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Theoretical accounts agree that German restrictive relative clauses (RCs) are integrated at the level of syntax as well as at the level of prosody (Brandt1990; Gärtner1998, 2002; Endriss and Gärtner2005; Catasso and Hinterhölzl2016; Sanfelici et al.2017) in both the default verb-final and the marked verb-second variant (referred to as iV2). Both variants are assumed to show the same prosodic pattern, i. e., prosodic integration into the main clause, and not unintegrated prosody, which would signal a sequence of two main clauses. To date strong empirical evidence for this close correspondence between prosody and syntax in RCs is missing. Findings regarding prosodic integration of verb-final RCs are not consistent, and research regarding the prosody of iV2 structures is very scarce. Using a delayed sentence-repetition task, our study investigated whether subordination is signaled by prosody in RCs in both the verb-final and the V2 variant in adults (n=21n=21). In addition, we asked whether young language learners (n=23n=23), who at the age of 3 have just started to produce embedded clauses, are already sensitive to this mapping. The adult responses showed significantly more patterns of prosodic integration than of prosodic non-integration in the V-final and the iV2 structures, with no difference between the two conditions. Notably, the child responses mirrored this adult behavior, showing significantly more patterns of prosodic integration than of prosodic non-integration in both V-final and iV2 structures. The findings regarding adults’ prosodic realizations provide novel empirical evidence for the claim that iV2 structures, just like verb-final RCs, show prosodic integration. Moreover, our study strongly suggests that subordination is signaled by prosody already by age 3 in both verb-final and V2 variants of RCs.

Using the standardized test LiSe-DaZ across four test rounds, we collected elicited production data from 22 typically developing early second language learners (eL2 TD) of German (mean age at T1: 3;7) and 11 older eL2 children with Specific Language Impairment (SLI) (mean age at T1: 7;1). Focusing on the relation between verb placement and verbal inflectional morphology two questions were addressed: Do eL2 children obey the ban on non-finite verbs in verb-second position (V2) in German, and do eL2 SLI children differ from their eL2 TD peers in their morpho-syntactic behavior? This is the first study on this issue to systematically differentiate between V2 and verb-final position (Vf) and between bare verb forms and infinitives, based on a large sample of elicited production data. Results show that from the first test round onwards verbal inflectional morphology and verb placement were strongly related in the TD and the SLI group. Bare verb forms occurred in V2 only and are argued to be finite; en-infinitives were restricted to Vf. We conclude that a) the restrictions for morphological markings are inextricably tied to specific syntactic positions, b) that this knowledge is still accessible when L2 acquisition starts around age 3, and c) that the ban on non-finite verbs in V2 is invulnerable in eL2 TD and in SLI, indicating that SLI is matter of severe delay.

Abstract Background Although the use of the Internet for health purposes has increased steadily in the last decade, only a few studies have explored the information provided by the websites of health institutions and no studies on the on-line activities of Italian hospitals have been performed to date. The aim of this study was to explore the characteristics of the contents and the user-orientation of Italian hospital websites. Methods The cross-sectional analysis considered all the Italian hospitals with a working website between December 2008 and February 2009. The websites were coded using an ad hoc Codebook, comprising eighty-nine items divided into five sections: technical characteristics, hospital information and facilities, medical services, interactive on-line services and external activities. We calculated a website evaluation score, on the basis of the items satisfied, to compare private (PrHs) and public hospitals, the latter divided into ones with their own website (PubHs-1) and ones with a section on the website of their Local Health Authority (PubHs-2). Lastly, a descriptive analysis of each item was carried out. Results Out of the 1265 hospitals in Italy, we found that 419 of the 652 public hospitals (64.3%) and 344 of the 613 PrHs (56.1%) had a working website (p = 0.01). The mean website evaluation score was 41.9 for PubHs-1, 21.2 for PubHs-2 and 30.8 for PrHs (p < 0.001). Only 5 hospitals out of 763 (< 1%) provided specific clinical performance indicators, such as the nosocomial infection rate or the surgical mortality rates. Regarding interactive on-line services, although nearly 80% of both public and private hospitals enabled users to communicate on-line, less than 18% allowed the reservation of medical services, and only 8 websites (1%) provided a health-care forum. Conclusions A high percentage of hospitals did not provide an official website and the majority of the websites found had several limitations. Very few hospitals provided information to increase the credibility of the hospital and user confidence in the institution. This study suggests that Italian hospital websites are more a source of information on admissions and services than a means of communication between user and hospital.

Caregivers for spouses with Alzheimer's disease and related dementias (ADRD) experience drastic changes in the marital relationship that may put them at risk for worsening well-being. Perceived partner responsiveness, or feeling cared for, understood, and appreciated by one's spouse, may help mitigate these effects. In this study, we investigated the associations between marital distress, perceived partner responsiveness, and psychological and physiological well-being indicators among ADRD spousal caregivers., Method: A sample of 161 caregivers provided blood samples and completed self-report measures of marital distress, perceived partner responsiveness, and depressive symptoms. We tested hypotheses in our sample cross-sectionally based on two theoretical frameworks., Results: Testing the marital discord model of depression, caregivers who reported greater marital distress also reported more depressive symptoms, and this association was stronger as participants reported lower perceived partner responsiveness. Caregivers who reported greater marital distress exhibited elevated proinflammatory cytokine production by in vitro lipopolysaccharide (LPS)-stimulated peripheral blood leukocytes at low levels of perceived partner responsiveness, but not mean or high levels. Testing the vulnerability-stress-adaptation model, caregivers who reported more depressive symptoms also reported greater marital distress. Further, caregivers who exhibited elevated LPS-stimulated proinflammatory cytokine production reported greater marital distress at mean and high levels of perceived partner responsiveness, but not low levels. These patterns of results held even when accounting for the dementia stage and reported hours of caregiving per day., Discussion: This study's findings contribute to the body of research examining interpersonal factors that shape health and well-being among the caregiver population., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 The Authors.)

