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Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer's disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson's disease with and without dementia, dementia with Lewy bodies, Huntington's disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Abstract: Arterial spin labeling (ASL) is a promising non-invasive magnetic resonance imaging (MRI) technique for measuring regional cerebral blood flow (rCBF) or perfusion in vivo. To evaluate the feasibility of ASL as a biomarker for clinical trials, it is important to examine test-retest reproducibility. We investigated both inter- and intra-session reproducibility of perfusion MRI using a pulsed ASL (PASL) sequence PICORE Q2TIPS with an echo-planar imaging (EPI) readout. Structural MRI regions of interest (ROIs) were extracted individually by automated parcellation and segmentation methods using FreeSurfer. These cortical and subcortical ROIs were used to assess regional perfusion stability. Our results indicated regional variability in grey matter rCBF. Although rCBF measurements were characterized by intersubject variation, our results also indicated relatively less within-subject variability estimated as within-subject standard deviation (SDW) (intersession SDW: 2.0 to 8.8; intrasession SDW: 2.8 to 9.6) and acceptable reliabilities as measured using intraclass correlation coefficient (ICC) (intersession ICC: 0.68 to 0.94; intrasession ICC: 0.66 to 0.95) for regional MRI perfusion measurements using the PICORE Q2TIPS technique. Overall, our findings suggest that PASL is a technique with good within and between session reproducibility. Further reproducibility studies in target populations relevant for specific clinical trials of neurovascular related agents will be important and the present results provide a framework for such assessments. [ABSTRACT FROM AUTHOR]

Introduction: The ADNI (Alzheimer's Disease Neuroimaging Initiative) is a large longitudinal study of patients with probable Alzheimer's disease (AD), patients with mild cognitive impairment (MCI) and healthy elderly controls followed for at least 2-3 years. Many participants in the ADNI are being treated with medications, and these may have beneficial or deleterious effects. Objective: The goal of the study was to characterize baseline medication use in the ADNI. Methods: Diagnosis, demographics, medication status, psychometric data and MRI measures of hippocampal volume and entorhinal cortex thickness were obtained for 818 participants from the ADNI cohort. Total number of medications, Beers list (potentially dangerous) medications and AD treatments were also tabulated. ANOVA and logistic regression were used to assess associations between baseline pharmacotherapy and diagnosis, demographics, and selected clinical and MRI variables. Results: Of the 818 enrolled ADNI participants, 809 were available for analysis in the present study, including 184 patients with AD, 399 patients with MCI and 226 healthy elderly controls. Significant gender differences in recruitment were observed in the MCI group. The average number of medications per participant was 8 (SD 4) and 22% reported treatment with one or more Beers list medications. For symptomatic treatment of MCI or AD, donepezil and memantine were the most commonly reported drugs. As expected, MCI and AD patients with more severe impairment were more likely to be treated. Men received treatment more frequently than women. Older subjects and those with less education were less likely to receive treatment. Conclusions: AD and MCI participants from the ADNI cohort were being treated with polypharmacy and many were also taking one or more medications with the potential for adverse effects. Off-label use of cholinesterase inhibitors and/or memantine for MCI was common, with more severely affected patients most likely to receive treatment. Differences in the frequency of symptomatic treatment were also observed as a function of age, years of education, gender and disease severity. [ABSTRACT FROM AUTHOR]

Abstract: Verbal fluency tests are employed regularly during neuropsychological assessments of older adults, and deficits are a common finding in patients with Alzheimer''s disease (AD). Little extant research, however, has investigated verbal fluency ability and subtypes in preclinical stages of neurodegenerative disease. We examined verbal fluency performance in 107 older adults with amnestic mild cognitive impairment (MCI, n =37), cognitive complaints (CC, n =37) despite intact neuropsychological functioning, and demographically matched healthy controls (HC, n =33). Participants completed fluency tasks with letter, semantic category, and semantic switching constraints. Both phonemic and semantic fluency were statistically (but not clinically) reduced in amnestic MCI relative to cognitively intact older adults, indicating subtle changes in the quality of the semantic store and retrieval slowing. Investigation of the underlying constructs of verbal fluency yielded two factors: Switching (including switching and shifting tasks) and Production (including letter, category, and action naming tasks), and both factors discriminated MCI from HC albeit to different degrees. Correlational findings further suggested that all fluency tasks involved executive control to some degree, while those with an added executive component (i.e., switching and shifting) were less dependent on semantic knowledge. Overall, our findings highlight the importance of including multiple verbal fluency tests in assessment batteries targeting preclinical dementia populations and suggest that individual fluency tasks may tap specific cognitive processes. [Copyright &y& Elsevier]

