Normal Cognition Research Articles

Interrater agreement and variability in visual reading of [18F] flutemetamol PET images.

The purpose of this study was to validate the concordance of visual ratings of [18F] flutemetamol amyloid positron emission tomography (PET) images and to investigate the correlation between the agreement of each rater and the Centiloid (CL) scale. A total of 192 participants, clinically classified as cognitively normal (CN) (n = 59), mild cognitive impairment (MCI) (n = 65), Alzheimer's disease (AD) (n = 55), or non-AD dementia (n = 13), participated in this study. Three experts conducted visual ratings of the amyloid PET images for all 192 patients, assigning a confidence level to each rating on a three-point scale (certain, probable, or neither). The positive or negative determination of amyloid PET results was made by majority vote. The CL value was calculated using the CapAIBL pipeline. Overall, 101 images were determined to be positive, and 91 images were negative. Of the 101 positive images, the three raters were in complete agreement for 92 images and in disagreement for 9 images. Of the 91 negative images, the three raters were in complete agreement for 75 images and in disagreement for 16 images. Interrater reliability among the three experts was particularly high, with both Fleiss' kappa and Conger's kappa measuring 0.83 (0.76-0.89). The CL values of the unanimous positive group were significantly greater than those of the other groups, whereas the CL values of the unanimous negative group were significantly lower than those of the other groups. Images with rater disagreement had intermediate CLs. In cases with a high confidence level, the positive or negative visual ratings were in almost complete agreement. However, as confidence levels decreased, experts' visual ratings became more variable. The lower the confidence level was, the greater the number of cases with disagreement in the visual ratings. Three experts independently rated 192 amyloid PET images, achieving a high level of interrater agreement. However, in patients with intermediate amyloid accumulation, visual ratings varied. Therefore, determining positive and negative decisions in these patients should be performed with caution.

Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease.

Accumulation of pathological tau isoforms, especially hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers, has been demonstrated in the retinas of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Previous studies have noted a decrease in retinal ganglion cells (RGCs) in AD patients, but the presence and impact of pathological tau isoforms in RGCs and RGC integrity, particularly in early AD stages, have not been explored. To investigate this, we examined retinal superior temporal cross-sections from 25 patients with MCI (due to AD) or AD dementia and 16 cognitively normal (CN) controls, matched for age and gender. We utilized the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining to assess neuronal density in the ganglion cell layer (GCL). Our study found that hypertrophic RGCs containing pS396-tau and T22-positive tau oligomers were more frequently observed in MCI and AD patients compared to CN subjects. Quantitative analyses indicated a decline in RGC integrity, with 46-55% and 55-56% reductions of RBPMS+ RGCs (P<0.01) and Nissl+ GCL neurons (P<0.01-0.001), respectively, in MCI and AD patients. This decrease in RGC count was accompanied by increases in necroptotic-like morphology and the cleaved caspase-3 apoptotic marker in RGCs of AD patients. Furthermore, there was a 2.1 to 3.1-fold increase (P<0.05-0.0001) in pS396-tau-laden RGCs in MCI and AD patients, with a greater abundance observed in individuals with higher Braak stages (V-VI), more severe clinical dementia ratings (CDR=3), and lower mini-mental state examination (MMSE) scores. Strong correlations were noted between the decline in RGCs and the total amount of retinal pS396-tau and pS396-tau+ RGCs, with pS396-tau+ RGC counts correlating significantly with brain neurofibrillary tangle scores (r= 0.71, P= 0.0001), Braak stage (r= 0.65, P= 0.0009), and MMSE scores (r= -0.76, P= 0.0004). These findings suggest that retinal tauopathy, characterized by pS396-tau and oligomeric tau in hypertrophic RGCs, is associated with and may contribute to RGC degeneration in AD. Future research should validate these findings in larger cohorts and explore noninvasive retinal imaging techniques that target tau pathology in RGCs to improve AD detection and monitor disease progression.