Background: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive., Methods: Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses., Findings: From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P < 0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P < 0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P < 0.0001)., Interpretation: This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings., Funding: This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604)., Competing Interests: Declaration of interests Paul E. Schulz declares payment or honoraria for lectures on disease modifying therapies at Biogen Inc., lectures on psychosis in Parkinsons at Acadia Healthcare Company, Inc., and lectures on disease in modifying therapies at Eisai Co., Ltd. He declares payment for legal expert testimony unrelated to the International Committee of Medical Journal Editors (ICJME). He declares participation on a data safety monitoring board or advisory board at Eli Lilly and Company and Eisai Co., Ltd. unrelated to this study. Other authors declare no conflict of interests regarding any financial and personal relationships with other people or organisations that could inappropriately influence our work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with varied patient progression. We aim to test the hypothesis that AD patients can be categorized into subgroups based on differences in progression. We leveraged data from three randomized clinical trials (RCTs) to develop a knowledge-guided, deep temporal clustering (KG-DTC) framework for AD subtyping. This model combined autoencoders for contextual information capture, k-means clustering for representation formation, and clinical outcome classification for clinical knowledge integration. The derived representations, encompassing demographics, APOE genotype, cognitive assessments, brain volumes, and biomarkers, were clustered using the Gaussian Mixture Model to identify AD subtypes. Our novel KG-DTC framework was developed using placebo data from 2,087 AD patients across three solanezumab clinical trials (EXPEDITION, EXPEDITION2, and EXPEDITION3), achieving high performance in outcome prediction and clustering. The KG-DTC model demonstrated superior clustering structures, especially when combined with k-means clustering loss. External validation with independent clinical trial data showed consistent clustering results, with a 0.33 silhouette score for three clusters. The model's stability was confirmed through a leave-one-out approach, with an average adjusted Rand Index around 0.945. Three distinct AD subtypes were identified, each exhibiting unique patterns of cognitive function, neurodegeneration, and amyloid beta levels. Notably, Subtype 3 (S3) showed rapid cognitive decline across multiple clinical measures (e.g., 0.64 in S1 vs. -1.06 in S2 vs. 15.09 in S3 of average ADAS total change score, p<.001). This innovative approach offers promising insights for understanding variability in treatment outcomes and personalizing AD treatment strategies.

Objective: Complex diseases exhibit heterogeneous progression patterns, necessitating effective capture and clustering of longitudinal changes to identify disease subtypes for personalized treatments. However, existing studies often fail to design clustering-specific representations or neglect clinical outcomes, thereby limiting the interpretability and clinical utility., Method: We design a unified framework for subtyping longitudinal progressive diseases. We focus on effectively integrating all data from disease progressions and improving patient representation for downstream clustering. Specifically, we propose a clinical Outcome-Guided Deep Temporal Clustering (OG-DTC) that generates representations informed by clustering and clinical outcomes. A GRU-based seq2seq architecture captures the temporal dynamics, and the model integrates k-means clustering and outcome regression to facilitate the formation of clustering structures and the integration of clinical outcomes. The learned representations are clustered using a Gaussian mixture model to identify distinct subtypes. The clustering results are extensively validated through reproducibility, stability, and significance tests., Results: We demonstrated the efficacy of our framework by applying it to three Alzheimer's Disease (AD) clinical trials. Through the AD case study, we identified three distinct subtypes with unique patterns associated with differentiated clinical declines across multiple measures. The ablation study revealed the contributions of each component in the model and showed that jointly optimizing the full model improved patient representations for clustering. Extensive validations showed that the derived clustering is reproducible, stable, and significant., Conclusion: Our temporal clustering framework can derive robust clustering applicable for subtyping longitudinal progressive diseases and has the potential to account for subtype variability in clinical outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul E. Schulz is funded by the McCord Family Professorship in Neurology, the Umphrey Family Professorship in Neurodegenerative Disorders, multiple NIH grants, several foundation grants, and contracts with multiple pharmaceutical companies related to the performance of clinical trials. He serves as a consultant and/or speaker for Eli Lilly, Eisai, and Acadia Pharmaceuticals. There is no perceived financial conflict between these activities and this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health., Methods: Spousal caregivers of individuals with Alzheimer's disease and related dementias ( N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. Multiple and mixed linear regressions were used to test the relationship between mitochondrial biology and well-being., Results: Spare respiratory capacity ( b = 12.76, confidence interval [CI] = 5.23-20.28, p = .001), maximum respiratory capacity ( b = 8.45, CI = 4.54-12.35, p < .0001), and ATP-linked respiration ( b = 10.11, CI = 5.05-15.18, p = .0001) were positively associated with physical functioning. At average ( b = -2.23, CI = -3.64 to -0.82, p = .002) and below average ( b = -4.96, CI = -7.22 to 2.70, p < .0001) levels of spare respiratory capacity, caregiver burden was negatively associated with daily positive affect. At above average levels of spare respiratory capacity, caregiver burden was not associated with positive affect ( p = .65)., Conclusions: Findings suggest that higher mitochondrial respiratory capacity is associated with better psychological and physical health-a pattern consistent with related research. These findings provide some of the earliest evidence that cellular bioenergetics are related to well-being., (Copyright © 2024 by the American Psychosomatic Society.)

Sporadic early-onset Alzheimer's disease (sEOAD) represents a significant but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis- regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered., (© 2024. The Author(s).)

Background: Alzheimer's Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas., Method: To better understand how AD-related data elements in these resources are interoperable with each other, we leverage different representation models to map data elements from different resources: NACC to ADNI, NACC to NIH CDE, and ADNI to NIH CDE. We explore bag-of-words based and word embeddings based models (Word2Vec and BioWordVec) to perform the data element mappings in these resources., Results: The data dictionaries downloaded on November 23, 2021 contain 1,195 data elements in NACC, 13,918 in ADNI, and 27,213 in NIH CDE Repository. Data element preprocessing reduced the numbers of NACC and ADNI data elements for mapping to 1,099 and 7,584 respectively. Manual evaluation of the mapping results showed that the bag-of-words based approach achieved the best precision, while the BioWordVec based approach attained the best recall. In total, the three approaches mapped 175 out of 1,099 (15.92%) NACC data elements to ADNI; 107 out of 1,099 (9.74%) NACC data elements to NIH CDE; and 171 out of 7,584 (2.25%) ADNI data elements to NIH CDE., Conclusions: The bag-of-words based and word embeddings based approaches showed promise in mapping AD-related data elements between different resources. Although the mapping approaches need further improvement, our result indicates that there is a critical need to standardize CDEs across these valuable AD research resources in order to maximize the discoveries regarding AD pathophysiology, diagnosis, and treatment that can be gleaned from them., (© 2024. The Author(s).)