Background: Obsessive-compulsive disorder (OCD) has been hypothesized to involve inhibitory control dysfunction related to abnormal frontal-striatal-thalamic-cortical (FSTC) circuitry. Methods: We examined the neural substrates of response inhibition in adults with OCD using functional magnetic resonance imaging (fMRI) and a go/no-go task. Participants consisted of 12 adults with OCD and 14 healthy comparison subjects. Results: During response inhibition, healthy adults showed predominantly right-hemisphere activation including the right inferior frontal gyrus, whereas the patient group showed a more diffuse, bilateral pattern of activation. Furthermore, the OCD group demonstrated less activation than the comparison group in several right-hemisphere regions during response inhibition, including inferior and medial frontal gyri. Symptom severity was inversely correlated with activation in right orbitofrontal and anterior cingulate gyri and positively correlated with thalamic and posterior cortical activations. Neither depressed mood nor medication status could account for the results. Conclusions: These findings indicate that adults with OCD demonstrate underactivation of FSTC circuitry during response inhibition. Results suggest that the thalamus and related circuitry may play a role in the expression or intensity of OCD symptoms, whereas right frontal subregions may be involved in the suppression of symptoms. [Copyright &y& Elsevier]

The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatment-induced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/or have independent effects on cognitive function. [ABSTRACT FROM AUTHOR]

This report presents a manual segmentation protocol for the hippocampus that yields a reliable and comprehensive measure of volume, a goal that has proven difficult with prior methods. Key features of this method include alignment of the images in the long axis of the hippocampus and the use of a three-dimensional image visualization function to disambiguate anterior and posterior hippocampal boundaries. We describe procedures for hippocampal volumetry and shape analysis, provide inter- and intra-rater reliability data, and examine correlates of hippocampal volume in a sample of healthy older adults. Participants were 40 healthy older adults with no significant cognitive complaints, no evidence of mild cognitive impairment or dementia, and no other neurological or psychiatric disorder. Using a 1.5 T GE Signa scanner, three-dimensional spoiled gradient recalled acquisition in a steady state (SPGR) sequences were acquired for each participant. Images were resampled into 1 mm isotropic voxels, and realigned along the interhemispheric fissure in the axial and coronal planes, and the long axis of the hippocampus in the sagittal plane. Using the BRAINS program (Andreasen et al., 1993), the boundaries of the hippocampus were visualized in the three orthogonal views, and boundary demarcations were transferred to the coronal plane for tracing. Hippocampal volumes were calculated after adjusting for intracranial volume (ICV). Intra- and inter-rater reliabilities, measured using the intraclass correlation coefficient, exceeded .94 for both the left and right hippocampus. Total ICV-adjusted volumes were 3.48 (±0.43) cc for the left hippocampus and 3.68 (±0.42) for the right. There were no significant hippocampal volume differences between males and females (p > .05). In addition to providing a comprehensive volumetric measurement of the hippocampus, the refinements included in our tracing protocol permit analysis of changes in hippocampal shape. Shape analyses may yield novel information about structural brain changes in aging and dementia that are not reflected in volumetric measurements alone. These and other novel directions in research on hippocampal function and dysfunction will be facilitated by the use of reliable, comprehensive, and consistent segmentation and measurement methods. [ABSTRACT FROM AUTHOR]

Abstract: The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimer''s disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests. [Copyright &y& Elsevier]

Objective: Altered patterns of brain activity during cognitive tasks have been demonstrated using functional magnetic resonance imaging (fMRI) in mild cognitive impairment and Alzheimer's disease. However, there have been few studies of adults at genetic risk for Alzheimer's disease prior to the onset of symptoms. The purpose of this study was to determine whether brain activation patterns associated with working memory differ as a function of apolipoprotein E (APOE) genotype in cognitively intact adults. Method: Participants were cognitively intact, healthy adults who completed genotyping, comprehensive neuropsychological testing, and structural and functional neuroimaging. Twenty-two participants had the APOE ϵ3/ϵ3 genotype, and 13 participants had the APOE ϵ3/ϵ4 genotype. The study employed an auditory verbal N-back task to probe working memory-related brain activity. Results: The ϵ3/ϵ3 and E3/E4 groups did not differ in demographic characteristics, cognitive ability, mood, or in-scanner task performance. The ϵ3/ϵ4 group showed greater activity during working memory in the medial frontal and parietal regions bilaterally and in the right dorsolateral prefrontal cortex. There were no regions in which the ϵ3/ϵ3 group showed greater activation than the ϵ3/ϵ4 group. Conclusions: These results indicate that differences in brain activity are evident in cognitively intact individuals who are at risk for late-onset Alzheimer's disease by virtue of their APOE allele status. As neuroprotective interventions become available, early detection will increase in importance. The combination of genetic and functional neuroimaging strategies may prove useful for monitoring individuals at risk for Alzheimer's disease before the onset of cognitive symptoms. [ABSTRACT FROM AUTHOR]

