition-related cognitive changes during normal aging. Here, we applied quantitative susceptibility mapping (QSM) to detect iron levels in cortical signature regions and assessed the relationships among iron, atrophy, and cognitive changes in older adults. METHODS: In this Taizhou Imaging Study, 770 older adults (mean age 62.0 ± 4.93 years, 57.5% women) underwent brain MRI to measure brain iron and atrophy, of whom 219 underwent neuropsychological tests nearly every 12 months for up to a mean follow-up of 2.68 years. Global cognition was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Domain-specific cognitive scores were obtained from MoCA subscore components. Regional analyses were performed for cortical regions and 2 signature regions where atrophy affected by aging and AD only: Aging (AG) -specific and AD signature meta-ROIs. The QSM and cortical morphometry means of the above ROIs were also computed. RESULTS: Significant associations were found between QSM levels and cognitive scores. In particular, after adjusting for cortical thickness of regions of interest (ROIs), participants in the upper tertile of the cortical and AG-specific signature QSM exhibited worse ZMMSE than did those in the lower tertile [ ß = -0.104, p = 0.026; ß = -0.118, p = 0.021, respectively]. Longitudinal analysis suggested that QSM values in all ROIs might predict decline in ZMoCA and key domains such as attention and visuospatial function (all p < 0.05). Furthermore, iron levels were negatively correlated with classic MRI markers of cortical atrophy (cortical thickness, gray matter volume, and local gyrification index) in total, AG-specific signature and AD signature regions (all p < 0.05). CONCLUSION: AG- and AD-selective iron deposition was associated with atrophy and cognitive decline in elderly people, highlighting its potential as a neuroimaging marker for cognitive aging.

Metabolic Syndrome Status Changes and Cognitive Functioning: Insights from the Lifelines Cohort Study.

BACKGROUND: Metabolic syndrome is associated with increased risk of dementia. Yet, findings on how longitudinal development of metabolic syndrome status affects cognition remain controversial. OBJECTIVES: This study examines whether individuals with different changes in metabolic syndrome status differ in cognitive functioning. Additionally, the prevalence of metabolic syndrome within the Lifelines population-based study is investigated. DESIGN: 14609 Lifelines participants (mean age 60.8, 56.4% women) were divided into four groups based on their metabolic syndrome status changes between 2007-2013 (1) and between 2014-2017 (2): without metabolic syndrome (N=10863; absent at 1 and 2), de novo metabolic syndrome (N=1340; absent at 1 and present at 2), remitting metabolic syndrome (N=825; present at 1 and absent at 2), and persistent metabolic syndrome (N=1581; present at 1 and 2). ANCOVA models were employed to assess group differences in psychomotor function, visual attention, visual learning, and working memory assessed using the Cogstate Brief Battery. RESULTS: Accounting for education, age, sex, and time between examinations, groups did not statistically differ in any of the four cognitive outcomes. The prevalence of metabolic syndrome within the Lifelines population increased with age and differed among men and women. CONCLUSION: Performance in psychomotor function, visual attention, visual learning, and working memory measured by the Cogstate Brief Battery did not differ between individuals with different changes in metabolic syndrome. The length of metabolic syndrome exposure was unknown, making our results exploratory and calling for future studies addressing this gap.

Continuous Associations between Remote Self-Administered Cognitive Measures and Imaging Biomarkers of Alzheimer's Disease.