The rate of progression of Alzheimer's disease (AD) differs dramatically between patients. Identifying the most is critical because when their numbers differ between treated and control groups, it distorts the outcome, making it impossible to tell whether the treatment was beneficial. Much recent effort, then, has gone into identifying RPs. We pooled de-identified placebo-arm data of three randomized controlled trials (RCTs), EXPEDITION, EXPEDITION 2, and EXPEDITION 3, provided by Eli Lilly and Company. After processing, the data included 1603 mild-to-moderate AD patients with 80 weeks of longitudinal observations on neurocognitive health, brain volumes, and amyloid-beta (Aβ) levels. RPs were defined by changes in four neurocognitive/functional health measures. We built deep learning models using recurrent neural networks with attention mechanisms to predict RPs by week 80 based on varying observation periods from baseline (e.g., 12, 28 weeks). Feature importance scores for RP prediction were computed and temporal feature trajectories were compared between RPs and non-RPs. Our evaluation and analysis focused on models trained with 28 weeks of observation. The models achieved robust internal validation area under the receiver operating characteristic (AUROCs) ranging from 0.80 (95% CI 0.79-0.82) to 0.82 (0.81-0.83), and the area under the precision-recall curve (AUPRCs) from 0.34 (0.32-0.36) to 0.46 (0.44-0.49). External validation AUROCs ranged from 0.75 (0.70-0.81) to 0.83 (0.82-0.84) and AUPRCs from 0.27 (0.25-0.29) to 0.45 (0.43-0.48). Aβ plasma levels, regional brain volumetry, and neurocognitive health emerged as important factors for the model prediction. In addition, the trajectories were stratified between predicted RPs and non-RPs based on factors such as ventricular volumes and neurocognitive domains. Our findings will greatly aid clinical trialists in designing tests for new medications, representing a key step toward identifying effective new AD therapies., Competing Interests: PS is funded by the McCord Family Professorship in Neurology, the Umphrey Family Professorship in Neurodegenerative Disorders, multiple NIH grants and several foundation grants (1R01AG080137-01A1, 1RF1AG072491-01, 1R03AG077191-01, 1U01AG079847-01A1, 5R01AG66749-03, 1R01AG083039-01, 5R01AG067498-03, 1RF1AG055053-0A1, 1R01AG062690-01, 1R01AG059321-01A1, 1R01DE07027, 1R01AG082721-01, 2124789, AGT002985, AGT008724, AGT009122), and contracts with multiple pharmaceutical companies related to the performance of clinical trials (ALZ-80-AD301-AGT005383, AGT004414, AGT003423, AGT003882, AGT006620, AGT005768, AGT004564, AGT009188, AGT006056, AGT006764, AGT008197, AGT010139, AGT011949). He serves as a consultant and speaker for Eli Lilly, and Acadia Pharmaceuticals. No other authors have declarations to disclose., (Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter-individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD., Methods: Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were analyzed blinded. The presence of prions was detected by a modified version of the PMCA technology, specifically optimized for high sensitive detection of sCJD prions., Results: The PMCA assay was first optimized to detect low quantities of prions in diluted brain homogenates from patients affected by all subtypes of sCJD spiked into healthy urine. Twenty-nine of the 81 patients affected by sCJD analyzed in this study were positive by PMCA testing, whereas none of the 160 controls showed any signal. These results indicate a 36% sensitivity and 100% specificity. The subtypes with the highest positivity rate were VV1 and VV2, which combined account for about 15-20% of all sCJD cases, and no detection was observed in MV1 and MM2., Interpretation: Our findings indicate that potentially infectious prions are secreted in urine of some sCJD patients, suggesting a possible risk for inter-individual transmission. Prion detection in urine might be used as a noninvasive preliminary screening test to detect sCJD., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Mexico has a rapidly aging population at risk for cognitive impairment. Social and leisure activities may protect against cognitive decline in older adults. The benefits of these behaviors may vary by patterns of cognitive impairment. The objectives of this study were to identify latent states of cognitive functioning, model the incidence of transitions between these states, and investigate how social and leisure activities were associated with state transitions over a 6-year period in Mexican adults aged 60 and older., Methods: We performed latent transition analyses to identify distinct cognitive statuses in the 2012 and 2018 waves of the Mexican Health and Aging Study (N = 9,091). We examined the transition probabilities between these states and their associations with social and leisure activities., Results: We identified 4 cognitive statuses at baseline: normal cognition (43%), temporal disorientation (30%), perceptual-motor function impairment (7%), and learning and memory impairment (20%). Various social and leisure activities were associated with reduced odds of death and disadvantageous cognitive transitions, as well as increased odds of beneficial transitions., Discussion: Mapping the effects of popular social and leisure activities onto common patterns in cognitive functioning may inform the development of more enjoyable and effective health-protective behavioral interventions., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the United States, the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) are two major data sharing resources for Alzheimer's Disease (AD) research. NACC and ADNI strive to make their data more FAIR (findable, interoperable, accessible and reusable) for the broader research community. However, there is limited work harmonizing and supporting cross-cohort interoperability of the two resources., Method: In this paper, we leverage an ontology-based approach to harmonize data elements in the two resources and develop a web-based query system to search patient cohorts across the two resources. We first mapped data elements across NACC and ADNI, and performed value harmonization for the mapped data elements with inconsistent permissible values. Then we built an Alzheimer's Disease Data Element Ontology (ADEO) to model the mapped data elements in NACC and ADNI. We further developed a prototype cross-cohort query system to search patient cohorts across NACC and ADNI., Results: After manual review, we found 172 mappings between NACC and ADNI. These 172 mappings were further used to construct common concepts in ADEO. Our data element mapping and harmonization resulted in five files storing common concepts, variables in NACC and ADNI, mappings between variables and common concepts, permissible values of categorical type data elements, and coding inconsistency harmonization, respectively. Our cross-cohort query system consists of three core architectural elements: a web-based interface, an advanced query engine, and a backend MongoDB database., Conclusions: In this work, ADEO has been specifically designed to facilitate data harmonization and cross-cohort query of NACC and ADNI data resources. Although our prototype cross-cohort query system was developed for exploring NACC and ADNI, its backend and frontend framework has been designed and implemented to be generally applicable to other domains for querying patient cohorts from multiple heterogeneous data sources., (© 2023. The Author(s).)

