To determine the association between blood markers of white matter injury (e.g., serum neurofilament light and phosphorylated neurofilament heavy) and a novel neuroimaging technique measuring microstructural white matter changes (e.g., diffusion kurtosis imaging) in regions (e.g., anterior thalamic radiation and uncinate fasciculus) known to be impacted in traumatic brain injury (TBI) and associated with symptoms common in those with chronic TBI (e.g., sleep disruption, cognitive and emotional disinhibition) in a heterogeneous sample of Veterans and non-Veterans with a history of remote TBI (i.e., >6 months).

Participants with complete imaging and blood data (N=24) were sampled from a larger multisite study of chronic mild-moderate TBI. Participants ranged in age from young to middle-aged (mean age = 34.17, SD age = 10.96, range = 19-58) and primarily male (66.7%). The number of distinct TBIs ranged from 1-5 and the time since most recent TBI ranged from 0-30 years. Scores on a cognitive screener (MoCA) ranged from 22-30 (mean = 26.75). We performed bivariate correlations with mean kurtosis (MK) in the anterior thalamic radiation (ATR; left, right) uncinate fasciculus (UF; left, right), and serum neurofilament light (NFL), and phosphorylated neurofilament heavy (pNFH). Both were log transformed for non-normality. Significance threshold was set at p<0.05.

pNFH was significantly and negatively correlated to MK in the right (r=-0.446) and left (r=-0.599) UF and right (r=-0.531) and left (r=-0.469) ATR. NFL showed moderate associations with MK in the right (r=-0.345) and left (r=-0.361) UF and little to small association in the right (r=-0.063) and left (r=-0.215) ATR. In post-hoc analyses, MK in both the left (r=0.434) and right (r=0.514) UF was positively associated with performance on a frontally-mediated list-learning task (California Verbal Learning Test, 2nd Edition; Trials 1-5 total).

Results suggest that serum pNFH may be a more sensitive blood marker of microstructural complexity in white matter regions frequently impacted by TBI in a chronic mild-moderate TBI sample. Further, it suggests that even years after a mild-moderate TBI, levels of pNFH may be informative regarding white matter integrity in regions related to executive functioning and emotional disinhibition, both of which are common presenting problems when these patients are seen in a clinical setting.

Several studies have noted associations of higher white matter hyperintensities (WMHs) with cognitive slowing and elevated depressive symptoms in older adults. Depression is also directly associated with cognitive slowing in later life. However, the influence of WMHs on the relationship between depressive symptoms and processing speed is unclear. This interrelationship between depression, processing speed, and WMH may differ between racial groups given the well-documented evidence of racial disparities in vascular disease, WMHs, and cognitive performance, however the literature is sparse. The goal of this current study, therefore, was to investigate whether WMHs mediate the relationship between depressive symptoms and processing speed, and if this relationship differs between Black and White older adults.

A total of 171 non-Hispanic White and 111 non-Hispanic Black older adults (total sample mean age = 82.71 ± 2.74; 42.91% male) from the Healthy Brain Project (a substudy of the Health, Aging, and Body Composition Study) underwent MRI as well as a neuropsychological evaluation. Total WMH volume was quantified for each participant using an automated procedure and normalized to total brain volume. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Digit Symbol Substitution Test (DSST) served as a measure of processing speed. Causal mediation analyses were performed between CES-D and DSST scores across the total sample as well as within racial groups (Black and White), with total WMH volume as the mediator.

The direct effect of the CES-D on DSST was significant (p = 0.012) for the total sample, reflecting slower processing speed at higher levels of depressive symptoms, but the indirect effect was not (p = 0.207). When analyses were stratified by racial group, the indirect effect was significant for Black (p = 0.054; 37.17% mediated) but not White participants (p = 0.207): For Black participants, the inverse relationship between depressive symptoms and processing speed was mediated by a positive relationship between depressive symptoms and WMHs.

While these data support previous findings relating depressive symptoms to slower processing speed across racial groups, our findings also demonstrate a greater impact of WMHs on this relationship in Black older adults compared to their White counterparts. This suggests that WMHs may serve as an important risk factor for cognitive slowing in older Black adults with higher depressive symptoms. Future studies are needed to further investigate the role of WMHs on depression-related deficits in processing speed and other cognitive domains in racially diverse groups.

To examine the relationships between baseline gray matter volumes, diagnostic status, and executive function performance at 24-month follow-up, and the relative importance of predictors of executive function in a cohort of non-demented older adults.