In this investigation, we analyzed the effect of age on fMRI activationduring semantic and phonological decision tasks using wholebrain echoplanarimaging Nine righthanded healthy younger adults were compared to nine righthandedhealthy older adult volunteers While undergoing fMRI scanning, subjects completedthree functional MRI auditory stimulation tasks requiring semantic or phonologicaldecisions (match/mismatch) about word pairs (category-exemplar, category-function,pseudo-word) Performance scores on these tasks did not differ between agegroups The fMRI images were motion corrected, spatially normalized, and statisticallyanalyzed for group similarities and differences using a randomeffects modelFor the semantic tasks, both older and younger adults showed activity withinthe inferior frontal gyrus (left more than right) and left superior temporalgyrus, whereas small regional age differences (younger > older)were found in the left inferior precentral region For the phonologic task,common areas of activation were found in the superior temporal gyrus (leftmore than right) Agerelated differences in the phonologic task were observedpredominantly in the right angular region The results were not changed byentry of a quantitative atrophy index as a covariate These findings highlightthe similarities in semantic processing across age groups and suggest thatglobal age related atrophy is not impacting activation significantly in healthyolder adults. [ABSTRACT FROM AUTHOR]

Purpose: The goal of the current study was to introduce a new methodology that holds a promise to be used in hippocampus-aging studies using sub-millimeter super-resolution hybrid diffusion imaging (HYDI) MRI. Methods: HYDI diffusion data were acquired in two groups of older and younger healthy participants recruited from the Indiana Alzheimer's Disease Research Center and community. These data were then transformed into super-resolution diffusion images before the hippocampal subfield analyses. We studied the correlation between the subjects' age and the structural connectivity involving the hippocampal subfields and the connectivity between the whole hippocampus and the cerebral cortex. Results: Structural integrity derived from the tractography streamlines between the hippocampal subfields was reduced in older than younger adults. Conclusion: The findings offered a new promising framework, and they opened avenues for future studies to explore the relationship between the structural connectivity in the hippocampal area and different types of dementia. [ABSTRACT FROM AUTHOR]

Background: There are various molecular hypotheses regarding Alzheimer's disease (AD) like amyloid deposition, tau propagation, neuroinflammation, and synaptic dysfunction. However, detailed molecular mechanism underlying AD remains elusive. In addition, genetic contribution of these molecular hypothesis is not yet established despite the high heritability of AD. Objective: The study aims to enable the discovery of functionally connected multi-omic features through novel integration of multi-omic data and prior functional interactions. Methods: We propose a new deep learning model MoFNet with improved interpretability to investigate the AD molecular mechanism and its upstream genetic contributors. MoFNet integrates multi-omic data with prior functional interactions between SNPs, genes, and proteins, and for the first time models the dynamic information flow from DNA to RNA and proteins. Results: When evaluated using the ROS/MAP cohort, MoFNet outperformed other competing methods in prediction performance. It identified SNPs, genes, and proteins with significantly more prior functional interactions, resulting in three multi-omic subnetworks. SNP-gene pairs identified by MoFNet were mostly eQTLs specific to frontal cortex tissue where gene/protein data was collected. These molecular subnetworks are enriched in innate immune system, clearance of misfolded proteins, and neurotransmitter release respectively. We validated most findings in an independent dataset. One multi-omic subnetwork consists exclusively of core members of SNARE complex, a key mediator of synaptic vesicle fusion and neurotransmitter transportation. Conclusions: Our results suggest that MoFNet is effective in improving classification accuracy and in identifying multi-omic markers for AD with improved interpretability. Multi-omic subnetworks identified by MoFNet provided insights of AD molecular mechanism with improved details. [ABSTRACT FROM AUTHOR]

Background: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. Objective: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. Methods: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. Results: Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. Conclusions: Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies. [ABSTRACT FROM AUTHOR]

The iDA Project (iPSCs to Study Diversity in Alzheimer's and Alzheimer's Disease-related Dementias) is generating 200 induced pluripotent stem cell lines from Alzheimer's Disease Neuroimaging Initiative participants. These lines are sex balanced, include common APOE genotypes, span disease stages, and are ancestrally diverse. Cell lines and characterization data will be shared openly. [ABSTRACT FROM AUTHOR]

