Cognitive Brain Research Articles

Impact of increasing one-carbon metabolites on traumatic brain injury outcome using pre-clinical models.

Traumatic brain injury is a major cause of death and disability worldwide, affecting over 69 million individuals yearly. One-carbon metabolism has been shown to have beneficial effects after brain damage, such as ischemic stroke. However, whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation. The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury. PubMed, Web of Science, and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes. The search terms included combinations of the following words: traumatic brain injury, dietary supplementation, one-carbon metabolism, and B-vitamins. The focus of each literature search was basic science data. The year of publication in the literature searches was not limited. Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recovery of animals with traumatic brain injury compared to controls. However, this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delivery of vitamin supplementation post-traumatic brain injury. The details of supplementation post-traumatic brain injury need to be further investigated. Overall, we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems. Further investigation in a clinical setting should be strongly considered in conjunction with current medical treatments for traumatic brain injury-affected individuals.

Rates of ICD-10 Code U09.9 Documentation and Clinical Characteristics of VA Patients With Post–COVID-19 Condition

A significant proportion of SARS-CoV-2 infected individuals experience post-COVID-19 condition months after initial infection. To determine the rates, clinical setting, risk factors, and symptoms associated with the documentation of International Statistical Classification of Diseases Tenth Revision (ICD-10), code U09.9 for post-COVID-19 condition after acute infection. This retrospective cohort study was performed within the US Department of Veterans Affairs (VA) health care system. Veterans with a positive SARS-CoV-2 test result between October 1, 2021, the date ICD-10 code U09.9 was introduced, and January 31, 2023 (n = 388 980), and a randomly selected subsample of patients with the U09.9 code (n = 350) whose symptom prevalence was assessed by systematic medical record review, were included in the analysis. Positive SARS-CoV-2 test result. Rates, clinical setting, risk factors, and symptoms associated with ICD-10 code U09.9 in the medical record. Among the 388 980 persons with a positive SARS-CoV-2 test, the mean (SD) age was 61.4 (16.1) years; 87.3% were men. In terms of race and ethnicity, 0.8% were American Indian or Alaska Native, 1.4% were Asian, 20.7% were Black, 9.3% were Hispanic or Latino, 1.0% were Native Hawaiian or Other Pacific Islander; and 67.8% were White. Cumulative incidence of U09.9 documentation was 4.79% (95% CI, 4.73%-4.87%) at 6 months and 5.28% (95% CI, 5.21%-5.36%) at 12 months after infection. Factors independently associated with U09.9 documentation included older age, female sex, Hispanic or Latino ethnicity, comorbidity burden, and severe acute infection manifesting by symptoms, hospitalization, or ventilation. Primary vaccination (adjusted hazard ratio [AHR], 0.80 [95% CI, 0.78-0.83]) and booster vaccination (AHR, 0.66 [95% CI, 0.64-0.69]) were associated with a lower likelihood of U09.9 documentation. Marked differences by geographic region and facility in U09.9 code documentation may reflect local screening and care practices. Among the 350 patients undergoing systematic medical record review, the most common symptoms documented in the medical records among patients with the U09.9 code were shortness of breath (130 [37.1%]), fatigue or exhaustion (78 [22.3%]), cough (63 [18.0%]), reduced cognitive function or brain fog (22 [6.3%]), and change in smell and/or taste (20 [5.7%]). In this cohort study of 388 980 veterans, documentation of ICD-10 code U09.9 had marked regional and facility-level variability. Strong risk factors for U09.9 documentation were identified, while vaccination appeared to be protective. Accurate and consistent documentation of U09.9 is needed to maximize its utility in tracking patients for clinical care and research. Future studies should examine the long-term trajectory of individuals with U09.9 documentation.

Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models.

Alzheimer's disease (AD) is a progressive memory loss and cognitive dysfunction brain disorder brought on by the dysfunctional amyloid precursor protein (APP) processing and clearance of APP peptides. Increased APP levels lead to the production of AD-related peptides including the amyloid APP intracellular domain (AICD) and amyloid beta (Aβ), and consequently modify the intrinsic excitability of the hippocampal CA1 pyramidal neurons, synaptic protein activity, and impair synaptic plasticity at hippocampal CA1-CA3 synapses. The goal of the present study is to build computational models that incorporate the effect of AD-related peptides on CA1 pyramidal neuron and hippocampal synaptic plasticity under the AD conditions and investigate the potential pharmacological treatments that could normalize hippocampal synaptic plasticity and learning in AD. We employ a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model that includes the separate receptor contributions on long-term potentiation (LTP) and long-term depression (LTD) and embed it into the a detailed compartmental model of CA1 pyramidal neuron. Modeling results show that partial blockade of Glu2NB-NMDAR-gated channel restores intrinsic excitability of a CA1 pyramidal neuron and rescues LTP in AICD and Aβ conditions. The model provides insight into the complex interactions in AD pathophysiology and suggests the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree of CA1 pyramidal neuron leads to restored synaptic plasticity.