BACKGROUND: Easily accessible and self-administered cognitive assessments that can aid early detection for Alzheimer's disease (AD) dementia risk are critical for timely intervention. OBJECTIVES/DESIGN: This cross-sectional study investigated continuous associations between Mayo Test Drive (MTD) - a remote, self-administered, multi-device compatible, web-based cognitive assessment - and AD-related imaging biomarkers. PARTICIPANTS/SETTING: 684 adults from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center participated (age=70.4±11.2, 49.7% female). Participants were predominantly cognitively unimpaired (CU; 94.0%). MEASUREMENTS: Participants completed (1) brain amyloid and tau PET scans and MRI scans for hippocampal volume (HV) and white matter hyperintensities (WMH); (2) MTD remotely, consisting of the Stricker Learning Span and Symbols Test which combine into an MTD composite; and (3) in-person neuropsychological assessment including measures to obtain Mayo Preclinical Alzheimer's disease Cognitive Composite (Mayo-PACC) and Global-z. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers and scores from remote and in-person cognitive measures. RESULTS: Lower performances on MTD were associated with greater amyloid, entorhinal tau, and global tau PET burden, lower HV, and higher WMH. Mayo-PACC and Global-z were associated with all imaging biomarkers except global tau PET burden. MCI/Dementia participants showed lower performance on all MTD measures compared to CU with large effect sizes (Hedge's g's=1.65-2.02), with similar findings for CU versus MCI only (Hedge's g's=1.46-1.83). CONCLUSION: MTD is associated with continuous measures of AD-related imaging biomarkers, demonstrating ability to detect subtle cognitive change using a brief, remote assessment in predominantly CU individuals and criterion validity for MTD.

Impact of APOE ε4 and ε2 on plasma neurofilament light chain and cognition in autosomal dominant Alzheimer's disease.

BACKGROUND: Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. METHODS: We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. RESULTS: Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18-75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. CONCLUSIONS: APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD.

[Dementia in Down syndrome]. / Nya forskningsrön om Alzheimers sjukdom vid Downs syndrom.

Individuals with Down syndrome (DS) have increased prevalence of Alzheimer's disease (AD) at an earlier age than the general population. Diagnostic tools that can improve diagnosis and treatment of dementia in DS and differentiate between dementia and intellectual disabilities include cognitive batteries, sensitive plasma assays, and PET imaging for amyloid and tau. Adults with DS should be included in memory clinic assessments and offered appropriate medications available to the general population with dementia. The Swedish dementia registry, SveDem, has added the diagnosis AD due to the genetic overload in DS, providing a national diagnostic registry for those with DS.

Validity of the Tablet-Based Digital Cognitive Test (SCST) in Identifying Different Degrees of Cognitive Impairment.

BACKGROUND: As society ages, the incidence of Alzheimer's disease and other dementias has surged, highlighting the importance of early dementia diagnosis. The Seoul Cognitive Status Test (SCST), a digital neuropsychological test, is designed for the early detection of cognitive impairment and has been standardized to establish reliability and validity. This study aims to verify whether the SCST effectively discriminates between groups based on three cognitive statuses (subjective cognitive decline [SCD], mild cognitive impairment [MCI], Dementia) in a large sample. We also seek to determine whether the SCST discriminates between individuals with three different cognitive statuses as defined by the Cognitive Dementia Rating (CDR). METHODS: We enrolled 254 participants from a dementia clinic who underwent a comprehensive neuropsychological battery (Seoul Neuropsychological Screening Battery-II) during the dementia evaluation by experienced neurologists (55 with SCD, 126 with MCI, 73 with dementia). In addition, the degree of cognitive decline in participants was classified by CDR level (186 with CDR 0.5, 52 with CDR 1, 15 with CDR 2). One-way analysis of variance was used to compare SCST scores according to each of the three cognitive status groups and CDR levels. RESULTS: The SCST total score, cognitive domain scores (attention, language, visuospatial function, memory, executive function), and most of the subtest scores decreased significantly in the order of SCD, MCI and dementia. Likewise, the differences in SCST scores between CDR levels were significant, particularly in distinguishing between CDR 0.5 and CDR 1. CONCLUSION: This study reaffirmed that the SCST can significantly discriminate between groups of individuals with SCD, MCI, and dementia based on a large sample. Furthermore, differences in SCT scores were found across the levels of CDR, confirming the clinical utility of the SCST. These findings suggest that the SCST is an efficient and useful neuropsychological test for the sensitive detection of early cognitive impairment.

[Post-stroke cognitive impairment in young patients]. / Postinsul'tnye kognitivnye narusheniya u molodykh patsientov.