Background: The Cognitive Change Index (CCI) is a widely-used measure of self-perceived cognitive ability and change. Unfortunately, it is unclear if the CCI predicts future cognitive and clinical decline. Objective: We evaluated baseline CCI to predict transition from normal cognition to cognitive impairment in nondemented older adults and in predementia groups including, subjective cognitive decline, motoric cognitive risk syndrome, and mild cognitive impairment. Different versions of the CCI were assessed to uncover any differential risk sensitivity. We also examined the effect of ethnicity/race on CCI. Methods: Einstein Aging Study participants (N = 322, Mage = 77.57±4.96, % female=67.1, Meducation = 15.06±3.54, % non-Hispanic white = 46.3) completed an expanded 40-item CCI version (CCI-40) and neuropsychological evaluation (including Clinical Dementia Rating Scale [CDR], Montreal Cognitive Assessment, and Craft Story) at baseline and annual follow-up (Mfollow - up=3.4 years). CCI-40 includes the original 20 items (CCI-20) and the first 12 memory items (CCI-12). Linear mixed effects models (LME) and generalized LME assessed the association of CCI total scores at baseline with rate of decline in neuropsychological tests and CDR. Results: In the overall sample and across predementia groups, the CCI was associated with rate of change in log odds on CDR, with higher CCI at baseline predicting faster increase in the odds of being impaired on CDR. The predictive validity of the CCI broadly held across versions (CCI-12, 20, 40) and ethnic/racial groups (non-Hispanic black and white). Conclusions: Self-perception of cognitive change on the CCI is a useful marker of dementia risk in demographically/clinically diverse nondemented samples. All CCI versions successfully predicted decline. [ABSTRACT FROM AUTHOR]

The pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiological mechanisms of the disease. In addition, the detection of gene-related connectome changes might aid in the early diagnosis of AD and facilitate the development of personalized therapeutic strategies that are effective at earlier stages of the disease spectrum. In this article, we review studies of the associations between connectome changes and amyloid-β and tau pathologies as well as molecular genetics in different subtypes and stages of AD. We also highlight the utility of connectome-derived computational models for replicating empirical findings and for tracking and predicting the progression of biomarker-indicated AD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic biomarkers. Methods: We performed co-expression network analysis to identify network modules associated with AD, its neuropathology markers, and cognition using brain tissue miRNA profiles from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) (N = 702) as a discovery dataset. We performed association analysis of hub miRNAs with AD, its neuropathology markers, and cognition. After selecting target genes of the hub miRNAs, we performed association analysis of the hub miRNAs with their target genes and then performed pathway-based enrichment analysis. For replication, we performed a consensus miRNA co-expression network analysis using the ROS/MAP dataset and an independent dataset (N = 16) from the Gene Expression Omnibus (GEO). Furthermore, we performed a machine learning approach to assess the performance of hub miRNAs for AD classification. Results: Network analysis identified a glucose metabolism pathway-enriched module (M3) as significantly associated with AD and cognition. Five hub miRNAs (miR-129-5p, miR-433, miR-1260, miR-200a, and miR-221) of M3 had significant associations with AD clinical and/or pathologic traits, with miR129-5p by far the strongest across all phenotypes. Gene-set enrichment analysis of target genes associated with their corresponding hub miRNAs identified significantly enriched biological pathways including ErbB, AMPK, MAPK, and mTOR signaling pathways. Consensus network analysis identified two AD-associated consensus network modules and two hub miRNAs (miR-129-5p and miR-221). Machine learning analysis showed that the AD classification performance (area under the curve (AUC) = 0.807) of age, sex, and APOE ε4 carrier status was significantly improved by 6.3% with inclusion of five AD-associated hub miRNAs. Conclusions: Integrative network and machine learning analysis identified miRNA signatures, especially miR-129-5p, as associated with AD, its neuropathology markers, and cognition, enhancing our understanding of AD pathogenesis and leading to better performance of AD classification as potential diagnostic/prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. Methods: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. Results: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment. Conclusion: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies. [ABSTRACT FROM AUTHOR]

Background: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. Methods: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. Results: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment. Conclusion: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies. [ABSTRACT FROM AUTHOR]

The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs. [ABSTRACT FROM AUTHOR]

Identification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOE ε 4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOE ε 4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD. [ABSTRACT FROM AUTHOR]