A growing literature supports a protective association between vaccines targeting an array of pathogens (e.g., influenza, pneumococcus, herpes zoster) and the risk of Alzheimer disease (AD). This article discusses the potential underlying mechanisms for this apparent protective effect of immunizations against infectious pathogens on the risk of AD; explores the basic and pharmacoepidemiologic evidence for this association, with particular attention paid to important methodological variations among the epidemiologic studies; and reviews the remaining uncertainties regarding the effects of anti-pathogen vaccines on Alzheimer disease and all-cause dementia, with recommendations for future directions to address those uncertainties.

Background: Several previous studies showed that patients who received angiotensin II-stimulating antihypertensive medications had a lower incident dementia rate than those angiotensin II-inhibiting antihypertensive users, but no study has been conducted in long-term cancer survivors., Objectives: To determine the risk of Alzheimer's disease (AD) and related dementia (ADRD) associated with the types of antihypertensive medications in a large cohort of survivors with colorectal cancer in 2007-2015 with follow-up from 2007 to 2016., Methods: We identified 58,699 men and women with colorectal cancer aged 65 or older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in 17 SEER areas in 2007-2015 with follow-up to 2016, who were free of any diagnosed ADRD at the baseline (within 12 months prior to and 12 months after the date of diagnosis for colorectal cancer). All patients who were defined as having hypertension by ICD diagnosis code or received antihypertensive drugs during this baseline 2-year period were classified into 6 groups based on whether they received angiotensin-II stimulating or inhibiting antihypertensive drugs., Results: Crude cumulative incidence rates of AD and ADRD were similar between those who received angiotensin II-stimulating antihypertensive medications (4.3% and 21.7%) and those receiving angiotensin II-inhibiting antihypertensive medications (4.2% and 23.5%). As compared to patients who received angiotensin II-stimulating antihypertensive drugs, those who received angiotensin II-inhibiting antihypertensives were significantly more likely to develop AD (adjusted hazard ratio: 1.15, 95% CI: 1.01-1.32), vascular dementias (1.27, 1.06-1.53), and total ADRD (1.21, 1.14-1.28) after adjusting for potential confounders. These results remained similar after adjusting for medication adherence and considering death as a competing risk., Conclusions: The risk of AD and ADRD in patients with hypertension who received angiotensin II-inhibiting antihypertensive medications was higher than in those receiving angiotensin II-stimulating antihypertensive drugs in patients with colorectal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Du, Li and Schulz.)

Amyloid-related imaging abnormalities (ARIA) is a term introduced in 2010 to encompass a spectrum of MRI findings observed in patients receiving investigational anti-amyloid beta (Aβ) immunotherapies for Alzheimer disease (AD). The entity can be broadly categorized into ARIA characterized by edema and effusion (ARIA-E) and ARIA characterized by microhemorrhages and superficial siderosis (ARIA-H). ARIA typically occurs early in the treatment course and has a higher incidence in patients who are apolipoprotein E ε4 allele carriers. ARIA-E has an additional dose dependence, with higher incidence in patients receiving higher doses of anti-Aβ immuno-therapies. ARIA is often asymptomatic and self-resolving. The recognition of ARIA has implications for patient selection and monitoring for Aβ immunotherapies, and its development can potentially lead to a pause or discontinuation of therapy. The FDA's first approval of an Aβ-targeting monoclonal antibody for AD treatment in 2021 will lead to such therapy's expanded use beyond the clinical trial setting and to radiologists more commonly encountering ARIA in clinical practice. This review explores the theorized pathophysiologic mechanisms for ARIA, describes the MRI findings and grading schemes for ARIA-E and AREA-H, and summarizes relevant Aβ immunotherapies. Through such knowledge, radiologists can optimally impact the management of patients receiving targeted AD therapies.

Although transcranial direct current stimulation (tDCS) is emerging as a convenient pain relief modality for several chronic pain conditions, its feasibility, acceptability, and preliminary efficacy on pain in patients with Alzheimer's disease and related dementias (ADRD) have not been investigated. The purpose of this pilot study was to assess the feasibility, acceptability, and preliminary efficacy of 5, 20-min home-based tDCS sessions on chronic pain in older adults with ADRD. We randomly assigned 40 participants to active ( n = 20) or sham ( n = 20) tDCS. Clinical pain intensity was assessed using a numeric rating scale (NRS) with patients and a proxy measure (MOBID-2) with caregivers. We observed significant reductions of pain intensity for patients in the active tDCS group as reflected by both pain measures (NRS: Cohen's d = 0.69, p -value = 0.02); MOBID-2: Cohen's d = 1.12, p -value = 0.001). Moreover, we found home-based tDCS was feasible and acceptable intervention approach for pain in ADRD. These findings suggest the need for large-scale randomized controlled studies with larger samples and extended versions of tDCS to relieve chronic pain on the long-term for individuals with ADRD.

Background: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings., Objective: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores., Methods: Visits between 2004-2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50-85- year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer's disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables., Results: The mean age of the sample set (n = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0-4 YOE (n = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety., Conclusion: The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0-4 YOE.

Background: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias., Objective: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus., Methods: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD., Results: For the Tdap/Td vaccine, 7.2% (n = 8,370) of vaccinated patients and 10.2% (n = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68-0.72) and ARR was 0.03 (95% CI, 0.02-0.03). For the HZ vaccine, 8.1% (n = 16,106) of vaccinated patients and 10.7% (n = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73-0.76) and ARR was 0.02 (95% CI, 0.02-0.02). For the pneumococcal vaccine, 7.92% (n = 20,583) of vaccinated patients and 10.9% (n = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71-0.74) and ARR was 0.02 (95% CI, 0.02-0.03)., Conclusion: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