A Quasi-Experimental Study on the Effectiveness of Early Interventional Techniques on Self-Esteem

Background: specific learning disability (SLD) as it is known is an aberration in the underpinning psychological process that exhibits itself in the flawed ability to think, listen, talk, read, and write. It can also be connected to spelling difficulties, mathematical derivations, and calculations. It tends to be related to cognitive impairments or brain injuries spurred by neurological disarray, aphasia, or additional problems.Aim: this specific review aims to summarise interventional techniques, stability of individual self-esteem, other societal-related skills, academic skills, and others among children with SLD. It is necessary to determine which interventional strategies can be implemented to assist kids with SLD issues identified in schools or academic centres to enhance their self-esteem, social skills and academic achievements.Methods: the articles were searched in databases like PubMed, Web of Science, Psyc INFO, and CINAHL with Boolean like “specific learning disabilities children” AND “intervention” OR “Self-esteem”, “Social skills” AND “Academic achievements”.Results: in the empirical studies, five objects were identified as appropriate for the research. Many types of interventions have been used to assess appreciation or liking for self-esteem, social skills, and vital academic skills among children of SLD.Children who underwent an experimental program receiving the Feuerstein Instrumental Enrichment Program reflected an increase in some of the cognitive functions. The student’s ability to execute data processing approaches during their academic activities hasimproved when the ability to recall, perceive, schedule, and executive intervention system is combined with other quadrant paradigms. Significant advancement was noticed in self-esteem, social skills and academic excellence. All these were possible due to a positive approach to the intervention. Conclusions: in the evaluation review, the researcher highlights how children with SLD perform better and that the positive psychological interventions examined have entirely eradicated all of their adverse effects. In this regard, there is a requirement to provide inclusive education for kids with Specific Learning Disabilities (SLD) and for persevering with SLD-related experimentation procedures

Grey matter volume predicts improvement in geriatric depression in response to Tai Chi compared to Health Education.

Geriatric depression (GD) is associated with cognitive impairment and brain atrophy. Tai-Chi-Chih (TCC) is a promising adjunct treatment to antidepressants. We previously found beneficial effects of TCC on resting state connectivity in GD. We now tested the effect of TCC on gray matter volume (GMV) change and the association between baseline GMV and clinical outcome. Forty-nine participants with GD (>=60 y) underwent antidepressant treatment (38 women). Participants completed 3 months of TCC (N = 26) or health and wellness education control (HEW; N = 23). Depression and anxiety symptoms and MRI scans were acquired at baseline and 3-month follow-up. General linear models (GLMs) tested group-by-time interactions on clinical scores. Freesurfer 6.0 was used to process T1-weighted images and to perform voxel-wise whole-brain GLMs of group on symmetrized percent GMV change, and on the baseline GMV and symptom change association, controlling for baseline symptom severity. Age and sex served as covariates in all models. There were no group differences in baseline demographics or clinical scores, symptom change from baseline to follow-up, or treatment-related GMV change. However, whole-brain analysis revealed that lower baseline GMV in several clusters in the TCC, but not the HEW group, was associated with larger improvements in anxiety. This was similar for right precuneus GMV and depressive symptoms. While we observed no effect on GMV due to the interventions, baseline regional GMV predicted symptom improvements with TCC but not HEW. Longer trials are needed to investigate the long-term effects of TCC on clinical symptoms and neuroplasticity.

Brain connectivity and academic skills in English learners.

English learners (ELs) are a rapidly growing population in schools in the United States with limited experience and proficiency in English. To better understand the path for EL's academic success in school, it is important to understand how EL's brain systems are used for academic learning in English. We studied, in a cohort of Hispanic middle-schoolers (n = 45, 22F) with limited English proficiency and a wide range of reading and math abilities, brain network properties related to academic abilities. We applied a method for localizing brain regions of interest (ROIs) that are group-constrained, yet individually specific, to test how resting state functional connectivity between regions that are important for academic learning (reading, math, and cognitive control regions) are related to academic abilities. ROIs were selected from task localizers probing reading and math skills in the same participants. We found that connectivity across all ROIs, as well as connectivity of just the cognitive control ROIs, were positively related to measures of reading skills but not math skills. This work suggests that cognitive control brain systems have a central role for reading in ELs. Our results also indicate that an individualized approach for localizing brain function may clarify brain-behavior relationships.