Novel hippocampus-centered methodology for informative instance selection in Alzheimer's disease data

The quantity and quality of a dataset play a crucial role in the performance of prediction models. Increasing the amount of data increases the computational requirements and can introduce negligible variations, outliers, and noise. These significantly impact the model performance. Thus, instance selection techniques are crucial for building prediction models with informative data, reducing the dataset size, improving performance, and minimizing computational costs. This study proposed a novel methodology for identifying the most informative two-dimensional slices derived from magnetic resonance imaging (MRI) to study Alzheimer's disease. The efficacy of our methodology was attributable to a hippocampus-centered analysis using data from multiple atlases. The methodology was evaluated by constructing convolutional neural networks to identify Alzheimer's disease, using a consolidated dataset constructed from three standard datasets: Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing, and Open Access Series of Imaging Studies. The proposed methodology demonstrated a commendable subject-level classification accuracy of approximately (95.00%) when distinguishing between normal cognition and Alzheimer's.

Cardiovascular dysautonomia and cognitive impairment in Parkinson's disease (Review).

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), which can result in significant disability and distress for patients and caregivers. There is a marked variation in the timing, characteristics and rate at which cognitive decline occurs in patients with PD. This decline can vary from normal cognition to mild cognitive impairment and dementia. Cognitive impairment is associated with several pathophysiological mechanisms, including the accumulation of β-amyloid and tau in the brain, oxidative stress and neuroinflammation. Cardiovascular autonomic dysfunctions are commonly observed in patients with PD. These dysfunctions play a role in the progression of cognitive impairment, the incidents of falls and even in mortality. The majority of symptoms of dysautonomia arise from changes in the peripheral autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. Cardiovascular changes, including orthostatic hypotension, supine hypertension and abnormal nocturnal blood pressure (BP), can occur in both the early and advanced stages of PD. These changes tend to increase as the disease advances. The present review aimed to describe the cognitive changes in the setting of cardiovascular dysautonomia and to discuss strategies through which these changes can be modified and managed. It is a multifactorial process usually involving decreased blood flow to the brain, resulting in the development of cerebral ischemic lesions, an increased presence of abnormal white matter signals in the brain, and a potential influence on the process of neurodegeneration in PD. Another possible explanation is this association being independent observations of PD progression. Patients with clinical symptoms of dysautonomia should undergo 24-h ambulatory BP monitoring, as they are frequently subtle and underdiagnosed.

Relationships between Serum Lipid, Uric Acid Levels and Mild Cognitive Impairment in Parkinson's Disease and Multiple System Atrophy.

Mild cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD) and multiple system atrophy (MSA). Few studies have previously been conducted on the correlation between serum uric acid (SUA) and lipid levels and mild cognitive impairment in PD and MSA. Participants included 149 patients with PD and 99 patients with MSA. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Evaluations were conducted on SUA and lipid levels, which included triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC). Patients with PD and MSA diagnosed with mild cognitive impairment demonstrated multiple cognitive domain impairment when compared with patients with normal cognition. Attentional impairment was more pronounced in patients with MSA when compared with PD (p = 0.001). In PD, the risk of mild cognitive impairment was lower in the highest quartiles and secondary quartile of SUA than in the lowest quartiles (odds ratio [OR] = 0.281, 95% confidence intervals [CI]: 0.097-0.810, p = 0.019; and OR = 0.317, 95% CI: 0.110-0.911, p = 0.033). In MSA, the risk of mild cognitive impairment was lower in the third and highest quartile of SUA than in the lowest quartile (OR = 0.233, 95% CI: 0.063-0.868, p = 0.030; and OR = 0.218, 95% CI: 0.058-0.816, p = 0.024). In patients with PD, the MoCA scores were negatively correlated with TC levels (r = -0.226, p = 0.006) and positively correlated with SUA levels (r = 0.206, p = 0.012). In MSA, the MoCA scores were positively correlated with SUA levels (r = 0.353, p = 0.001). Lower SUA levels and higher TC levels are a possible risk factor for the risk and severity of mild cognitive impairment in PD. Lower SUA levels are a possible risk factor for the risk and severity of mild cognitive impairment in MSA.