Investigating the relationship between genetic variation and phenotypic traits is a key issue in quantitative genetics. Specifically for Alzheimer's disease, the association between genetic markers and quantitative traits remains vague while, once identified, will provide valuable guidance for the study and development of genetics-based treatment approaches. Currently, to analyze the association of two modalities, sparse canonical correlation analysis (SCCA) is commonly used to compute one sparse linear combination of the variable features for each modality, giving a pair of linear combination vectors in total that maximizes the cross-correlation between the analyzed modalities. One drawback of the plain SCCA model is that the existing findings and knowledge cannot be integrated into the model as priors to help extract interesting correlations as well as identify biologically meaningful genetic and phenotypic markers. To bridge this gap, we introduce preference matrix guided SCCA (PM-SCCA) that not only takes priors encoded as a preference matrix but also maintains computational simplicity. A simulation study and a real-data experiment are conducted to investigate the effectiveness of the model. Both experiments demonstrate that the proposed PM-SCCA model can capture not only genotype-phenotype correlation but also relevant features effectively. • Canonical correlation analysis guided by a matrix with confidence in feature linkages. • PM-guided sparse CCA overpowers prototypes in both generalizability and CC recovery. • PM-SCCA achieves bimodal feature selection; computationally feasible while accurate. • Detects PET-gene associations, biologically validated by functional annotation & GSEA. [ABSTRACT FROM AUTHOR]

Background: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. Methods: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency‐matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy‐Cognitive Function) and physical (Medical Outcomes Study Short Form‐12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed‐effects models tested survivor‐control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. Results: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p =.001–.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p =.001–.04), and among this group, an older EEA related to worse self‐reported cognition (p =.047) relative to controls. An older epigenetic age related to worse physical function in all women (p <.001–.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non‐Hispanic White survivors. Conclusion: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women. Older breast cancer survivors were biologically older than matched noncancer controls across multiple epigenetic aging measures at 24 months or more after enrollment (which was presystemic therapy for survivors). Older breast cancer survivors who had received chemotherapy showed the greatest epigenetic aging, and among this group, an older epigenetic age was associated with worse self‐reported cognition relative to controls. [ABSTRACT FROM AUTHOR]

Background: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. Methods: Women >60 years old with primary breast cancer (stages 0–III) (n = 400) were assessed before systemic therapy with frequency‐matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin‐6 (IL‐6), IL‐8, IL‐10, tumor necrosis factor α (TNF‐α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate‐adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. Results: Participants were aged 60–90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor–positive tumors (87.6%). Survivors had significantly higher IL‐6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤.001–.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p <.05). Levels of IL‐6, IL‐10, and TNF‐α were related to APE, with IL‐6 explaining part of the relationship between survivor/control group and APE (p =.01). The magnitude of this mediation effect decreased but remained significant (p =.047) after the consideration of additional covariates. Conclusions: Older breast cancer survivors had worse long‐term neurocognitive performance than controls, and this relationship was explained in part by elevated IL‐6. The mechanisms that contribute to cognitive problems among cancer survivors remain unclear. This study found that one inflammatory/immune activation marker, interleukin‐6, mediated some of the relationship between older breast cancer survivors/noncancer control group and cognitive performance. [ABSTRACT FROM AUTHOR]

Abstract Background Contralateral brain structures represent a unique, within-patient reference element for disease, and asymmetries can provide a personalized measure of the accumulation of past disease processes. Neuroanatomical shape asymmetries have recently been associated with the progression of Alzheimer’s disease (AD), but the biological basis of asymmetric brain changes in AD remains unknown. Methods We investigated genetic influences on brain asymmetry by identifying associations between magnetic resonance imaging–derived measures of asymmetry and candidate single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for AD diagnosis and for brain subcortical volumes. For analyzing longitudinal neuroimaging data (1241 individuals, 6395 scans), we used a mixed effects model with interaction between genotype and diagnosis. Results Significant associations between asymmetry of the amygdala, hippocampus, and putamen and SNPs in the genes BIN1 , CD2AP , ZCWPW1 , ABCA7 , TNKS , and DLG2 were found. Conclusions The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with AD pathology. For AD candidate SNPs, we extend previous work to show that their effects on subcortical brain structures are asymmetric. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker. [ABSTRACT FROM AUTHOR]

The article cites a research study that analyzes cognitive sequelae of breast cancer and its treatment, particularly the adjuvant chemotherapy effects for such cancer. Lower function in long-term survivors treated with chemotherapy was seen in early retrospective neuropsychological studies. The neurotoxic effects of systemic chemotherapy were presumed to be reflected by alterations in cognitive functioning.

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. Methods: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10–9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10–8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10–8). GRN (rs5848, P = 4.21 × 10–8) and PURG (rs117523305, P = 1.73 × 10–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10–8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10–9) and PTPRD (rs145989094, P = 8.34 × 10–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10–8) and PTPRD (rs145989094, P = 3.85 × 10–8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias. [ABSTRACT FROM AUTHOR]