Cardiometabolic disease, cognitive decline, and structural brain differences in mid‐ and late‐life: a large population‐based cohort study

AbstractBackgroundThe impact of cardiometabolic diseases (CMDs; including type 2 diabetes [T2D], heart disease [HD], and stroke) on cognitive trajectories and brain structural changes across the life course is unclear. We aimed to explore the association of patterns of co‐morbid CMDs with cognitive decline and structural brain MRI measures in mid‐ vs. late‐ life.MethodWithin the UK Biobank, 46,562 dementia‐free participants aged 40‐70 were followed for 9 years. Baseline CMDs were ascertained medical records. A battery of 5 cognitive tests was administered at baseline and follow‐up and used to derive global and domain‐specific cognitive function scores. A subsample (n = 39,353) underwent brain magnetic resonance imaging (MRI) scans at the follow‐up examination. Volumes of total brain, white matter, grey matter, hippocampus, and white matter hyperintensities (TBV, WMV, GMV, HV, and WMHV) were assessed. Data were analyzed using multivariate adjusted mixed‐effects models and linear regression.ResultAt baseline, 3,437 (7.4%) participants had 1 CMD and 297 (0.6%) had ≥2. In mixed‐effects models, the presence of any CMD was related to a steeper decline in global cognitive function (β [95% confidence interval]: ‐0.005 [‐0.008, ‐0.003]) as well as working memory (‐0.024 [‐0.033, ‐0.014]), visual declarative memory (‐0.004 [‐0.007, ‐0.001]), and processing speed (‐0.002 [‐0.002, ‐0.001]), especially for those with CMD profiles involving T2D and/or HD. In stratified analysis by age (mid‐ [<60] vs. late‐ [≥60] life), CMDs were related to a decline in only processing speed in mid‐life, while in late‐life, CMDs were additionally related to a decline in verbal/numeric reasoning. In linear regression, people with CMDs had significantly lower TBV (‐0.15 [‐0.18, ‐0.12]), GMV (‐0.17 [‐0.20, ‐0.14]), WMV (‐0.11 [‐0.14, ‐0.08]), HV (‐0.14 [‐0.18, ‐0.11]) and significantly higher WMH (0.05 [0.02, 0.09]), and this was exacerbated among people with ≥2 CMDs compared to 1 CMD. Similar results were observed in both mid‐ and late‐life.ConclusionThe presence of CMDs is associated global/domain‐specific cognitive decline and brain MRI measures involving neurodegenerative and vascular markers in both mid‐ and late‐ life. Our findings highlight the need for the effective management of CMDs in mid‐life for the prevention of dementing disorders in late‐life.

Association of cognitive reserve indicator with cognitive decline and structural brain differences in mid‐ and late life: a large population‐based cohort study

AbstractBackgroundCognitive reserve (CR) contributes to preserving cognition when facing brain aging and damage. CR has been linked to reduced dementia risk in late life. However, the association between CR and brain imaging measures, especially in mid‐life, is unclear. We aimed to explore the association of CR with cognitive decline and structural brain differences in mid‐ and late life.MethodWithin the UK Biobank, 42,301 dementia‐free participants aged 40‐70 were followed for a median of 9 (interquartile range: 8 to 10) years. Latent class analysis was used to generate an indicator of CR (categorized as high, moderate, and low) based on education, occupation, and multiple cognitively stimulating activities at baseline. Cognitive tests for global and domain‐specific cognitive function were administrated at baseline and follow‐up. A subsample (n = 34,041) underwent brain magnetic resonance imaging (MRI) scans at the follow‐up examination. Volumes of total brain, white matter, grey matter, hippocampus, and white matter hyperintensities (TBV, WMV, GMV, HV, and WMHV) were assessed. Data were analyzed using mixed‐effects models and linear regression.ResultAt baseline, 16,032 (37.90%), 10,709 (25.32%), and 15,560 (36.78%) participants had low, moderate, and high levels of CR, respectively. In multi‐adjusted mixed‐effects models, compared to low CR, high CR was associated with a slower decline in global cognitive function (β [95% confidence interval, CI]: 0.10 [0.08, 0.11]), prospective memory (0.10 [0.06, 0.15]), fluid intelligence (0.07 [0.04, 0.10]), and reaction time (0.04 [0.02, 0.06]). In MRI data analysis, high CR was related to lesser TBV (‐0.03 [‐0.04, ‐0.02]), WMV (‐0.03 [‐0.04, ‐0.02], GMV (‐0.02 [‐0.04, ‐0.01]), and WMHV (‐0.03 [‐0.05, ‐0.002]), but greater HV (0.04 [0.02, 0.06]) compared to low CR. In analyses stratified by baseline age, the significant associations between high CR and global cognition and TBV were present among both mid‐life (<60 years) and late‐life (≥60 years) participants. The CR‐cognitive decline association remained significant after additional adjustment for MRI measures.ConclusionHigher CR is associated with slower cognitive decline, lesser TBV, greater HV, and lower microvascular burden, especially in mid‐life. The protective role of high CR on cognition is independent of structural brain differences.