Association of education attainment, smoking status, and alcohol use disorder with dementia risk in older adults: a longitudinal observational study

BackgroundPrevious research on the risk of dementia associated with education attainment, smoking status, and alcohol use disorder (AUD) has yielded inconsistent results, indicating potential heterogeneous treatment effects (HTEs) of these factors on dementia risk. Thus, this study aimed to identify the important variables that may contribute to HTEs of these factors in older adults.MethodsUsing 2005–2021 data from the National Alzheimer’s Coordinating Center (NACC), we included older adults (≥ 65 years) with normal cognition at the first visit. The exposure of interest included college education or above, current smoking, and AUD and the outcome was all-cause dementia. We applied doubly robust learning to estimate risk differences (RD) and 95% confidence intervals (CI) between exposed and unexposed groups in the overall cohort and subgroups identified through a decision tree model.ResultsOf 10,062 participants included, 929 developed all-cause dementia over a median 4.4-year follow-up. College education or above was associated with a lower risk of all-cause dementia in the overall population (RD, -1.5%; 95%CI, -2.8 to -0.3), especially among the subpopulations without hypertension, regardless of the APOE4 status. Current smoking was not related to increased dementia risk overall (2.8%; -1.5 to 7.2) but was significantly associated with increased dementia risk among men with (21.1%, 3.1 to 39.1) and without (8.4%, 0.9 to 15.8) cerebrovascular disease. AUD was not related to increased dementia risk overall (2.0%; -7.7 to 11.7) but was significantly associated with increased dementia risk among men with neuropsychiatric disorders (31.5%; 7.4 to 55.7).ConclusionsOur studies identified important factors contributing to HTEs of education, smoking, and AUD on risk of all-cause dementia, suggesting an individualized approach is needed to address dementia disparities.

A new test for evaluation of marginal cognitive function deficits in idiopathic normal pressure hydrocephalus through expressing texture recognition by sound symbolic words.

The number of dementia patients is increasing with population aging. Preclinical detection of dementia in patients is essential for access to adequate treatment. In previous studies, dementia patients showed texture recognition difficulties. Onomatopoeia or sound symbolic words (SSW) are intuitively associated with texture impressions and are less likely to be affected by aphasia and description of material perception can be easily obtained. In this study, we aimed to create a test of texture recognition ability expressed by SSW to detect the presence of mild cognitive disorders. The sound symbolic words texture recognition test (SSWTRT) is constructed from 12 close-up photos of various materials and participants were to choose the best SSW out of 8 choices to describe surface texture in the images in Japanese. All 102 participants seen in Juntendo University Hospital from January to August 2023 had a diagnosis of possible iNPH (age mean 77.9, SD 6.7). The answers were scored on a comprehensive scale of 0 to 1. Neuropsychological assessments included MMSE, FAB, and the Rey Auditory Verbal Learning Test (RAVLT), Pegboard Test, and Stroop Test from the EU-iNPH Grading Scale (GS). In study 1 the correlation between SSWTRT and the neuropsychological tests were analyzed. In study 2, participants were divided into two groups: the Normal Cognition group (Group A, n = 37) with MMSE scores of 28 points or above, and the Mild Cognitive Impairment group (Group B, n = 50) with scores ranging from 22 to 27 points, and its predictability were analyzed. In study 1, the total SSWTRT score had a moderate correlation with the neuropsychological test results. In study 2, there were significant differences in the SSWTRT scores between groups A and B. ROC analysis results showed that the SSWTR test was able to predict the difference between the normal and mildly impaired cognition groups. The developed SSWTRT reflects the assessment results of neuropsychological tests in cognitive deterioration and was able to detect early cognitive deficits. This test not only relates to visual perception but is likely to have an association with verbal fluency and memory ability, which are frontal lobe functions.

Life-space mobility and cognition in community-dwelling late-life women: A cross-sectional analysis.