OBJECTIVE: To evaluate the effect of Cortexin treatment on cognitive function and quality of life for young patients after ischemic stroke. MATERIAL AND METHODS: The open prospective observational study included 30 patients from 18 to 45 years old with confirmed ischemic stroke in the carotid blood supply who received a course of treatment with Cortexin. Before and after therapy, all patients in the study group underwent examination to assess their neuropsychological status (MoCA test), The Short Form-36 (SF-36) questionnaire was used to assess quality of life. The study results were processed using statistical analysis. RESULTS: Based on the results of neurocognitive tests, changes in indicators of neurodynamic, visual-spatial and mnestic functions were determined. Thus, in the beginning of the study the MoCA test scores were 25.1±1.4 points. Over time, there was an improvement mainly in the areas of attention, short-term memory, and multiple aspects of executive functions. However, statistical significance for MoCA was achieved by the end of the second course of treatment with Cortexin (visit 4) - 28.4±1.3 points. Delayed neuropsychological testing showed encouraging results - the achieved level of cognitive functioning was maintained (28.0±1.1). According to SF-36 questionnaire at the stage of inclusion in the observation, low results were noted, which indicated the negative impact of the underlying disease on the daily life of the patient who had suffered a stroke. Low quality of life scores persisted until the third visit; a significant improvement in SF-36 results was recorded at visit 4 and persisted with a positive trend at the fifth visit. CONCLUSION: Cortexin therapy has been shown to be effective, safe and well tolerated in young people with cognitive deficits in the poststroke period.

The association between physical activity and delayed neurocognitive recovery in elderly patients: a mediation analysis of pro-inflammatory cytokines.

BACKGROUND: Delayed neurocognitive recovery (dNCR) can result in unfavorable outcomes in elderly surgical patients. Physical activity (PA) has been shown to improve cognitive function, potentially by reducing systemic inflammatory responses. However, there is a lack of supportive data indicating whether PA has a protective effect against dNCR. AIMS: To examine the correlation between dNCR and PA, and to further analyze if pro-inflammatory cytokines mediate this relationship. METHODS: This study is a prospective nested case-control investigation of elderly patients who had knee replacement surgery. dNCR was defined as a decline in cognitive function compared with baseline by using a battery of neuropsychological tests. PA was assessed with the Physical Activity Scale for the Elderly (PASE). Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of IL-6, IL-1ß, and TNF-α. Multivariable logistic regression analysis was conducted to assess the association between PA and dNCR. Mediation analysis was employed to evaluate whether pro-inflammatory cytokines mediate the relationship between them. RESULTS: A cohort of 152 patients was included, resulting in an incidence rate of dNCR of 23.68%. PA was associated with dNCR after full adjustment [OR = 0.199, (95% CI, 0.061; 0.649), P = 0.007]. Mediation analysis showed that the IL-6 mediated the statistical association between PA and dNCR, with mediation proportions (%) of 77.68 (postoperative concentration of IL-6) or 27.58 (the absolute change in IL-6 before and after surgery). CONCLUSIONS: PA serves as a protective factor against dNCR, possibly through the reduction of pro-inflammatory cytokine concentrations. THE CHINESE CLINICAL TRAIL REGISTRY: : www.http://chictr.org.cn , Registration No. ChiCTR2300070834, Registration date: April 24, 2023.

Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study.

Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer's disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer's Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.

[Classification of mild cognitive impairment and normal cognition using an automated voice-based testing application].