Association of resting heart rate with cognitive decline and brain age in older adults: a large‐scale cohort study in the UK Biobank

AbstractBackgroundThe relationship of resting heart rate (RHR), a common indicator of cardiovascular health, with cognitive decline is unclear. We aimed to investigate the association of RHR with cognitive trajectory and brain age assessed by brain Magnetic Resonance Imaging (MRI) in the UK Biobank.MethodWithin the UK Biobank 18,210 chronic brain disorders‐free participants aged 60+ were followed for up to 16 years. RHR was assessed by blood pressure monitor and categorized into <60, 60‐69 (reference), 70‐79, and ≥80 beats per minute (bpm). Cognitive function including global cognition, numeric memory, prospective memory, pairs matching, fluid intelligence, and reaction time was collected at baseline and each follow‐up wave. A subsample of 10,458 participants underwent brain MRI (T1‐weighted MRI, T2‐FLAIR, T2∗, diffusion‐MRI, task fMRI, and resting‐state fMRI) to detect brain age and brain predicted age difference (PAD) using Lasso regression. Data were analyzed using mixed‐effects model and linear regression model.ResultCompared to reference group, RHR≥80 bpm was associated with faster decline in global cognition (β: ‐0.03, 95% confidence interval [CI]: ‐0.05, ‐0.01) and reaction time (β: ‐0.03, 95% CI: ‐0.07, ‐0.01). In the MRI data analysis, RHR≥80 bpm was associated with older brain age (β [95% CI]: 0.50 [0.25, 0.76]) and bigger brain PAD (β [95% CI]: 0.50 [0.26, 0.74]).ConclusionHigher RHR is associated with faster cognitive decline and older brain age. Monitoring and controlling elevated RHR could be a promising interventional target in preserving cognitive function.

Lifestyle activities contribute to cognitive reserve in mid‐life, independently of education, in cognitively healthy middle‐aged individuals at risk for late‐life Alzheimer’s disease

AbstractBackgroundIt is now acknowledged that Alzheimer’s Disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid‐life. Intellectually, physically, and socially stimulating lifestyle activities are associated with maintenance of late‐life cognitive abilities (Chan et al., 2018), and lower cognitive impairment in AD (Livingston et al., 2020). We asked whether such activities contribute to cognitive reserve (CR) from mid‐life, in cognitively healthy individuals who are at risk for late‐life AD.MethodMiddle‐aged individuals (aged 40‐59 years, mean = 52 years) from the PREVENT Dementia study (www.preventdementia.co.uk) were assessed at baseline (N = 210, 62/148 male/female) and two‐year follow‐up (N = 188, 55/133 male/female), with cognitive ability (multidomain battery) and brain health (total grey matter volume, functional brain network segregation) measures. Mid‐life activities were measured using the Lifetime of Experiences Questionnaire, which comprises occupational as well as intellectually, physically, and socially stimulating leisure activities. Dementia risk was assessed with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score.ResultMultivariable linear regression showed that intellectual, physical, and social activities undertaken in mid‐life made a unique contribution to episodic and relational memory in mid‐life, independent of occupation and CAIDE at baseline (β (se) = 0.04 (0.02), p = 0.02, Figure 1a) and follow‐up (β (se) = 0.07 (0.02), p = 0.002, Figure 1b). Furthermore, these activities moderated the relationship between cognitive ability and brain health at follow‐up (β (se) = 3.47 (1.40), p = 0.01), with verbal and visuospatial functions, and short‐term (conjunctive) memory of people with higher activity levels less dependent on their brain functional integrity (Figure 2), consistent with the concept of CR (Brayne et al., 2010). Such a moderation by these mid‐life activities was more prominent in individuals with higher CAIDE scores (β (se) = 4.28 (1.83), p = 0.02, Figure 3).ConclusionThese findings suggest that modifiable lifestyle activities contribute uniquely to CR and may offset cognitive decrements due to AD risk in mid‐life. They support the targeting of modifiable lifestyle activities for the prevention of Alzheimer’s disease.