The study sample included 147 participants from the Alzheimer’s Disease Neuroimaging Initiative (mean age = 70.6, SD = 6.4; mean education = 17 years, SD = 2.4). At baseline, 49 participants were diagnosed as cognitively normal (CN), 60 as early mild cognitive impairment (EMCI), and 38 as late mild cognitive impairment (LMCI). Magnetic resonance imaging (MRI) data were collected at baseline. A composite score of executive function and FreeSurfer-derived gray matter regions-of-interest (ROI; whole brain, superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, orbitofrontal cortex, anterior cingulate cortex, superior parietal lobule, inferior parietal lobule, hippocampus) were examined. Hierarchical linear regression models were employed to assess whether brain volume predicted executive function at 24-month follow-up and interaction effects between baseline ROI volume and diagnostic status. Age, gender, education, Mini-Mental State Examination scores, and APOE-e4 allele status were included as control variables in each model. Relative importance metrics, which quantifies an individual regressor’s contribution to a multiple regression model, were computed using the Lindemen, Merenda, and Gold (lmg) method to assess the relative contribution of each variable in predicting executive function performance.

Across all participants, baseline gray matter ROI volume accounted for a significant amount of variance in executive function at 24-months after accounting for control variables. Specifically, anterior cingulate cortex and superior parietal lobule accounted for an additional 7% and 6% of variance in executive function at 24-months. Significant brain region X diagnostic status interaction effects were observed in executive function performance at 24-months. Relative importance metrics within each group indicated that age is the most important predictor of executive function at 24-months for CN, anterior cingulate cortex is most important for EMCI, and Mini-Mental Examination score is most important for LMCI.

Our findings implicate frontoparietal gray matter regions as significant predictors of executive function performance at 24-months, and that this relationship is moderated by diagnostic status. Our results indicate that the value of specific variables to predict executive function performance varies based on diagnostic status. Specifically, anterior cingulate cortex was a significant predictor of executive function performance across all participants and was the most important variable in predicting performance in the earliest stage of mild cognitive impairment. These results support previous studies examining gray matter correlates of executive function and extend the literature by exploring predictors of executive function in early and late stages of mild cognitive impairment.

In the field of neurocognitive disorders, the perspective offered by new disease-modifying therapy increases the importance of etiological diagnosis. The prescription of cerebrospinal fluid analysis (CSF) and imaging biomarkers is a common practice in the clinic but is often driven more by personal expertise and local availability of diagnostic tools than by evidence of efficacy and cost-effectiveness analysis. This leads to a widely heterogeneous dementia care across Europe. Therefore, a European initiative is currently being conducted to establish a consensus for biomarker-based diagnosis of patients with mild cognitive impairment (MCI) and mild dementia.

Since November 2020, a European multidisciplinary task force of 22 experts from 11 scientific societies have been defining a diagnostic workflow for the efficient use of biomarkers. The Delphi consensus procedure was used to bridge the gaps of incomplete scientific evidence on biomarker prioritization. The project has been in two phases. During Phase 1, we conducted a literature review on the accuracy of imaging, CSF, neurophysiological and blood biomarkers in predicting the clinical progression or in defining the underpinning aetiology of main neurocognitive disorders. Evidence was provided to support the panelists’ decisions. In phase 2, a modified Delphi procedure was implemented, and consensus was reached at a threshold of 70% agreement, or 50%+1 when a question required rediscussion.

In phase 1, 167 out of 2,200 screened papers provided validated measures of biomarker diagnostic accuracy compared with a gold standard or in predicting progression or conversion of MCI to the dementia stage (i.e., MRI, CSF, FDG-PET, DaT-imaging, amyloid-PET, tau-PET, and myocardial MIBG-scintigraphy and EEG). During phase 2, panelists agreed on the clinical workspace of the workflow, the stage of application, and the patient age window. The workflow is patient-centered and features three levels of assessment (W): W1 defines eleven clinical profiles based on integrated results of neuropsychology, MRI atrophy patterns, and blood tests; W2 describes the first-line biomarkers according to W1 versus clinical suspicion; and W3 suggests the second-line biomarkers when the results of first-line biomarkers are inconsistent with the diagnostic hypothesis, uninformative or inconclusive. CSF biomarkers are first-line in the suspect of Alzheimer’s disease (AD) and when inconsistent neuropsychological and MRI findings hinder a clear diagnostic hypothesis; dopamine SPECT/PET for those leading to suspect Lewy body spectrum. FDG-PET is first-line for the clinical profiles leading to suspect frontotemporal lobar degeneration and motor tauopathies and is followed by CSF biomarkers in the case of atypical metabolic patterns, when an underlying AD etiology is conceivable.

The workflow will promote consistency in diagnosing neurocognitive disorders across countries and rational use of resources. The initiative has some limitations, mainly linked to the Delphi procedure (e.g., kickoff questions were driven by the moderators, answers are driven by the Delphi panel composition, a subtle phrasing of the questions may drive answers, and 70% threshold for convergence is conventional). However, the diagnostic workflow will be able to help clinicians achieve an early and sustainable etiological diagnosis and enable the use of disease-modifying drugs as soon as they become available.