Life-space mobility captures the daily, enacted mobility of older adults. We determined cross-sectional associations between life-space mobility and cognitive impairment (CI) among community-dwelling women in the 9th and 10th decades of life. A total of 1375 (mean age 88 years; 88% White) community-dwelling women enrolled in a prospective cohort of older women. Life-space score was calculated with range 0 (daily restriction to one's bedroom) to 120 (daily trips leaving town without assistance) and categorized (0-20, 21-40, 41-60, 61-80, 81-120). The primary outcome was adjudicated CI defined as mild cognitive impairment or dementia; scores on a 6-test cognitive battery were secondary outcomes. Compared to women with life-space scores of 81-120 and after adjustment for demographics and depressive symptoms, the odds of CI was 1.4-fold (OR 1.36, 95% CI 0.91-2.03) higher for women with life-space scores of 61-80, twofold (OR 1.98, 95% CI 1.33-2.94) higher for women with life-space scores of 41-60, 2.6-fold (OR 2.62, 95% CI 1.71-4.01) higher for women with life-space scores of 21-40, and 2.7-fold (OR 2.71, 95% CI 1.27-5.79) higher for women with life-space scores of 0-20. The association of life-space scores with adjudicated CI was primarily due to higher odds of dementia; the odds of dementia versus normal cognition was eightfold (OR 8.63, 95% CI 3.20-23.26) higher among women with life-space scores of 0-20 compared to women with life-space scores of 81-120. Lower life-space scores were associated in a graded manner with lower mean scores on tests of delayed recall (California Verbal Learning Test-II delayed recall) and language and executive function (phonemic fluency, category fluency, and Trails B). Life-space score was not associated with scores on tests of attention and working memory (forward and backward digit span). Lower life-space mobility is associated in a graded manner with CI among community-dwelling White women in the 9th and 10th decades of life.

Resting-state functional connectivity abnormalities in subjective cognitive decline: A 7T MRI study

Resting-state functional connectivity (FC) MRI is sensitive to brain changes in Alzheimer’s disease in preclinical stages, however studies in persons with subjective cognitive decline (SCD) have reported conflicting findings, and no study is available at 7T MRI. In this study, we investigated FC alterations in sixty-six participants recruited at the Geneva Memory Center (24 controls, 14 SCD, 28 cognitively impaired [CI]). Participants were classified as SCD if they reported cognitive complaints without objective cognitive deficits, and underwent 7T fMRI to assess FC in canonical brain networks and their association with cognitive/clinical features. SCD showed normal cognition, a trend for higher depressive symptoms, and normal AD biomarkers. Compared to the other two groups, SCD showed higher FC in frontal default mode network (DMN) and insular and superior temporal nodes of ventral attention network (VAN). Higher FC in the DMN and VAN was associated with worse cognition but not depression, suggesting that hyper-connectivity in these networks may be a signature of age-related cognitive decline in SCD at low risk of developing AD.

Relationships between brain structure-function coupling in normal aging and cognition: A cross-ethnicity population-based study

Increased efforts in neuroscience seek to understand how macro-anatomical and physiological connectomes cooperatively work to generate cognitive behaviors. However, the structure-function coupling characteristics in normal aging individuals remain unclear. Here, we developed an index, the Coupling in Brain Structural connectome and Functional connectome (C-BSF) index, to quantify regional structure-function coupling in a large community-based cohort. C-BSF used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) data from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study (PRECISE) cohort (2007 individuals, age: 61.15 ± 6.49 years) and the Sydney Memory and Ageing Study (MAS) cohort (254 individuals, age: 83.45 ± 4.33 years). We observed that structure-function coupling was the strongest in the visual network and the weakest in the ventral attention network. We also observed that the weaker structure-function coupling was associated with increased age and worse cognitive level of the participant. Meanwhile, the structure-function coupling in the visual network was associated with the visuospatial performance and partially mediated the connections between age and the visuospatial function. This work contributes to our understanding of the underlying brain mechanisms by which aging affects cognition and also help establish early diagnosis and treatment approaches for neurological diseases in the elderly.