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology

AbstractBackgroundThe association between hearing impairment and Alzheimer’s disease (AD) and the mechanisms involved remain unclear.MethodsSurvival analyses were performed in 66,577 participants from the UK Biobank to investigate whether hearing impairment is associated with an increased risk of AD. The association of hearing status with cognitive function, brain structure and CSF proteins were explored in cross‐sectional, longitudinal, and mediation analyses across the UK Biobank (n = 165,550), Chinese Alzheimer’s Biomarker and Lifestyle (CABLE, n = 867), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 802).ResultsHearing impairment was associated with an increased risk of AD over 11 years of follow‐up (HR 1.80, 95%CI 1.50‐2.15). Poor hearing status was associated with worse cognitive function in cross‐sectional and longitudinal studies. Moreover, hearing impairment was significantly related to lower volume of the temporal cortex, hippocampus, amygdala, inferior parietal lobe, precuneus and orbitofrontal cortex, to lower integrity of white matter tracts, and to a higher level of CSF tau protein. Mediation analyses showed that brain structure and CSF tau partly mediated the association between hearing impairment and cognitive decline.ConclusionHearing impairment is a risk factor for AD, and is associated with brain structure, tau pathology, and cognitive decline.

What influence does self‐reported history of single or repeated mild TBI have on cognitive performance and brain volume at mid‐life?

AbstractBackgroundThe long‐term consequences of mild traumatic brain injury (mTBI) are poorly understood. Prior studies have shown that a history of mTBI is associated with a 2 fold increase of dementia diagnosis. However, the precise mechanisms for increased dementia risk which could start in mid‐life remain unclear. TBI can cause varying degrees of damage to different regions of the brain, and as a result, may affect distinct subdomains of cognitive function in distinct ways. This study investigated cognitive performance and brain volume among individuals at risk of Alzheimer’s Disease (AD) in mid‐life with a history of self‐reported mTBI.Method578 participants (118 no head injury, 116 single mTBI & 344 repeated mTBI) aged 40‐60 years participating in the PREVENT study, a large cohort study examining the risk of AD in mid‐life, underwent structural 3T MRI and neuropsychometric evaluation (ACE‐III and COGNITO) at baseline. Self‐reported, cross‐sectional data on head injury were collected through the Brain Injury Screening Questionnaire (BISQ). FSL (version 6.0.1) was used to calculate brain volume (correcting for head size). Comparisons between participants with no history of head injury and single or repeated mTBI were done using a one‐way ANOVA.ResultThere was no statistically significant difference in total brain volume between participants with or without a history of mTBI (F(2,576) = 1.24, p = 0.29). There was also no significant difference between self‐reported mTBI and ACE‐III total scores F(2,579) = 0.0112, p = 0.99) or performance on memory (p = 0.87), language (p = 0.24), visuospatial abilities (p = 0.61) and attention (p = 0.14) in the COGNITO battery.ConclusionWe found no evidence that a history of mTBI (single or repeated) is associated with cognitive impairment in this cohort. Future longitudinal studies are necessary to further evaluate self‐reported mTBI and how the aging process might interact with cognitive outcome post‐injury. Future analysis of covariates such as lower socioeconomic status, gender, physical health and history of alcohol/drug use, that are known to impact cognitive performance and are related to greater rates of TBI, will be studied to determine the influence of a history of mTBI on dementia risk.

The circulating sclerostin as a biomarker for brain white matter damage in hemodialysis patients

AbstractBackgroundPatients with kidney disease, especially those receiving hemodialysis, presented a higher risk of cognitive impairment and brain white matter damage than those without kidney disease. Previous research suggests an association between lower bone marrow densities and cognitive impairments. However, the study investigating the relationship between bone turnover biomarkers and brain white matter damage in hemodialysis patients is sparse.MethodsThe enrolled hemodialysis participants were examed on the Fazekas scale of brain magnetic resonance imaging (MRI) white matter lesions and measured 8 bone turnover proteins using the Luminex bead‐based multiplex assay. The Fazekas scale of periventricular lesions was from grade 0 to grade 3. Multivariable ordinal regression and logistic regression models were examined to determine the independent relationship between bone turnover proteins and the Fazekas scale of periventricular lesions.ResultsIn 59 hemodialysis patients, older patients had more periventricular lesions on the Fazekas scale, which was connected with a worse Mini‐Mental State Examination score (MMSE). The serum level of sclerostin, one of eight bone turnover proteins, displayed a dose‐response relationship (P value for trend = 0.004), meaning that a greater sclerostin level was connected with a lower grade on the Fazekas scale. Both the ordinal regression model (odds ratio [OR] 0.886; 95% confidence interval [CI] 0.828‐0.947, P value 0.001) and the logistic regression model (odds ratio [OR] 0.828; 95% 0.712‐0.963, P value = 0.014) determined a negative association between sclerostin and the Fazekas scale of periventricular lesions after complete adjustment for potential confounders.ConclusionsThe brain white matter damage was inversely correlated with the level of circulating sclerostin. Our finding suggested a possible connection between bone turnover proteins and brain damage.