Glioblastomas, Grade 4 astrocytomas, comprise about 60% of all astrocytomas and have a median survival rate between 14 and 16 months. The extent of resection impacts the prognosis, with an eloquent balance of preserving the patient's functional status. As preoperative imaging and intraoperative techniques improve to maximize safe operative resection, thorough neuropsychological evaluation can aid in assessing cognitive decline and quality of life pre- and post-treatment. In light of the tumors' progressive nature and potential presence in precarious brain locations, it is imperative that the functional burden of the various presentations of glioblastomas be understood. Given the limited data on cognitive presentations of glioblastomas, we present a case study describing a neuropsychological and neuroradiologic profile of a Grade 4 astrocytoma in a patient with a left temporal glioblastoma.

The patient signed consent for clinical evaluation and research. At the time of evaluation, he was 68 years old with a master's degree and was working at multiple start-up companies. He began noticing subtle cognitive functioning changes approximately two months prior with difficulty understanding information. His challenges progressed to difficulty composing emails, word-finding issues, and some slurring and mispronunciations. He was diagnosed with a brain tumor after an emergency MRI was performed. He participated in a neuropsychological evaluation just prior to surgery. The evaluation included a battery of neuropsychological tests examining attention, processing speed, executive functioning, learning and memory, language functioning, visuospatial functioning, motor functioning, and mood.

The imaging results revealed a non-enhancing intra-axial mass in the left superior temporal lobe with surrounding edema. Also noted were rare scattered nonspecific T2 hyperintensities. The scores showed variable motor functioning and deficits within attention for complex information, executive functioning abilities (i.e., motor planning and sequencing, phonemic fluency), language functioning, visuospatial functioning, and learning and memory of information relative to his premorbid level of functioning, indicating total brain involvement consistent with imaging findings of edema.

Taken together, the results of the evaluation and imaging were suggestive of a level of cognitive decline that is more than expected with normal aging. Moreover, there was a lack of evidence representative of a lateralized profile. Notably, the evaluation was conducted before resection surgery, and therefore, the patient continued to experience significant brain edema due to the tumor. Although medication may have contributed to dysfunction, particularly with motor and cognitive slowing, it is not likely that it explained his presentation entirely. As such, the evaluation results were suggestive of neurocognitive dysfunction, which was partially attributable to the tumor and edema displacing neuronal tissue. Given the potential for improvement following tumor resection and secondary decline resulting from recurrence or treatment, it is crucial to have a baseline and the ability to map out higher order functioning, including frontal and temporal lobe functioning. Ultimately, as the field continues to look toward long-term survival for patients with currently lethal brain tumors, the goal is to achieve maximum resection with minimal neurocognitive loss.

Individuals with Parkinson's disease (PD) have varying trajectories of cognitive decline. One reason for this heterogeneity may be "cognitive reserve": where higher education/IQ/current mental engagement compensates for increasing brain burden (Stern et al., 2020). With few exceptions, most studies examining cognitive reserve in PD fail to include brain metrics. This study's goal was to examine whether cognitive reserve moderated the relationship between neuroimaging indices of brain burden (diffusion free water fraction and T2-weighted white matter changes) and two commonly impaired domains in PD: executive function and memory. We hypothesized cognitive reserve would mitigate the relationship between higher brain burden and worse cognitive performance.

Participants included 108 individuals with PD without dementia (age mean=67.9±6.3, education mean=16.6±2.5) who were prospectively recruited for two NIH-funded projects at the University of Florida. All received neuropsychological measures of executive function (Trails B, Stroop, Letter Fluency) and memory (delayed recall: Hopkin's Verbal Learning Test-Revised, WMS-III Logical Memory). Domain specific z-score composites were created using data from age/education matched non-PD peer controls (N=62). For the Cognitive Reserve (CR) proxy, a z-score composite included years of education, WASI-II Vocabulary, and Wechsler Test of Adult Reading. At the time of testing, participants completed multiple MRI scans (T1-weighted, diffusion, Fluid Attenuated Inversion Recovery) from which the following were extracted: 1) whole-brain free water within the white matter (a measure of microstructural integrity and neuroinflammation), 2) white matter hyperintensities/white matter total volume (WMH/WMV), and bilaterally-averaged edge weights of white matter connectivity between 3) dorsolateral prefrontal cortex and caudate and 4) entorhinal cortex and hippocampi. Separate linear regressions for each brain metric used executive function and memory composites as dependent variables; predictors were age, CR proxy, respective brain metric, and a residual centered interaction term (brain metric*CR proxy). Identical models were run in dichotomized short and long disease duration groups (median split=6 years).