AIM: An easy-to-use tool that can detect cognitive decline in mild cognitive impairment (MCI) is required. In this study, we aimed to construct a machine learning model that discriminates between MCI and cognitively normal (CN) individuals using spoken answers to questions and speech features. METHODS: Participants of ≥50 years of age were recruited from the Silver Human Resource Center. The Japanese Version of the Mini-Mental State Examination (MMSE-J) and Clinical Dementia Rating (CDR) were used to obtain clinical information. We developed a research application that presented neuropsychological tasks via automated voice guidance and collected the participants' spoken answers. The neuropsychological tasks included time orientation, sentence memory tasks (immediate and delayed recall), and digit span memory-updating tasks. Scores and speech features were obtained from spoken answers. Subsequently, a machine learning model was constructed to classify MCI and CN using various classifiers, combining the participants' age, gender, scores, and speech features. RESULTS: We obtained a model using Gaussian Naive Bayes, which classified typical MCI (CDR 0.5, MMSE ≤26) and typical CN (CDR 0 and MMSE ≥29) with an area under the curve (AUC) of 0.866 (accuracy 0.75, sensitivity 0.857, specificity 0.712). CONCLUSIONS: We built a machine learning model that can classify MCI and CN using spoken answers to neuropsychological questions. Easy-to-use MCI detection tools could be developed by incorporating this model into smartphone applications and telephone services.

The whole is greater than the sum of its parts: Using cognitive profiles to predict academic achievement.

BACKGROUND: Executive functions (EFs) are thought to work in concert to support academic skill. However, EFs are often examined independently, obscuring their symbiotic contribution. We examined the relationship between students' holistic EF profiles and their academic success. METHODS: We sampled over 1200 7-15 year old students from a diverse school district (16 % White; 32 % low income) in the United States. We used 9 EF assessments to construct cognitive profiles via self-organizing maps. We then related profiles to academic achievement scores from both laboratory-based assessments and state-administered standardized tests of reading and math. RESULTS: Six profiles differed in EF performance, but their differences in academic achievement did not suggest a linear relationship between individual EFs and academic skill. CONCLUSIONS: We show cognitive profiles based on individual strengths and weaknesses in EFs can reveal multiple cognitive paths to the same academic outcome.

Reliability of the assessment of the clinical dementia rating scale from the analysis of medical records in comparison with the reference method.

BACKGROUND: The Clinical Dementia Rating (CDR) scale allows to detect the presence of dementia and to assess its severity, however its evaluation requires a significant time (45 min). We evaluated the agreement between two methods of collection of the CDR: face-to-face interview or based on the information available in the patient's medical record. METHODS: The CLIMER study was conducted among patients attending a memory center. The CDR scale was evaluated during face-to-face interviews between neuropsychologists and patients and their caregivers and based on blind analysis of the information of the patients' medical record by neuropsychologists. The agreement of the CDR sum of boxes (CDR-SB), the 5-point scale CDR and the different domains of the CDR evaluated between the different methods was measured using intraclass correlation (ICC) coefficient, Bland and Altman method, and linearly weighted Kappa. RESULTS: The study included 139 patients (means ± SD age 80.1 ± 6, 58.3% women, 71.9% with dementia). The ICC for the CDR-SB score assessed by face-to-face and with all the information available in the patient's medical record was 0.95 (95% CI: 0.93-0.97). The mean difference between the CDR-SB score assessed by face-to-face and with the medical record was 0.098 ± 1.036, and 92.4% of the patients lay within the 95% limits of agreement. The ICC for the 5-point scale CDR assessed by face-to-face and with the patient's medical record was 0.92 (95% CI: 0.88-0.95) when all the available information of the patient's medical record was used. The linear weighted Kappa coefficients was 0.79 (95% CI: 0.68-0.91) for the 5-point scale CDR comparison between the two evaluation methods. The analysis by domain of the CDR showed ICC ranging from 0.65 to 0.91 depending of the domains and the methods of evaluation. CONCLUSION: This study showed an excellent level of agreement of the evaluation of the CDR- SB and the 5-point scale CDR when using all the information of the patient's medical record compared to the face-to-face interview. TRIAL REGISTRATION: https//clinicaltrials.gov/ct2/show/NCT04763941 Registration Date 02/17/2021.

Cognitive function in pituitary adenoma patients: A cross-sectional study.