Objective: Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and even more in Alzheimer's disease (AD). The symptom‐based cluster including nighttime disturbances, depression, appetite changes, anxiety, and apathy (affective and vegetative symptoms) was associated with an increased risk of dementia in MCI and has common neuroanatomical associations. Our objective was to investigate the differences in brain morphology associations with affective and vegetative symptoms between three groups: cognitively normal older adults (CN), MCI and AD. Material and Methods: Alzheimer's Disease Neuroimaging Initiative data of 223 CN, 367 MCI and 175 AD, including cortical volumes, surface areas and thicknesses and severity scores of the five NPS were analyzed. A whole‐brain vertex‐wise general linear model was performed to test for intergroup differences (CN‐MCI, CN‐AD, AD‐MCI) in brain morphology associations with five NPS. Multiple regressions were conducted to investigate cortical change as a function of NPS severity in the AD‐MCI contrast. Results: We found (1) signature differences in nighttime disturbances associations with prefrontal regions in AD‐MCI, (2) signature differences in NPS associations with temporal regions in AD‐MCI for depression and in CN‐AD for anxiety, (3) decreased temporal metrics in MCI as nighttime disturbances and depression severity increased, (4) decreased pars triangularis metrics in AD as nighttime disturbances and apathy severity increased. Conclusion: Each NPS seems to have a signature on brain morphology. Affective and vegetative NPS were primarily associated with prefrontal and temporal regions. These signatures open the possibility of potential future assessments of links between brain morphology and NPS on an individual level. Key points: Signature differences in nighttime disturbances associations with prefrontal regions in Alzheimer's disease mild cognitive impairment (AD‐MCI).Signature differences in Neuropsychiatric symptoms associations with temporal regions in AD‐MCI for de‐pression and in cognitively normal‐AD for anxiety.Dreased temporal metrics in MCI as nighttime dis‐turbances and depression severity increased.Decreased pars triangularis metrics in AD as nighttime disturbances and apathy severity increased. [ABSTRACT FROM AUTHOR]

Simple Summary: While numerous publications have shown that some patients experience cancer- and treatment-related cognitive decline, the role of genetics in risk for cognitive decline has not yet been established. In this study, our goal was to identify genetic factors affecting risk for cognitive decline in older female breast cancer survivors. The study identified several genetic variants and genes that were associated with differences in patterns of cognitive decline in cancer patients compared to controls, suggesting that genetics can play an important role in modifying risk for cognitive decline in older cancer survivors. It will be important for additional research to replicate these findings in other cancer populations; if validated, these findings could inform therapeutic research, as well as inform evaluations of risk for cognitive decline in older cancer survivors. Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10−8), and rs78786199 (chromosome 2, p = 1.925 × 10−8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD. [ABSTRACT FROM AUTHOR]

DNA methylation is a key epigenetic marker, and its alternations may be involved in Alzheimer's disease (AD). CpGs sharing similar biological functions or pathways tend to be co-methylated. We performed an integrative network-based DNA methylation analysis on 2 independent cohorts (N = 941) using brain DNA methylation profiles and RNA-sequencing as well as AD pathology data. Weighted co-methylation network analysis identified 6 modules as significantly associated with neuritic plaque burden. In total, 15 hub CpGs including 3 novel CpGs were identified and replicated as being significantly associated with AD pathology. Furthermore, we identified and replicated 4 target genes (ATP6V1G2 , VCP , RAD52 , and LST1) as significantly regulated by DNA methylation at hub CpGs. In particular, VCP gene expression was also associated with AD pathology in both cohorts. This integrative network-based multiomics study provides compelling evidence for a potential role of DNA methylation alternations and their target genes in AD. [ABSTRACT FROM AUTHOR]

Cancer- and treatment-related cognitive changes have been a focus of increasing research since the early 1980s, with meta-analyses demonstrating poorer performance in cancer patients in cognitive domains including executive functions, processing speed, and memory. To facilitate collaborative efforts, in 2011 the International Cognition and Cancer Task Force (ICCTF) published consensus recommendations for core neuropsychological tests for studies of cancer populations. Over the past decade, studies have used neuroimaging techniques, including structural and functional magnetic resonance imaging (fMRI) and positron emission tomography, to examine the underlying brain basis for cancer- and treatment-related cognitive declines. As yet, however, there have been no consensus recommendations to guide researchers new to this field or to promote the ability to combine data sets. We first discuss important methodological issues with regard to neuroimaging study design, scanner considerations, and sequence selection, focusing on concerns relevant to cancer populations. We propose a minimum recommended set of sequences, including a high-resolution T1-weighted volume and a resting state fMRI scan. Additional advanced imaging sequences are discussed for consideration when feasible, including task-based fMRI and diffusion tensor imaging. Important image data processing and analytic considerations are also reviewed. These recommendations are offered to facilitate increased use of neuroimaging in studies of cancer- and treatment-related cognitive dysfunction. They are not intended to discourage investigator-initiated efforts to develop cutting-edge techniques, which will be helpful in advancing the state of the knowledge. Use of common imaging protocols will facilitate multicenter and data-pooling initiatives, which are needed to address critical mechanistic research questions. [ABSTRACT FROM AUTHOR]

Examines neuropsychological functions in schizophrenic patients who had never been exposed to neuroleptic drugs and who are experiencing their first episode of psychosis. Profiles of patient groups; Comparison of neurological functions in previously treated and FE patients; Importance of neuropsychological evaluations.