Association of liver dysfunction with incident dementia, cognition, and brain structure

AbstractBackgroundAn association between liver dysfunction and cognitive impairment has been previously identified; however, further clarification is required due to the lack of comprehensive evidence. This study aimed to investigate the association between liver dysfunction and the risk of different types of incident dementia, cognitive function, and brain structural abnormalities.MethodA total of 431,754 UK Biobank participants without dementia at baseline were included between 2006 and 2010. The longitudinal associations between liver dysfunction and incident dementia were assessed using the Cox proportional hazards model, and the relationship between cognitive performance and brain structure was investigated using a linger regression model.ResultAfter 9.04 (Standard Deviation 2.61) years of follow‐up, 5,627 participants were diagnosed with all‐cause dementia, including 2,438 Alzheimer’s disease and 1,312 vascular dementia cases. We found that decreased alanine transaminase (Hazard Ratio 0.992, 95% Confidential Interval 0.989‐0.995, P<0.001) and increased aspartate aminotransferase (HR 1.006, 95% CI 1.002‐1.011, P = 0.002), increased aspartate aminotransferase to alanine transaminase ratio (HR 1.593, 95% CI 1.471‐1.724, P<0.001), increased direct bilirubin (HR 1.052, 95% CI 1.005‐1.101, P = 0.028), increased gamma‐glutamyl transpeptidase (HR 1.002, 95% CI 1.001‐1.006, P<0.001), alcoholic liver disease (HR 2.870, 95% CI 1.863‐4.420, P<0.001), fibrosis and cirrhosis of liver (HR 2.284, 95% CI 1.454‐3.588, P<0.001), and other liver disease (HR 1.433, 95% CI 1.040‐1.973, P = 0.028) were significantly associated with all‐cause dementia risk. Similar outcomes were obtained for Alzheimer’s disease and vascular dementia. Additionally, liver dysfunction was associated with poor cognition in four different cognitive tests and altered cortical and subcortical brain regions.ConclusionOur findings provide amplified evidence to suggest that liver dysfunction is associated with the risk of different types of incident dementia, and a close relationship has been identified between poor cognitive performance and altered brain structure.

Neuropathological changes of a patient with AD treated with verubecestat

AbstractBackgroundClinical trials with BACE‐1 inhibitors in patients with Alzheimer’s disease (AD) have been discontinued due to safety concerns. The adverse effects included reversible early cognitive worsening and brain atrophy. Some data suggest that these effects could be due to an off‐target effect of the inhibitor on other BACE‐1 substrates that could impact synaptic function and structure. However, the precise underlying mechanisms of these effects in humans remain controversial.MethodWe describe the neuropathological examination of a patient with AD treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat.ResultBrain examination showed small plaque size, reduced dystrophic neurites around plaques, and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated sporadic AD (SAD) cases. We also describe a detailed analysis of synaptic morphology in this case.ConclusionOur findings suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD. Neuropathological data could help to understand the effect of BACE inhibition in humans.

Structural Correlates of Speech Biomarkers in Alzheimer’s Disease and Mild Cognitive Impairment

AbstractBackgroundIn the present study, we aimed to confirm the association between speech characteristics of individuals with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI) and brain regions, and to investigate the neurobiological basis of speech‐based AD detection.MethodIndividuals with MCI (n = 13, age = 78.3), mild‐to‐moderate AD (n = 12, age = 77.8) underwent a structural MRI scan and engaged in three speech tasks: an interview, sentence repetition, and paragraph recall. From the speech samples, we extracted frequency‐related, intensity‐related, and temporal features which were found to be altered in the course of AD and MCI pathology. We selected nine regions of interest (ROI) which were found to be involved in speech production and reduced in MCI and AD pathology; the Inferior Frontal Gyrus (IFG), the Medial Frontal Gyrus (MFG), the Precuneus, the Inferior Parietal Lobe (IPL), Inferior Temporal Gyrus (ITG), Medial Temporal Gyrus (MTG), the Superior Temporal Gyrus (STG), the Fusiform Gyrus (FFG), and the Cerebellum. The linear mixed‐effect analysis was used to identify the associations between speech features and regional brain volumes.ResultThe Left IPL (χ2 (1) = 7.69, corrected P = 0.033), the Right ITG (χ2 (1) = 11.5, corrected P = 0.0128) the Right FFG (χ2 (1) = 9.35, corrected P = 0.0198) reduced the pitch of voice by about 0.887 ± 0.292, 1.368 ± 0.329, and 1.69 ± 0.429 respectively. The associations between the Right FFG (χ2 (1) = 4.58, corrected P = 0.0900), Left FFG (χ2 (1) = 5.87, corrected P = 0.0675) and loudness were marginally significant, with the reduction of volumes in the Right FFG and Left FFG decreasing the loudness by 0.096 ± 0.041, and 0.1165 ± 0.0454. The marginally significant associations were observed between the Right IPL (χ2 (1) = 4.75, corrected P = 0.0900), the Left FFG (χ2 (1) = 0.39, corrected P = 0.53) and the speech rate, and the atrophy of brain regions decreased the speech rate by 0.0824 ± 0.0363, 0.0535 ± 0.0079.ConclusionThe present study identified the associations between speech biomarkers and regional brain volumes providing clinical validity for the speech‐based Alzheimer’s disease detection.