This study examines CTE-related knowledge and information-seeking behaviors of caregivers of persons who are at high risk of CTE. Online survey responses were collected from 64 females, ages 18-74, who were married to former college, semiprofessional, or professional football players and were fluent in English. Ranging from 0 to 18, a score was calculated to represent level of CTE knowledge. Participants were classified into groups based on their spouse's reported symptoms and diagnosis. Approximately 87% of participants reported that their spouses have been diagnosed with a football-related concussion and were significantly more likely to seek out information from a healthcare provider, a scientific journal or article, and post/comment on social media compared to spouses of symptomatic/undiagnosed and non-symptomatic groups. Participants reported 77% of available information as probably true, with social media thought to be highly credible. Highest levels of dissatisfaction were reported for league-sponsored websites and physicians/healthcare providers. Although the majority of participants sought CTE related information on regular or social media, and the internet, information sources differed amongst the groups. These findings may help healthcare providers and organizations develop more effective health-related educational programs that will help the wives make informed decisions regarding care for their spouses with respect to CTE.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has emerged as a quite efficacious therapy for treatment resistant depression (TRD), leading to rapid antidepressant effects. In this study, we complete our assessment of our first 10 enrolled patients throughout one year post-implantation, showing sustained antidepressant effect up to 5 years. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area. An insertional effect was seen during the 4-week sham stimulation phase (29% mean MADRS reduction, p = 0.02). However, after 2 weeks of initiating stimulation, five patients met response criteria (47% mean MADRS reduction, p < 0.001). One patient withdrew from study participation at 6 weeks. Twelve weeks after initiating stimulation, six of nine remaining patients had a >50% decrease in MADRS scores relative to baseline (52% mean MADRS reduction, p = 0.001); these same six patients continued to meet response criteria at 52 weeks (63% overall mean MADRS reduction, p < 0.001). Four of five patients who achieved the 5-year time point analysis continued to be responders (81% mean MADRS reduction, p < 0.001). Evaluation of modulated fiber tracts reveals significant common prefrontal/orbitofrontal connectivity to the target region in all responders. Key points learned from this study that we can incorporate in future protocols to better elucidate the effect of this therapy are a longer blinded sham stimulation phase and use of scheduled discontinuation concomitant with functional imaging., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Alzheimer's disease and related dementias (ADRD) is a multifactorial disease that involves several different etiologic mechanisms with various comorbidities. There is also significant heterogeneity in the prevalence of ADRD across diverse demographics groups. Association studies on such heterogeneous comorbidity risk factors are limited in their ability to determine causation. We aim to compare counterfactual treatment effects of various comorbidity in ADRD in different racial groups (African Americans and Caucasians). We used 138,026 ADRD and 1:1 matched older adults without ADRD from nationwide electronic health records, which extensively cover a large population's long medical history in breadth. We matched African Americans and Caucasians based on age, sex, and high-risk comorbidities (hypertension, diabetes, obesity, vascular disease, heart disease, and head injury) to build two comparable cohorts. We derived a Bayesian network of 100 comorbidities and selected comorbidities with potential causal effect to ADRD. We estimated the average treatment effect (ATE) of the selected comorbidities on ADRD using inverse probability of treatment weighting. Late effects of cerebrovascular disease significantly predisposed older African Americans (ATE = 0.2715) to ADRD, but not in the Caucasian counterparts; depression significantly predisposed older Caucasian counterparts (ATE = 0.1560) to ADRD, but not in the African Americans. Our extensive counterfactual analysis using a nationwide EHR discovered different comorbidities that predispose older African Americans to ADRD compared to Caucasian counterparts. Despite the noisy and incomplete nature of the real-world data, the counterfactual analysis on the comorbidity risk factors can be a valuable tool to support the risk factor exposure studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Disordered sleep is associated with poor cognitive function and cognitive decline. However, little is known regarding the association of sleep-related factors with cognitive function in underrepresented cohorts such as the Hispanic/Latino population. Leveraging the National Sleep Research Resource, one of the most comprehensive collections of sleep studies, we identified a Hispanic/Latino cohort of 1,031 lower cognitive function cases and 2,062 normal controls. We developed a novel dual random forest (DRF) approach to discriminate cases against controls for estimating the potential impact of sleep-related variables related to the decline of cognitive function. Several important sleep-related factors were identified which may be associated with cognitive function in the Hispanics/Latinos cohort, such as heart rate, sleep duration, trouble falling asleep, and apnea/hypopnea index, which are consistent with existing research findings. Our DRF approach is effective in validating the association between disordered sleep and cognitive decline in this unique minority population., (©2018 AMIA - All rights reserved.)

There is growing evidence for neuronal hyperexcitability in Alzheimer's disease. Hyperexcitability is associated with an increase in epileptiform activity and the disruption of inhibitory activity of interneurons. Interneurons fire at a high rate and are frequently associated with high-frequency oscillations in the gamma frequency band (30-150 Hz). It is unclear how hyperexcitability affects the organization of functional brain networks. A sample of 63 amnestic mild cognitive impairment patients underwent a magnetoencephalography resting-state recording with eyes closed. Twenty (31.75%) mild cognitive impairment patients had epileptiform activity. A cluster-based analysis of the magnetoencephalography functional connectivity revealed a region within the right temporal cortex whose global connectivity in the gamma frequency band was significantly reduced in patients with epileptiform activity relative to those without epileptiform activity. A subsequent seed-based analysis showed that this was largely due to weaker gamma band connectivity of this region with ipsilateral frontal and medial regions, and the upper precuneus area. In addition, this reduced functional connectivity was associated with higher grey matter atrophy across several cortical regions in the patients with epileptiform activity. These functional network disruptions and changes in brain physiology and morphology have important clinical implications as they may contribute to cognitive decline in mild cognitive impairment and Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized., Objective: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database., Methods: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up., Results: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu-vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29-48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59-0.61) and ARR was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4., Conclusion: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.