The Test of Practical Judgment (TOP-J) is increasingly used by neuropsychologists to measure everyday judgment ability in older adulthood. In the present study, we developed an alternate TOP-J Form B, which may be used to reduce practice effects for repeat assessment situations or in place of the original Form A. In developing the measure, special attention was given to limiting cultural bias and making items similar in content and difficulty to Form A. The TOP-J Form B was piloted in a clinical geriatric sample (N = 77) in the Midwestern U.S. Subsequently, older adults (N = 130) were recruited from several boroughs of New York City and surrounding areas (mean age = 77; mean years of education = 16; 69% female; 28% Black/African-American, 11% Hispanic). In this validation sample, both the 9-item and 15-item versions of the TOP-J Form B showed strong psychometric properties, including good unidimensional model fit in confirmatory factor analysis, preliminary convergent/divergent and criterion validity evidence, and strong inter-rater reliability, ICC (2, 1) =.93. The means and standard deviations for the TOP-J Form A and Form B were highly similar, particularly for the 9-item forms in which there was less than a one-point mean difference. Preliminary normative data for cognitively intact participants (n = 73) were established. We present means and standard deviations that will allow for the calculation of z scores as Form B scores were normally distributed. The newly developed TOP-J Form B should be useful in diverse clinical and research settings. [ABSTRACT FROM AUTHOR]

Background: Older cancer survivors are at risk for cognitive decline. Physical activity can improve cognition, and better cognitive function may facilitate greater physical activity.Purpose: We examined the potential bidirectional relationship between cognitive function and physical activity in older breast cancer survivors and controls.Methods: The sample included women with newly diagnosed, nonmetastatic breast cancer (n = 395) and women without cancer (n = 374) ages 60-98. Participants were recruited as part of a larger multisite study, assessed prior to systemic therapy, and followed yearly for 36 months. Attention, processing speed, and executive function was measured using six neuropsychological tests, self-reported cognitive function using the Perceived Cognitive Impairments subscale of the Functional Assessment of Cancer Therapy-Cognitive Function , and physical activity using the International Physical Activity Questionnaire-Short Form. Separate random intercepts cross-lagged panel models were used to examine the between- and within-person effects for survivors and controls, controlling for age, education, and study site.Results: Survivors reported significantly less physical activity than controls at baseline (1,284.92 vs. 2,085.98 MET min/week, p < .05). When survivors reported higher activity, they simultaneously had better objective cognition at 12 months (β = 0.24, p = .04) and reported better perceived cognition at 12 and 24 months (β = 0.25, p = .03), but this relationship was not seen in controls. Cognition did not predict subsequent physical activity or vice versa in either group.Conclusions: Cognition and physical activity are cross-sectionally associated in survivors, but the expected prospective relationships were not found. [ABSTRACT FROM AUTHOR]

Motivation With the rapid development of modern technologies, massive data are available for the systematic study of Alzheimer's disease (AD). Though many existing AD studies mainly focus on single-modality omics data, multi-omics datasets can provide a more comprehensive understanding of AD. To bridge this gap, we proposed a novel structural Bayesian factor analysis framework (SBFA) to extract the information shared by multi-omics data through the aggregation of genotyping data, gene expression data, neuroimaging phenotypes and prior biological network knowledge. Our approach can extract common information shared by different modalities and encourage biologically related features to be selected, guiding future AD research in a biologically meaningful way. Method Our SBFA model decomposes the mean parameters of the data into a sparse factor loading matrix and a factor matrix, where the factor matrix represents the common information extracted from multi-omics and imaging data. Our framework is designed to incorporate prior biological network information. Our simulation study demonstrated that our proposed SBFA framework could achieve the best performance compared with the other state-of-the-art factor-analysis-based integrative analysis methods. Results We apply our proposed SBFA model together with several state-of-the-art factor analysis models to extract the latent common information from genotyping, gene expression and brain imaging data simultaneously from the ADNI biobank database. The latent information is then used to predict the functional activities questionnaire score, an important measurement for diagnosis of AD quantifying subjects' abilities in daily life. Our SBFA model shows the best prediction performance compared with the other factor analysis models. Availability Code are publicly available at https://github.com/JingxuanBao/SBFA. Contact qlong@upenn.edu [ABSTRACT FROM AUTHOR]

Background: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. Objective: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. Methods: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. Results: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. Conclusion: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD. [ABSTRACT FROM AUTHOR]