FedExosome: profiling AD‐related mitochondrial DNA and microRNAs isolated from neuronal‐enriched peripheral blood packages

AbstractBackgroundAlzheimer’s disease (AD) is a complex disease characterized by impaired memory, diminished cognition, and specific brain pathology (i.e., accumulation of amyloid beta plaques and tau tangles). AD progression is often difficult to detect with the earliest clinical symptoms appearing decades after key neuropathological changes have occurred. Accurate diagnosis early, between initial disease onset and clinical manifestation, could reveal critical aspects of pathogenesis and inform the development of effective therapeutic strategies to prevent neuronal death. Evidence suggests that early alterations in the AD brain can propagate to local and distal cells through the biological packages secreted by neurons. These neuronal‐enriched extracellular vesicles (NEEVs) can cross the blood‐brain barrier and are capable of mediating systemic inflammation in response to CNS‐sourced stress through their mitochondrial DNA (mtDNA) and microRNA (miRNA) cargo. Circulating NEEVs may therefore serve as an easily accessible, early indicator of the forthcoming neuropathological changes in the AD brain. Here, we develop a higher throughput workflow for profiling mtDNA and miRNA in plasma NEEVs and apply the workflow to clinical samples collected longitudinally from participants in the Texas Alzheimer’s Research and Care Consortium.MethodHuman plasma samples were processed using a two‐step method involving (1) precipitation of total exosomes with ExoQuick (SBI) and (2) immunoprecipitation‐based enrichment of NEEVs with a biotinylated antibody against a well‐established neuronal surface marker (CD171). Captured NEEVs were stained and analyzed using flow cytometry as well as nanoparticle tracking analysis (NTA). DNA and RNA were then extracted for mtDNA quantification and miRNA sequencing.ResultThe protocol modifications implemented in this project were compared based on particle size, distribution, and purity as well as absolute mtDNA load and spike‐in normalized miRNA read counts. These data not only demonstrate the feasibility of profiling the mtDNA and miRNA from 500µL of plasma NEEVs but have also resulted in a higher throughput workflow for processing TARCC patient samples.ConclusionThis work represents the first successful attempt to simultaneously quantify mtDNA and sequence miRNA in the relatively small subpopulation of plasma EVs that originate from neurons. Future studies will harness the protocol developed herein to assess the biomarker potential of NEEVs in the TARCC cohort.

Sex modifies the associations of regional fat with cognitive functioning and AD‐related brain volumes, in Israeli middle‐aged adults at high AD risk

AbstractBackgroundHigh body mass index (BMI) has been consistently linked to poorer cognition and higher dementia risk, with different associations in males and females. However, BMI does not represent well specific fat depots. We examined in middle‐aged adults at high Alzheimer’s dementia (AD) risk, whether regional abdominal adiposity is associated with cognitive functioning and brain indices and whether sex modifies these associations.Methods204 healthy Israeli middle‐aged AD offspring (59.44 [SD = 7.60] years old, 60% females) underwent abdominal Magnetic Resonance Imaging (MRI) to quantify hepatic, pancreatic, and peripheral fat %‐visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A broad cognitive battery defined global cognition and specific cognitive domains (episodic memory, working memory, executive functions, and language). A subsample of 142 participants had brain MRI to assess regional brain volumes (total gray matter [GM], hippocampus, and inferior, middle, and superior frontal gyrus [IFG, MFG, and SFG, respectively]). Partial correlations examined associations of regional abdominal adiposity with cognitive functioning, and brain indices, adjusting for age, sex, education, BMI, and time interval between abdominal MRI and the dependent variable. Fisher‐z transformation compared partial correlations between males and females.ResultsIn the whole sample, the only significant association was of higher hepatic fat % with lower GM volume (r = ‐264, p = 0.003), with similar associations in males and females. Only in males, higher pancreatic fat % was associated with lower global cognitive functioning (Males: r = ‐.276, p = .028; Females: r = 0.009, p = 0.93), executive functioning (Males: r = ‐0.267, p = 0.034; Females: r = 0.015, p = 0.87) and episodic memory (Males: r = ‐0.278, p = 0.027; Females: r = 0.068, p = 0.484) as well as with lower IFG volume (Males: r = ‐0.343, p = .017; Females: r = 0.117; p = 0.326). Also only in males, higher VAT% was associated with SFG volume (Males: r = .261, p = .045; Females: r = ‐0.198; p = 0.091).ConclusionIn middle‐aged males, but not in females, at high AD risk, regional abdominal adiposity, primarily pancreatic fat, was associated with lower cognitive functioning and lower AD‐related brain volumes. Results suggest sex differences in the contributions of fat to brain and cognitive aging. Since fat % is modifiable, these results may suggest that interventions to decrease distinct fats for the advancement of brain health must be sex‐specific.