A - 114 Exploring Alzheimer’s Disease: the Interplay of Depression, Substance Use, and Neurocognition

Abstract Objective Depression and substance use (SU) can significantly impact one’s neurocognition and are potential risk factors for Alzheimer’s Disease (ad). The project aimed to explore whether a history of depression and/or SU could predict baseline performance on neuropsychological assessment among individuals with and without ad. Method Data from the National Alzheimer’s Coordinating Center (NACC) was analyzed. N = 9114 participants (41.5% Male, 58.5% Female; 56.7% Normal Cognition, 43.2% ad) at their first visit were selected. A series of linear regression models, separated by presence of ad diagnosis, were run to determine if a history of depression, and/or SU, age, race, sex, education level, and APOE status would predict performance on selected neuropsychological assessments measuring facets of executive functioning (EF) (Trail Making, Digit Span, and Wechsler Adult Intelligence Scale (WAIS)). Results Depression was a significant predictor of performance on the WAIS in the normal cognition (β = −0.12,p &amp;lt; 0.001) and ad (β = −0.14,p &amp;lt; 0.001) groups, on Number of Correct Digit Span Backward Trials in the normal cognition (β = 0.09,p &amp;lt; 0.01) and ad (β = −0.10,p &amp;lt; 0.01) groups, and on Number of Correct Digit Span Forward Trials in the ad group (β = −0.11,p &amp;lt; 0.001). SU was a significant predictor of performance on Number of Correct Digit Span Backward Trials in the ad group (β = 0.20,p &amp;lt; 0.01). Demographic variables were also significant. Conclusions Depression predicted performance on multiple neuropsychological assessments across diagnostic groups compared to SU. EF facets measured across assessments may have been further impacted by ad and mental health history compared to those with normal cognition endorsing mental health history.

A - 79 Comparison of Neuropsychological Test Performance between Monolingual Older Adults with Varying Cognitive Profiles

Abstract Objective With the rapid aging and cultural differences of the Latinx population, psychologists have expressed concerns regarding neuropsychological evaluations used for Alzheimer’s disease (ad), including the appropriateness of normative data and misinterpretation of test scores. This study explores various facets of neuropsychological performance between Spanish and English-speaking older adults with ad or normal cognition (NC). Method Participants (N = 17,716) from a de-identified database from the National Alzheimer’s’ Coordinating Center were administered Boston Naming Test-30 items (BNT-30), Animal &amp; Vegetable Verbal Fluency, Digit Symbol, Mini-Mental Status Examination (MMSE), Logical Memory I &amp; II (LM-I &amp; II), and Trail Making Test A &amp; B (TMT-A &amp; B). Correlations, multiple linear hierarchical regressions, and two-factor Analyses of Variance (ANOVAs) were used. Results Significant associations between interest areas (e.g., sex, ethnicity, race, age, education level, and/or age of cognitive onset) and test performances were found in each diagnosis group. Primary language, education level, and diagnosis were found to be significant predictors of LM-I (f2 = 0.19), LM-II (f2 = 0.22), and TMT-B (f2 = 0.15) performance. Significant interactions of primary language and diagnosis group were found among test performances for the MMSE, LM-II, Animals Verbal Fluency, TMT-A, and TMT-B (p &amp;lt; 0.05). Conclusions Further research is warranted to understand the complexity of using neuropsychological assessments to detect ad-related deficits among Spanish-speaking Latinx individuals. Evidence-based neuropsychological practice guidelines must acknowledge the importance of education level and primary language on test performance.