Background: No study on the long-term incidence of Alzheimer's disease (AD) and related dementias (ADRD) has been reported in women with breast cancer by vascular diseases., Objective: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in women with breast cancer., Methods: Study identified 246,686 women diagnosed with breast cancer at age≥65 years in 1991-2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Women were free of ADRD at the time of cancer diagnosis and followed from 1991 to 2016., Results: Cumulative incidence of AD over 26 years of follow-up varied from 10.7% to 13.6% by CVD, stroke, hypertension, and diabetes. Cumulative incidence of ADRD was higher in those with CVD (40.75%) versus no-CVD (31.32%), stroke (40.24%) versus no-stroke (31.34%), hypertension (33.06%) versus no-hypertension (30.47%), and diabetes (33.38%) versus no-diabetes (31.77%). After adjusting for confounders, those with CVD (hazard ratio:1.30, 95% CI: 1.27-1.33), stroke (1.50,1.47-1.54), hypertension (1.08,1.06-1.09), and diabetes (1.26,1.24-1.29) had significantly higher risks of developing ADRD. Women aged 80-84, and≥85 had 5- and 7-fold higher risks of AD than those aged 65-69. As compared to white women, black women had a significantly higher risk of AD (1.21, 1.16-1.27), whereas Asians/Pacific-Islanders had a significantly lower risk of AD (0.77, 0.71-0.83)., Conclusion: In women with breast cancer, CVD, stroke, hypertension, and diabetes were associated with a significantly higher risk of developing any ADRD combined. The risk of ADRD was higher in black women and lower in Asian/Pacific-Islanders than white women.

Background: Long term risk of Alzheimer's disease (AD) and related dementias (ADRD) associated with vascular diseases in people with colorectal cancer is unknown., Objective: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in a cohort of patients with colorectal cancer., Methods: This retrospective cohort study consisted of 210,809 patients diagnosed with colorectal cancer at age≥65 years in 1991-2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with follow-up from 1991-2016, who were free of any ADRD at the baseline (<12 months prior to or < 30 days after the date of cancer diagnosis)., Results: The crude 26-year cumulative incidence of total ADRD in men and women with colorectal cancer was higher in those with versus without CVD (31.92% versus 28.12%), with versus without stroke (39.82% versus 26.39%), with versus without hypertension (31.88% versus 24.88%), and with versus without diabetes (32.01% versus 27.66%). After adjusting for socio-demographic and tumor factors, the risk of developing ADRD was significantly higher in patients with CVD (adjusted hazard ratio: 1.17, 95% confidence intervals: 1.14-1.20), stroke (1.65, 1.62-1.68), hypertension (1.07, 1.05-1.09), and diabetes (1.26, 1.24-1.29) versus persons without. For those with 1, 2, 3 and 4 vascular diseases present versus absent, the risk of AD increased from 1.12 (1.07-1.16) to 1.31 (1.25-1.36), 1.66 (1.57-1.75), and 2.03 (1.82-2.27)., Conclusion: In older patients with colorectal cancer, a significant dose-response relationship was observed between an increasing number of these vascular diseases and the risk of all types of dementia.

Alzheimer's disease (AD) is a progressive form of dementia marked by cognitive and memory deficits, estimated to affect ∼5.7 million Americans and account for ∼$277 billion in medical costs in 2018. Depression is one of the most common neuropsychiatric disorders that accompanies AD, appearing in up to 50% of patients. AD and Depression commonly occur together with overlapped symptoms (depressed mood, anxiety, apathy, and cognitive deficits.) and pose diagnostic challenges early in the clinical presentation. Understanding their relationship is critical for advancing treatment strategies, but the interaction remains poorly studied and thus often leads to a rapid decline in functioning. Modern systems and control theory offer a wealth of novel methods and concepts to assess the important property of a complex control system, such as the brain. In particular, the brain controllability analysis captures the ability to guide the brain behavior from an initial state (healthy or diseased) to a desired state in finite time, with suitable choice of inputs such as external or internal stimuli. The controllability property of the brain's dynamic processes will advance our understanding of the emergence and progression of brain diseases and thus helpful in the early diagnosis and novel treatment approaches. This study aims to assess the brain controllability differences between mild cognitive impairment (MCI), as prodromal AD, and Depression. This study used diffusion tensor imaging (DTI) data from 60 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 15 cognitively normal subjects and 45 patients with MCI, including 15 early MCI (EMCI) patients without depression, 15 EMCI patients with mild depression (EMCID), and 15 late MCI (LMCI) patients without depression. The structural brain network was firstly constructed and the brain controllability was characterized for each participant. The controllability of default mode network (DMN) and its sub-regions were then compared across groups in a structural basis. Results indicated that the brain average controllability of DMN in EMCI, LMCI, and EMCID were significantly decreased compared to healthy subjects (P < 0.05). The EMCI and LMCI groups also showed significantly greater average controllability of DMN versus the EMCID group. Furthermore, compared to healthy subjects, the regional controllability of the left/right superior prefrontal cortex and the left/right cingulate gyrus in the EMCID group showed a significant decrease (P < 0.01). Among these regions, the left superior prefrontal region's controllability was significantly decreased (P < 0.05) in the EMCID group compared with EMCI and LMCI groups. Our results provide a new perspective in understanding depressive symptoms in MCI patients and provide potential biomarkers for diagnosing depression from MCI and AD., (Copyright © 2021. Published by Elsevier B.V.)

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer's disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18 F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18 F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18 F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18 F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Normative aging and Alzheimer's disease (AD) propagation alter anatomical connections among brain parcels. However, the interaction between the trajectories of age- and AD-linked alterations in the topology of the structural brain network is not well understood. In this study, diffusion-weighted magnetic resonance imaging (MRI) datasets of 139 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were used to document their structural brain networks. The 139 participants consist of 45 normal controls (NCs), 37 with early mild cognitive impairment (EMCI), 27 with late mild cognitive impairment (LMCI), and 30 AD patients. All subjects were further divided into three subgroups based on their age (56-65, 66-75, and 71-85 years). After the structural connectivity networks were built using anatomically-constrained deterministic tractography, their global and nodal topological properties were estimated, including network efficiency, characteristic path length, transitivity, modularity coefficient, clustering coefficient, and betweenness. Statistical analyses were then performed on these metrics using linear regression, and one- and two-way ANOVA testing to examine group differences and interactions between aging and AD propagation. No significant interactions were found between aging and AD propagation in the global topological metrics (network efficiency, characteristic path length, transitivity, and modularity coefficient). However, nodal metrics (clustering coefficient and betweenness centrality) of some cortical parcels exhibited significant interactions between aging and AD propagation, with affected parcels including left superior temporal, right pars triangularis, and right precentral. The results collectively confirm the age-related deterioration of structural networks in MCI and AD patients, providing novel insight into the cross effects of aging and AD disorder on brain structural networks. Some early symptoms of AD may also be due to age-associated anatomic vulnerability interacting with early anatomic changes associated with AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Gao, Potter, Benoit, Shen, Schulz, Zhang and The Alzheimer’s Disease Neuroimaging Initiative.)