Various factors may affect cognition in patients with pituitary adenoma, including size and extension of the tumor, degree of pituitary hormone deficiencies, and treatment of the tumor, most often being transsphenoidal surgery (TSS). The aim of this cross-sectional study was to evaluate cognitive function in patients with clinically significant pituitary adenoma and to identify factors influencing cognition. Sixty-eight patients with pituitary adenoma were included. Of these, 31 patients were evaluated before TSS and 37 patients 12 months following TSS. Cognitive function was evaluated by using the Repeatable Battery for the Assessment of Neuropsychological Status. Patients had lower mean scores on cognitive assessment compared to age-adjusted normative data. Variability in cognition, analyzed by linear regression analysis, was explained by sex, educational level, and self-perceived fatigue, but not by pituitary hormone deficiencies, diabetes insipidus, or surgical treatment. Our results are in line with previous findings, namely that pituitary adenoma affects cognition. To better evaluate the factors affecting cognition, longitudinal studies are recommended. Such studies would allow for within-individual comparisons, effectively controlling for the considerable influence of sex and education on test results.

Comparison of the Effect of Pump Flow Type (Pulsatile or Non-Pulsatile) on Postoperative Neurocognitive Functions in Coronary Artery Surgery.

INTRODUCTION: The effect of pump flow type on perfusion in coronary surgery using cardiopulmonary bypass (CPB) is discussed. We aimed to evaluate the effect of pump flow type on cognitive functions with neurocognitive function tests. METHODS: One hundred patients who underwent isolated coronary artery bypass surgery between November 2020 and July 2021 were divided into two equa groups. Groups were formed according to pump flow type pulsatile (Group 1) and non-pulsatile (Group 2). Clock drawing test (CDT) and standardized mini mental test (SMMT) were performed on the patients in both groups in the preoperative period, on the 1st preoperative day, and on the day before discharge. Neurocognitive effects were compared with all follow-up parameters. RESULTS: There was no difference between the groups in terms of demographic data and in terms of neurocognitive tests performed before the operation. SMMT on postoperative day 1 (Group I: 27.64 ± 1.05; Group II: 24.44 ± 1.64; P=0.001) and CDT (Group I: 5.4 ± 0.54; Group II: 4 .66 ± 0.52; P=0.001), and SMMT on the day before discharge (Group I: 27.92 ± 1.16; Group II: 24.66 ± 1.22; P=0.001) and CDT (Group I: 5 It was calculated as .66 ± 0.48; Group II: 5.44 ± 0.5; P=0.001). The duration of intensive care and hospitalization were higher in the non-pulsatile group. CONCLUSION: We think that the type of pump flow used in coronary artery bypass surgery using CPB is effective in terms of neurocognitive functions and that pulsatile flow makes positive contributions to this issue.

Assessment of long-term psychosocial outcomes in N-methyl-D-aspartate receptor encephalitis - the SAPIENCE study protocol.

BACKGROUND: N-methyl-D-aspartate-receptor (NMDAR) encephalitis is a rare neurological autoimmune disease with severe neuropsychiatric symptoms during the acute phase. Despite good functional neurological recovery, most patients continue to experience cognitive, psychiatric, psychological, and social impairments years after the acute phase. However, the precise nature and evolving patterns over time of these long-term consequences remain unclear, and their implications for the well-being and quality of life of predominantly young patients have yet to be thoroughly examined. METHODS: SAPIENCE is a European multi-center (n = 3) prospective observational cohort study studying the long-term cognitive, psychiatric, psychological, and social outcome in patients with NMDAR encephalitis. The study consists of three interconnected levels. Level 1 comprises a qualitative interview and focus groups with patients and their caregivers. Level 2 consists of a condensed form of the interview, standardized questionnaires, and a detailed neuropsychological examination of patients. Level 3 involves an online survey that will be open to patients world-wide and explores patient-reported outcomes (PROMs), and patient-reported experiences (PREMs) in association with clinical and cognitive outcomes. Levels 1 to 3 will progressively contribute developing of structured interviews, survey questions, and treatment guidelines by informing one another. DISCUSSION: SAPIENCE is an in-depth study of the long-term effects of NMDAR encephalitis and bridges the gap between standardized assessments and individual patient experiences, intending to improve patient care and to increase awareness of the psychosocial long-term consequences of the disease. Through collaboration of experts in clinical neurology and social and health psychology across Europe, SAPIENCE aims to create online assessment tools and formulate guidelines for patient-centered post-acute care that will help enhance the quality of life for patients and caregivers.