The Relevance of Dual Language Experience in Interhemispheric Brain Connectivity in Older Adults

Abstract Objectives to analyze the volumes of sections of the corpus callosum (CC) and the integrity of the interhemispheric fibers that connect homotopic regions of the frontal and temporal lobes in bilinguals and monolinguals and to correlate neuroimaging data with cognitive measures and bilingual variables. Method 107 bilinguals and 89 monolinguals from the 1Florida ADRC were clinically diagnosed as cognitively normal (CN), MCI, or dementia; mean age = 71.28 (10.94). CC volume was calculated from a T1-weighted scan using Freesurfer. Free water (FW) and free water-corrected fractional anisotropy (FAt) maps were calculated from a diffusion MRI scan within frontal and temporal transcallosal tracts (TCATT). Results Bilinguals had a larger proportion of the anterior CC volume compared to monolinguals independent of the diagnostic group. FAt values in the Supplementary Motor Area (SMA) and the inferior temporal lobe tracts (IT TCATTs) were higher in bilinguals compared to monolinguals indicating better white matter integrity. A significant interaction demonstrated that these values were higher in bilinguals for the dementia group. Correlations were significant between the SMA FW values and several cognitive tests particularly executive function tests in both language groups. In bilinguals, the IT TCATTs correlated with language test scores. FAt in the SMA TCATT correlated with the percentage of English exposure and FAt in the IT TCATTs positively correlated with English proficiency. Conclusions Bilingualism interacts with cognitive status in aging and is associated with CC volume and the integrity of white matter in the frontal and temporal lobes supporting its role in the increase of neural reserve.

Comorbidity-based framework for Alzheimer’s disease classification using graph neural networks

Alzheimer’s disease (AD), the most prevalent form of dementia, requires early prediction for timely intervention. Current deep learning approaches, particularly those using traditional neural networks, face challenges such as handling high-dimensional data, interpreting complex relationships, and managing data bias. To address these limitations, we propose a framework utilizing graph neural networks (GNNs), which excel in modeling relationships within graph-structured data. Our study employs GNNs on data from the Alzheimer’s Disease Neuroimaging Initiative for binary and multi-class classification across the three stages of AD: cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). By incorporating comorbidity data derived from electronic health records, we achieved the most effective multi-classification results. Notably, the GNN model (Chebyshev Convolutional Neural Networks) demonstrated superior performance with a 0.98 accuracy in multi-class classification and 0.99, 0.93, and 0.94 in the AD/CN, AD/MCI, and CN/MCI binary tasks, respectively. The model’s robustness was further validated using the Australian Imaging, Biomarker & Lifestyle dataset as an external validation set. This work contributes to the field by offering a robust, accurate, and cost-effective method for early AD prediction (CN vs. MCI), addressing key challenges in existing deep learning approaches.

Enlarged Perivascular Spaces Are Independently Associated with High Pulse Wave Velocity: A Cross-Sectional Study.

Recent studies have demonstrated an association between pulse wave velocity (PWV), cerebral small vessel disease (SVD), and cognitive impairment such as Alzheimer's disease. However, the association between brachial-ankle PWV and enlarged perivascular spaces (EPVS), one component of cerebral SVD remains controversial. To investigate the relationship between brachial-ankle PWV and EPVS severity in participants without dementia. We performed a cross-sectional study of data of 74 participants from sub-analysis of ongoing research. We assessed cognitive function, brachial-ankle PWV, and brain magnetic resonance imaging (MRI) features. Using brain MRI, EPVS were separately assessed as basal ganglia (BG)-EPVS or centrum semiovale (CSO)-EPVS on the basis of their location. The relationship between EPVS severity and brachial-ankle PWV was evaluated using multivariable ordinal logistic regression analyses. We analyzed 74 participants (women: 47%, mean age: 73 years, mild cognitive impairment [MCI]: 74%). Compared with participants with normal cognition, those with MCI were more likely to have both severe BG-EPVS and severe CSO-EPVS. In multivariable analyses, high brachial-ankle PWV and age were independently associated with BG-EPVS severity (odds ratio [95% confidence interval]: 1.19 [1.02-1.38], 1.09 [1.01-1.17], respectively), whereas only age was independently associated with CSO-EPVS severity. A causal mediation analysis under a counterfactual approach revealed a significant pure natural indirect effect of brachial-ankle PWV on MCI that was mediated by BG-EPVS (estimate: 1.04, 95% CI: 1.01-1.12, p = 0.006). Brachial-ankle PWV was associated with BG-EPVS severity. High PWV may cause cerebrovascular pulsatility, which accelerates BG-EPVS and may worsen cognitive impairment.