Introduction: Cognitive impairment after concussion has been widely reported, but there is no reliable imaging biomarker that predicts the severity of cognitive decline post-concussion. This study tests the hypothesis that patients with a history of concussion and persistent cognitive impairment have fractional anisotropy (FA) and mean diffusivity (MD) values from diffusion tensor imaging (DTI) that are specifically associated with poor performance on the Montreal Cognitive Assessment (MoCA). Methods: Fifty-three subjects (19 females) with concussions and persistent cognitive symptoms had MR imaging and the MoCA. Imaging was analyzed by atlas-based, whole-brain DTI segmentation and FLAIR lesion segmentation. Then, we conducted a random forest-based recursive feature elimination (RFE) with 10-fold cross-validation on the entire dataset, and with partial correlation adjustment for age and lesion load. Results: RFE showed that 11 DTI variables were found to be important predictors of MoCA scores. Partial correlation analyses, corrected for age and lesion load, showed significant correlations between MoCA scores and right fronto-temporal regions: inferior temporal gyrus MD ( r = -0.62, p = 0.00001), middle temporal gyrus MD ( r = -0.54, p = 0.0001), angular gyrus MD ( r = -0.48, p = 0.0008), and inferior frontal gyrus FA ( r = 0.44, p = 0.002). Discussion: This is the first study to demonstrate a correlation between MoCA scores and DTI variables in patients with a history of concussion and persistent cognitive impairment. This kind of research will significantly increase our understanding of why certain persons have persistent cognitive changes after concussion which, in turn, may allow us to predict persistent impairment after concussion and suggest new interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gonzalez, Kim, Keser, Ibrahim, Singh, Ahmad, Hasan, Kamali, Hasan and Schulz.)

The gut microbiota is a complex ecosystem that comprises of more than 100 trillion symbiotic microbial cells. The microbiota, the gut, and the brain form an association, 'the microbiota-gut-brain axis,' and synchronize the gut with the central nervous system and modify the behavior and brain immune homeostasis. The bidirectional communication between gut and brain occurs via the immune system, the vagus nerve, the enteric nervous system, and microbial metabolites, including short-chain fatty acids (SCFAs), proteins, and tryptophan metabolites. Recent studies have implicated the gut microbiota in many neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we present an overview of gut microbiota, including Firmicutes, Bacteroidetes, SCFA, tryptophan, bacterial composition, besides age-related changes in gut microbiota composition, the microbiota-gut-brain axis pathways, the role of gut metabolites in amyloid-beta clearance, and gut microbiota modulation from experimental and clinical AD models. Understanding the role of the microbiota may provide new targets for treatment to delay the onset, progression, or reverse AD, and may help in reducing the prevalence of AD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Previous studies reveal that a newly described white matter pathway, the frontal aslant tract (FAT), connecting inferior and superior frontal gyri has a role in speech and language functions. We explored the role of this tract in a phonemic and semantic fluency tasks in a cohort of multiple sclerosis patients diagnosed with cognitive impairment., Methods: Thirty-five MS patients with varying degrees of cognitive impairment underwent diffusion tensor imaging and the Controlled Associated Word Test. Fractional anisotropy (FA) of FAT and arcuate fasciculus (AF) were obtained through a supervised, atlas-based tissue segmentation and parcellation method. Phonemic and semantic fluency scores were obtained from COWAT. We ran a multivariate regression model, and partial correlation analyses adjusted for age, education, and lesion load, and corrected for multiple comparisons. False discovery rate (FDR) was used for the correction of multiple comparisons., Results: Bilateral FAT FA showed significant association with phonemic verbal fluency task (Left; r = 0.46, p = 0.0058 and right; r = 0.46, p = 0.0059) but not semantic fluency task and this relation remained significant after FDR correction (p = 0.02 bilaterally). Although left AF showed some significant association with phonemic fluency task, this relation was insignificant after FDR correction., Conclusion: We show that bilateral FAT are correlates of phonemic verbal fluency task but not semantic in an MS cohort with cognitive impairment. This finding suggests that FAT is more specialized in lexical retrieval function as semantic fluency test encompasses all the functions except the lexical retrieval.

Theories of semantic memory based on neuropsychological findings have posited a distinction between stored semantic representations and the mechanisms used to access and manipulate them (e.g., Lambon Ralph, Jefferies, Patterson, & Rogers, 2017; Warrington & Cipolotti, 1996). The most recent instantiation of this view, the controlled semantic cognition theory (Lambon Ralph et al., 2017), is supported by findings suggesting that multimodal (i.e., both verbal and nonverbal) semantic deficits may result from qualitatively different impairments: on the one hand, damage to a semantic access mechanism related to executive control, which is observed in semantic aphasia (SA), and on the other, damage to semantic representations, which is observed in semantic dementia (SD) (Jefferies & Lambon Ralph, 2006). In this study we compared SA and SD patients on several phenomena previously used to support these distinctions. Contrary to the prior results, we found that (1) overall, cross-task consistency was equivalent for the two groups; (2) neither patient group showed consistency driven by item identity across different semantic tasks; (3) correlations among task performance were not obviously driven by the semantic control demands of different tasks; (4) both groups showed executive function deficits; and (5) both groups showed strong effects of distractor interference in a synonym judgment task. Furthermore, we investigated the components of executive ability that could underlie semantic control deficits by correlating performance on updating, shifting, and inhibition tasks with performance on tasks testing semantic abilities. We found that updating was related to semantic processing generally, whereas shifting and inhibition were not. These results also suggest that complex executive function tasks relate to semantic tasks through their shared relationship with language abilities. Overall, evidence from SA and SD patients does not differentiate representations and access mechanisms in the semantic system, as has previously been suggested. Implications for the storage-access distinction are discussed.