Leveraging systems biology approaches and single‐nucleus RNA‐seq to study sex differences in AD

AbstractBackgroundThere is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences in the rates of cognitive decline and brain atrophy. Sex‐related differences in AD‐associated genes are starting to emerge, but these have not been systematically studied at cell‐type‐specific transcriptome‐wide expression levels. We leveraged single‐nucleus RNA‐seq (snRNA‐seq) and systems biology approaches to identify transcriptomic modules in human brains and determine the modules associated with sex‐AD interactions.MethodsWe studied snRNA‐seq data from the parietal cortex of 67 pathologically confirmed controls, sporadic AD (sAD), autosomal dominant AD (ADAD), and other neurodegenerative samples from the Knight ADRC and DIAN cohorts1, and used Celda2 to co‐cluster cells and genes into subpopulations and modules. This approach identified clusters that correspond to previously described cell types1. We used linear mixed models to identify those modules associated with a sex‐AD interaction. For each nominally significant (P<0.05) module, we isolated the top genes that accounted for 80% of the module expression signature and tested each for a sex‐AD interaction.ResultsWhen run on 38,584 astrocytes, Celda split 13,302 genes into 65 gene modules. Module L17 was nominally significant (P = 0.04), with 55 out of 194 genes accounting for ∼80% of the module signature. After multiple testing correction, two genes, ENTREP1/FAM189A2 (Adj.P = 1.57´10−2) and CD38 (Adj.P = 1.80´10−2), showed a significant sex‐sAD interaction in expression (Figure 1, Table 1). ENTREP1 facilitates the removal of the chemokine receptor CXCR4 from the plasma membrane reducing the downstream effects of CXCL12/CXCR4 signaling3 including astrocytic inflammation response4 and release of glutamate as a gliotransmitter5. Studies have linked ENTREP16 and CXCL12/CXCR47 to neurodegeneration. CD38 expression is influenced by cytokine and chemokines released by senescent cells, which increase with age, AD, and other neurodegenerative diseases8. Increased expression of CD38 increases proinflammatory cytokine release and reduces NAD‐dependent enzyme activity, increasing DNA mutations, mitochondrial dysfunction, and oxidative stress. Knockouts of CD38 in mouse showed significant decreases in Aβ plaque load and soluble Aβ levels9.ConclusionThese results suggest that the known neurodegenerative genes ENTREP1 and CD38 are uniquely modulated by biological sex in relation to AD within astrocytes potentially contributing to the clinical differences seen between males and females.

Clinical Manifestations.

Type 2 diabetes (T2DM) is recognised as a major contributor to cognitive decline. People with T2DM demonstrate abnormalities on MRI compared to control individuals. The aim of this analysis was to investigate differences in cognitive performance and brain volume between individuals with T2DM participating in the Diabetes-and-Dementia (D2) study and a group of healthy controls (HC) part of the Cognition And Neocortical Volume After Stroke (CANVAS) study. One hundred and fifty individuals with T2DM and 36 cognitively-normal participants completed neuropsychological assessments and a 3T-MRI scan. FreeSurfer was used to estimate total brain volume (TBV), mean cortical thickness and subcortical volumes, including the thalami and caudate nuclei. Averages between left and right volumes were calculated for subcortical structures. WMH volumes were estimated manually using FLAIR MRI. Five cognitive domains, including attention, visuospatial skills, memory, language and executive function were computed using z-scores. These domains were used to compare cognitive performance between individuals with and without T2DM. Demographic and clinical comparisons were completed in MATLAB using Two-Sample t-test (age), Fisher Exact test (education, sex, APOE-e4), and Wilcoxon Rank Sum test (BMI). A linear regression model was used to compare cognitive performance between the two groups with correction for age, sex and education level (more/less than 12 years), as well as total intracranial volume for comparing brain volumes. Participants with T2DM were significantly younger, with a higher BMI, had reduced cortical thickness, significantly smaller TBV and smaller subcortical volumes including thalamic, brainstem, amygdala, accumbens area and choroid plexus. Individuals with T2DM exhibited a poorer cognitive performance on tests of language, memory, attention, and visuospatial skills compared to the HC group. There were no significant differences between the two groups in terms of sex, education level, APOE-e4 carriage, WMH, hippocampal volume (see Table 1). T2DM is associated with accelerated structural brain aging, manifesting as cerebral atrophy and poorer cognitive function.