TRanscranial AlterNating current stimulation FOR patients with mild Alzheimer's Disease (TRANSFORM-AD): a randomized controlled clinical trial.

BACKGROUND: The mechanistic effects of gamma transcranial alternating current stimulation (tACS) on hippocampal gamma oscillation activity in Alzheimer's Disease (AD) remains unclear. This study aimed to clarify beneficial effects of gamma tACS on cognitive functioning in AD and to elucidate effects on hippocampal gamma oscillation activity. METHODS: This is a double-blind, randomized controlled single-center trial. Participants with mild AD were randomized to tACS group or sham group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 days. Cognitive functioning, structural magnetic resonance imaging (MRI), and simultaneous electroencephalography-functional MRI (EEG-fMRI) were evaluated at baseline, the end of the intervention and at 3-month follow-up from the randomization. RESULTS: A total of 46 patients were enrolled (23 in the tACS group, 23 in the sham group). There were no group differences in the change of the primary outcome, 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) score after intervention (group*time, p = 0.449). For secondary outcomes, compared to the control group, the intervention group showed significant improvement in MMSE (group*time, p = 0.041) and MoCA scores (non-parametric test, p = 0.025), which were not sustained at 3-month follow-up. We found an enhancement of theta-gamma coupling in the hippocampus, which was positively correlated with improvements of MMSE score and delayed recall. Additionally, fMRI revealed increase of the local neural activity in the hippocampus. CONCLUSION: Effects on the enhancement of theta-gamma coupling and neural activity within the hippocampus suggest mechanistic models for potential therapeutic mechanisms of tACS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03920826; Registration Date: 2019-04-19.

Correlation Between the Fractional Amplitude of Low-Frequency Fluctuation and Cognitive Defects in Alzheimer's Disease.

Background: The fractional amplitude of low-frequency fluctuations (fALFFs) can detect spontaneous brain activity. However, the association between abnormal brain activity and cognitive function, amyloid protein (Aß), and emotion in Alzheimer's disease (AD) patients remains unclear. Objective: This study aimed to survey alterations in fALFF in different frequency bands and the relationship between abnormal brain activity, depressive mood, and cognitive function to determine the potential mechanism of AD. Methods: We enrolled 34 AD patients and 32 healthy controls (HC). All the participants underwent resting-state magnetic resonance imaging, and slow-4 and slow-5 fALFF values were measured. Subsequently, the study determined the correlation of abnormal brain activity with mood and cognitive function scores. Results: AD patients revealed altered mfALFF values in the slow-5 and slow-4 bands. In the slow-4 band, the altered mfALFF regions were the right cerebellar crus I, right inferior frontal orbital gyrus (IFOG), right supramarginal gyrus, right precuneus, angular gyrus, and left middle cingulate gyrus. Elevated mfALFF values in the right IFOG were negatively associated with Montreal Cognitive Assessment scores, Boston Naming Test, and Aß1-42 levels. The mfALFF value of the AD group was lower than the HC group in the slow-5 band, primarily within the right inferior parietal lobule and right precuneus. Conclusions: Altered mfALFF values in AD patients are linked with cognitive dysfunction. Compared with HCs, Aß1-42 levels in AD patients are related to abnormal IFOG activity. Therefore, mfALFF could be a potential biomarker of AD.

Path Integration Detects Prodromal Alzheimer's Disease and Predicts Cognitive Decline.

Background: The entorhinal cortex is the very earliest involvement of Alzheimer's disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. Objective: We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Methods: Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI-). Results: Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI-. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Conclusions: Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12-15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD.

Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer's Disease: Clues from [18F]FDG PET Voxel-Wise Analysis.

Background: Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective: To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods: We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results: DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions: Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.