The goal of this retrospective cohort study was to determine whether stressors related to military service, determined by a diagnosis of chronic post-traumatic stress disorder (cPTSD) or receiving a Purple Heart (PH), are associated with an increased risk of vascular risk factors and disease, which are of great concern for veterans, who constitute a significant portion of the aging US population. The Veterans Integrated Service Network (VISN) 16 administrative database was searched for individuals 65 years or older between October 1, 1997 to September 30, 1999 who either received a PH but did not have cPTSD (PH+/cPTSD-; n = 1499), had cPTSD without a PH (PH-/cPTSD+; n = 3593), had neither (PH-/cPTSD-; n = 5010), or had both (PH+/cPTSD+; n = 153). In comparison to the control group (PH-/cPTSD-), the PH+/cPTSD- group had increased odds ratios for incidence and prevalence of diabetes mellitus, hypertension, and hyperlipidemia. The PH-/cPTSD+ group had increased odds ratios for prevalence of diabetes mellitus and for the incidence and prevalence of hyperlipidemia. The PH-/cPTSD+ and PH+/cPTSD- groups were associated with ischemic heart disease and cerebrovascular disease, but not independently of the other risk factors. The PH+/cPTSD+ group was associated only with an increase in the incidence and prevalence of hyperlipidemia, though this group's much smaller sample size may limit the reliability of this finding. We conclude that certain physical and psychological stressors related to military service are associated with a greater incidence of several vascular risk factors in veterans aged 65 years or older, which in turn are associated with greater rates of ischemic heart disease and cerebrovascular disease.

Objective: Concussions in adolescents are a growing public health concern as the popularity of high school sports increases. The aim of this study was to identify clinical (e.g., prior concussion, migraine history, learning disabilities/attention deficit hyperactivity disorders [ADHD]) and demographic factors (e.g., sex, race, health insurance, mechanism of injury/sport, education) that predict concussion recovery times., Design: In a retrospective cohort study of adolescents 13-19 years old evaluated for an acute concussion (≤ 10 days from injury), recovery times were calculated from the date of concussive injury to the date of clearance to return to play or normal activities., Results: The sample (N = 227) was primarily male (75%), and the median age was 15 years. Predictors of protracted recovery were ADHD (hazard ratio [HR] =.449, 95% confidence interval [CI] =.272-.741, p = .002) and prior concussion (HR =.574, 95% CI =.397-.828, p = .003) in all sex and race groups, while shorter recovery times were predicted by Hispanic and African American race (HR = 2.12, 95% CI = 1.30-3.46, p = .003), with White females as the reference group., Conclusions: Further research is needed to examine the role of sex, race, ADHD, and concussion history on concussion outcomes.

Background: Alzheimer's disease (AD) is projected to become one of the most expensive diseases in modern history, and yet diagnostic uncertainties exist that can only be confirmed by postmortem brain examination. Machine Learning (ML) algorithms have been proposed as a feasible alternative to the diagnosis of several neurological diseases and disorders, such as AD. An ideal ML-derived diagnosis should be inexpensive and noninvasive while retaining the accuracy and versatility that make ML techniques desirable for medical applications., New Methods: Two portable modalities, Electroencephalography (EEG) and functional Near-Infrared Spectroscopy (fNIRS) have been widely employed in constructing hybrid classification models to compensate for each other's weaknesses. In this study, we present a hybrid EEG-fNIRS model for classifying four classes of subjects including one healthy control (HC) group, one mild cognitive impairment (MCI) group, and, two AD patient groups. A concurrent EEG-fNIRS setup was used to record data from 29 subjects during a random digit encoding-retrieval task. EEG-derived and fNIRS-derived features were sorted using a Pearson correlation coefficient-based feature selection (PCCFS) strategy and then fed into a linear discriminant analysis (LDA) classifier to evaluate their performance., Results: The hybrid EEG-fNIRS feature set was able to achieve a higher accuracy (79.31 %) by integrating their complementary properties, compared to using EEG (65.52 %) or fNIRS alone (58.62 %). Moreover, our results indicate that the right prefrontal and left parietal regions are associated with the progression of AD., Comparison With Existing Methods: Our hybrid and portable system provided enhanced classification performance in multi-class classification of AD population., Conclusions: These findings suggest that hybrid EEG-fNIRS systems are a promising tool that may enhance the AD diagnosis and assessment process., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) varies a great deal cognitively regarding symptoms, test findings, the rate of progression, and neuroradiologically in terms of atrophy on magnetic resonance imaging (MRI). We hypothesized that an unbiased analysis of the progression of AD, regarding clinical and MRI features, will reveal a number of AD phenotypes. Our objective is to develop and use a computational method for multi-modal analysis of changes in cognitive scores and MRI volumes to test for there being multiple AD phenotypes. In this retrospective cohort study with a total of 857 subjects from the AD (n = 213), MCI (n = 322), and control (CN, n = 322) groups, we used structural MRI data and neuropsychological assessments to develop a novel computational phenotyping method that groups brain regions from MRI and subsets of neuropsychological assessments in a non-biased fashion. The phenotyping method was built based on coupled nonnegative matrix factorization (C-NMF). As a result, the computational phenotyping method found four phenotypes with different combination and progression of neuropsychologic and neuroradiologic features. Identifying distinct AD phenotypes here could help explain why only a subset of AD patients typically respond to any single treatment. This, in turn, will help us target treatments more specifically to certain responsive phenotypes.

Brain structural network changes provide key information about the aging process of the brain. Unfortunately, there has yet to be a detailed characterization of these structural networks across different age groups. Efforts to classify these networks have also been hampered by their reliance on technically limited traditional methods, which are unable to track multiple fiber orientations within a voxel and consequently are prone to false detection and artifacts. In this study, a newly developed Ensemble Average Propagator (EAP) based probabilistic tractography method was applied to construct a structural network, with the strength of the link between any two brain functional regions estimated according to the alignment of the EAP along connecting pathways. Age-related changes in the topological organization of human brain structural networks were thereby characterized across a broad age range (ages 8-75 years). The data from 48 healthy participants were divided into four age groups (Group 1 aged 8-15 years; Group 2 aged 25-35 years; Group 3 aged 45-55 years; and, Group 4 aged 65-75 years; N = 12 per group). We found that the brain structural network continues to strengthen during later adolescence and adulthood, through the first 20-30 years of life. Older adults, aged 65-75, had a significantly less optimized topological organization in their structural network, with decreased global efficiency and increased path lengths versus subjects in other groups. This study suggests that probabilistic tractography based on EAP provides a reliable method to construct macroscale structural connectivity networks to capture the age-associated changes of brain structures., (Copyright © 2020 Wu, Peng, Selvaraj, Schulz and Zhang.)