Background: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. Objective: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. Methods: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. Results: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. Conclusion: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. Methods: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. Results: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Conclusions: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins. [ABSTRACT FROM AUTHOR]

This literature review investigates the significant overlap between myelin-repair signaling pathways and pathways known to contribute to hallmark pathologies of Alzheimer’s disease (AD). We discuss previously investigated therapeutic targets of amyloid, tau, and ApoE, as well as other potential therapeutic targets that have been empirically shown to contribute to both remyelination and progression of AD. Current evidence shows that there are multiple AD-relevant pathways which overlap significantly with remyelination and myelin repair through the encouragement of oligodendrocyte proliferation, maturation, and myelin production. There is a present need for a single, cohesive model of myelin homeostasis in AD. While determining a causative pathway is beyond the scope of this review, it may be possible to investigate the pathological overlap of myelin repair and AD through therapeutic approaches. [ABSTRACT FROM AUTHOR]

This literature review investigates the significant overlap between myelin-repair signaling pathways and pathways known to contribute to hallmark pathologies of Alzheimer's disease (AD). We discuss previously investigated therapeutic targets of amyloid, tau, and ApoE, as well as other potential therapeutic targets that have been empirically shown to contribute to both remyelination and progression of AD. Current evidence shows that there are multiple AD-relevant pathways which overlap significantly with remyelination and myelin repair through the encouragement of oligodendrocyte proliferation, maturation, and myelin production. There is a present need for a single, cohesive model of myelin homeostasis in AD. While determining a causative pathway is beyond the scope of this review, it may be possible to investigate the pathological overlap of myelin repair and AD through therapeutic approaches. [ABSTRACT FROM AUTHOR]

Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment. Complementary multi-omics approach, in silico metabolic flux, and neuroimaging analyses link the sphingolipid pathway to Alzheimer's disease pathogenesis with therapeutic targets validated using behavioral assessments in amyloidogenic APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Objective The Test of Practical Judgment (TOP-J) has shown utility in inpatient and outpatient settings in older adults who present with mild cognitive impairment and various dementia subtypes. The TOP-J has two versions (i.e. 9 items and 15 items), and was initially validated within a small rural non-Hispanic White sample. In the current study, we re-evaluated the psychometric evidence and refined scoring criteria and administration guidelines in older adults with more diverse demographic characteristics than the original validation sample. Method: Participants (N = 348) were recruited from several boroughs of New York City and surrounding areas (mean/median age = 79; mean years education = 15, median = 15.5; 68% female; 30% Black/African-American, 8% Hispanic). Results: Reliability and validity were comparable to original findings. Based on confirmatory factor analysis, one item was replaced on the 9-item version, now called TOP-J Form A. Normative data for cognitively intact participants (n = 261) were updated and stratified by two education groups. Conclusions: The TOP-J is increasingly used in clinical and research settings in the U.S. and abroad, and the current study provides improved normative data and administration and scoring guidelines for use with demographically diverse older individuals. [ABSTRACT FROM AUTHOR]

Purpose: Several studies have reported sleep disturbances during the COVID‐19 virus pandemic. Little data exist about the impact of the pandemic on sleep and mental health among older women with breast cancer. We sought to examine whether women with and without breast cancer who experienced new sleep problems during the pandemic had worsening depression and anxiety. Methods: Breast cancer survivors aged ≥60 years with a history of nonmetastatic breast cancer (n = 242) and frequency‐matched noncancer controls (n = 158) active in a longitudinal cohort study completed a COVID‐19 virus pandemic survey from May to September 2020 (response rate 83%). Incident sleep disturbance was measured using the restless sleep item from the Center for Epidemiological Studies‐Depression Scale (CES‐D). CES‐D score (minus the sleep item) captured depressive symptoms; the State‐Anxiety subscale of the State Trait Anxiety Inventory measured anxiety symptoms. Multivariable linear regression models examined how the development of sleep disturbance affected changes in depressive or anxiety symptoms from the most recent prepandemic survey to the pandemic survey, controlling for covariates. Results: The prevalence of sleep disturbance during the pandemic was 22.3%, with incident sleep disturbance in 10% and 13.5% of survivors and controls, respectively. Depressive and anxiety symptoms significantly increased during the pandemic among women with incident sleep disturbance (vs. no disturbance) (β = 8.16, p < 0.01 and β = 6.14, p < 0.01, respectively), but there were no survivor‐control differences in the effect. Conclusion: Development of sleep disturbances during the COVID‐19 virus pandemic may negatively affect older women's mental health, but breast cancer survivors diagnosed with the nonmetastatic disease had similar experiences as women without cancer. [ABSTRACT FROM AUTHOR]