Cerebral white matter damage in patients with end stage kidney disease associates with cognitive impairment

Abstract Background and hypothesis Damages in brain white matter often occurs in individuals with chronic kidney disease, which might be related to their cognitive decline. This study aims to investigate tract specific white matter damage in patients with end stage renal disease by using fixel based analysis. Methods Images of 31 end stage renal disease patients and 16 normal controls (aged: 61.1 ± 10.4 years; 11 men) were acquired from a 1.5 T MR scanner. The patients were subsequently divided into with normal cognition (N = 17, aged: 66.9 ± 7.2 years; 10 men) and cognitive impairment (N = 14, aged: 72.4 ± 9.4 years; 7 men). Cognitive assessment, neurologic, hematologic and biochemical samples were collected. Fixel-based analysis was used to examine the tract-specific damage within white matter. Differences between groups were evaluated through connectivity-based fixel enhancement and non-parametric permutation testing. Correlation with biomarkers was conducted through general linear model. Significance was determined with familywise error-corrected p-value &amp;lt; 0.05. Results Reduced fixel-based metrics were observed in specific tract located the cerebral peduncle, internal capsule, corpus callosum, fornix, and superior corona radiata in patients when compared to normal controls, indicating a reduction in fiber content. The fibers crossing the corpus callosum and the fornix/stria terminalis are particularly vulnerable sites, which can be associated with the decrease in both Mini-Mental State Examination (R2 ranged between 0.420 and 0.556) and Montreal Cognitive Assessment (R2 ranged between 0.425 and 0.509), as well as the plasma concentration of calcium (R2 ranged between 0.207 and 0.322). The plasma concentration of indoxyl sulfate was associated with the descending tracts from right posterior limb of internal capsule to cerebral peduncle (R2 ranged between 0.262 and 0.335). Conclusions Tract specific white matter damage can be noticed in the patients with end stage renal disease, and can be associated with their cognitive decline.

CD14+CD16+ monocyte transmigration across the blood-brain barrier is associated with HIV-NCI despite viral suppression.

HIV-associated neurocognitive impairment (HIV-NCI) affects 15%-50% of people with HIV (PWH), despite viral suppression with antiretroviral therapy (ART). HIV neuropathogenesis is mediated, in part, by transmigration of infected CD14+CD16+ monocytes across the blood-brain barrier (BBB) into the central nervous system (CNS). In the CNS, CD14+CD16+ monocytes contribute to infection and activation of parenchymal cells, resulting in production of neurotoxic viral and host factors that cause neuronal damage. Mechanisms by which CD14+CD16+ monocytes contribute to HIV-NCI have not been characterized in a study population of PWH on ART without contribution from confounders that affect cognition (e.g., substance use, hepatitis C virus coinfection). We assessed cognitive function, PBMC transmigration across the BBB, and neuronal health markers in a well-defined cohort of 56 PWH on ART using stringent criteria to eliminate confounding factors. We demonstrated that PWH on ART with HIV-NCI have significantly increased transmigration of their CD14+CD16+ monocytes across the BBB compared with those with normal cognition. We showed that hypertension and diabetes may be effect modifiers on the association between CD14+CD16+ monocyte transmigration and cognition. This study underscored the persistent role of CD14+CD16+ monocytes in HIV-NCI, even in PWH with viral suppression, suggesting them as potential targets for therapeutic interventions.

Impact of Cognitive Impairment on Long-Term Outcomes After Transcatheter Aortic Valve Implantation.

Cognitive impairment assessed using the Mini-Mental Status Examination (MMSE) is associated with short-term mortality after transcatheter aortic valve implantation (TAVI). We assessed the long-term prognostic impact of cognitive impairment in patients with severe aortic stenosis post-TAVI. We enrolled 1,057 consecutive patients who underwent TAVI at the Kokura Memorial Hospital and prospectively assessed them using the MMSE. Results showed that 319 (30%) patients had cognitive impairment. Compared with normal cognition, cognitive impairment was associated with an increased risk for 5-year all-cause mortality (55% vs. 39%; P<0.001), cardiovascular mortality (23% vs. 14%; P=0.007), and non-cardiovascular mortality (42% vs. 29%; P<0.001). Multivariable analysis showed that cognitive impairment was independently associated with all-cause mortality (adjusted hazard ratio [aHR] 1.37; 95% confidence interval [CI] 1.10-1.70; P=0.005), and this result was consistent regardless of stratification based on age, sex, body mass index, left ventricular ejection fraction and clinical frailty scale without significant interaction. Patients with MMSE scores <16 had a significantly higher mortality rate compared with patients with MMSE scores >25, 21-25, and 16-20, respectively. Cognitive impairment assessed using MMSE scores is independently associated with an increased risk for 5-year all-cause mortality in patients undergoing TAVI.

Characteristics of Alzheimer’s Disease and Mild Cognitive Impairment Influenced by the Time of Onset

Introduction: Although the prevalence of Alzheimer’s disease (AD) is higher in older people compared to younger people, dementia has also been documented in younger adults. Although early-onset dementia and late-onset dementia had been considered a single disease in pathological investigations, many studies revealed differences in cognitive and neuroimaging changes between them. We evaluated differences in cognitive and neuroimaging changes among the following groups: individuals with early-onset AD (EOAD), late-onset AD (LOAD), early-onset mild cognitive impairment (EOMCI), or late-onset MCI (LOMCI), and healthy controls (HCs). Methods: Patients underwent both a 1.5 Tesla magnetic resonance imaging scan and the Mini-Mental State Examination (MMSE). Differences in regional gray matter volumes and MMSE subscales were investigated among the five diagnostic groups. Results: Compared to the EOAD group, the LOAD group had significantly higher scores on orientation in place. Compared to the LOMCI patients, the EOMCI patients achieved significantly higher recall scores. The LOAD and LOMC groups showed significant volume reductions in bilateral medial temporal regions compared to the HCs. The EOAD and EOMCI groups did not show significant atrophy of the medial temporal region compared to the HC group. Conclusions: The hippocampal volume and memory were preserved in the patients with EOMCI or EOAD compared to those with LOMCI or LOAD. These findings may indicate that the distinct and differing patterns of neuropsychological changes between EOAD and LOAD are also common in MCI, which is intermediate between normal cognition and AD.

Associations between differential connectivity patterns of executive control networks and APOE ɛ4 in the Alzheimer continuum

The APOE ɛ4 allele and age are risk factors for Alzheimer’s disease (AD) and contribute to decreased executive function. However, the influence of APOE ɛ4 on the executive control network (ECN) in the AD continuum is still unclear. This study included 269 participants aged between 50 and 95 years old, based on ADNI data, including 104 cognitively normal (CN) individuals, 72 individuals with early mild cognitive impairment (EMCI), 55 individuals with late mild cognitive impairment (LMCI), and 38 AD patients. Within each disease group, participants were subdivided into APOE ɛ4 carriers and non-carriers. We explored brain regions within the ECN affected by the interactions between genes and disease states by resting-state functional magnetic resonance imaging (fMRI) and voxel-based two-way analysis of variance (ANOVA). Subsequently, functional connectivity (FC) between seeds and peak clusters were extracted and correlated with the cognitive performance. We found that the damages of carrying APOE ɛ4 in ECNs mainly distributed in the fronto-parietal and parietal-temporal systems. Functional network intergroup differences indicated increased intrafrontal and fronto-parietal connectivity at the early stage of AD and increased connectivity between the parietal lobe and related regions at late disease in these APOE ɛ4 carriers. Our conclusion is that the functional connectivity in the ECN exhibits different distinguishably patterns of impairment in the AD continuum under the influence of the APOE ɛ4 allele. Patients with different genotypes showed heterogeneity in functional network changes in the early stages of disease, which may be a potential biomarker for early AD.