In all models, a lower CR proxy significantly predicted worse executive function (WMH/WMV: beta=0.49, free water: beta=0.54, frontal edge weight: beta=0.49, p's<0.001) and memory (WMH/WMV: beta=0.42, free water: beta=0.35, temporal edge weight: beta=0.39, p's <0.01). For neuroimaging metrics, higher free water significantly predicted worse executive function (beta=-0.39, p=0.002) but not memory. No other brain metrics were significant predictors of either domain. Accounting for PD duration, higher free water predicted worse executive function for those with both short (beta=-0.49, p=0.04) and long disease duration (beta=-0.48, p=0.02). Specifically in those with long disease duration, higher free water (beta=-0.57 p=0.02) and lower edge weights between entorhinal cortex and hippocampi (beta=0.30, p=0.03) predicted worse memory. Overall, no models contained significant interactions between the CR proxy and any brain metric.

Results replicate previous work showing that a cognitive reserve proxy relates to cognition. However, cognitive reserve did not moderate brain burden's relationship to cognition. Across the sample, greater neuroinflammation was associated with worse executive function. For those with longer disease duration, higher neuroinflammation and lower medial temporal white matter connectivity related to worse memory. Future work should examine other brain burden metrics to determine whether/how cognitive reserve influences the cognitive trajectory of PD.

Alzheimer's disease (AD) is associated with the accumulation of neuropathological beta-amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab-38 and Ab-40 due to their high solubility, may be indicators of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. This overabundance of Ab and later sequestration onto plaques eventually triggers a cascade of subsequent brain changes that may lead to cognitive decline. Indeed, alterations in gray matter integrity may play a role, as imaging studies have shown specific atrophy patterns in preclinical AD, particularly in language regions of the bilateral temporal lobes, which relate to cognitive performance. Here, we aimed to explore whether temporal lobe cortical volume is implicated in the relationship between increased CSF Ab levels and cognitive decline, as measured by confrontation naming performance -- an age-independent language task often impaired in preclinical AD -- in AD-vulnerable populations.

We selected 87 non-demented Veterans (Sex: 99% male; Age: M=68.2, SD=3.7; Education: M=15.5, SD=2.2) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense (ADNI-DOD) database based on available Boston Naming Test (BNT) scores, CSF measures of Ab-38 and Ab-40, and structural neuroimaging data. The 30-item BNT assessed confrontation naming performance. CSF Ab concentrations were measured using a 2D-UPLC-tandem mass spectrometry method outlined by ADNI-DOD. T1-weighted images were acquired on a 3T scanner and processed by ADNI to calculate cortical volumes (CVs) for regions of interest (ROIs); the present study focused on three bilateral ROIs in the temporal lobe (fusiform gyrus [FFG], inferior temporal gyrus [ITG], and middle temporal gyrus [MTG]). All CVs were adjusted (CV_adj) for intracranial volume (ICV) using the covariance formula (CV_adj = CV - b [ICV - mean(ICV)]). Linear regression models explored the relationship between CSF Ab peptides and BNT with temporal lobe ROIs as moderators using the PROCESS macro.

CV of the bilateral FFG significantly moderated the relationship between BNT performance and both CSF Ab-38 (p=.025, R2=.05, b=.0008) and Ab-40 (p=.016, R2=.06, b=.0002) levels. We then explored effects of the left and right FFG separately and found that the relationship between CSF Ab-38 and BNT was significantly moderated by the left FFG (p=.032, R2=.05, b=.0006) and nominally by the right FFG (p=.072, R2=.03, b=.0006). The relationship between CSF Ab-40 and BNT was significantly moderated by both the left (p=.032, R2=.05, b=.0001) and right (p=.038, R2=.04, b=.0001) FFG. CV of the bilateral ITG and MTG had no effect on any model (all p >.10).

Increased Ab may trigger alterations in neural gray matter integrity, specifically in the FFG of the temporal lobe, and these changes may in turn be implicated in AD-related cognitive decline, particularly in the language domain. These findings suggest that biomarker models incorporating CSF Ab and CV may aid early identification of disease and risk for cognitive decline in preclinical AD stages, which could help inform early interventions.

Previous research has found that trauma is a risk factor for developing early-onset psychosis (EOP), both exhibiting widespread structural abnormalities and social cognitive dysfunction (Hoy et al., 2012; Nair et al., 2020; Rotiker et al., 2018). However, few studies have investigated the association between trauma, neural architecture, and social behaviors. The current study examines whether trauma exposure moderates the association between cortical volume and thickness and social cognition in EOP.

T1-weighted whole-brain magnetic resonance data were acquired on a 3T Siemens scanner for 23 adolescents with EOP aged 12-21 years (M = 16.12), and 20 age-matched controls (M = 17.22). Cortical volume and thickness were calculated using the Freesurfer software suite (v5.3; Reuter et al., 2012). Based on prior research, bilateral structures of interest included the rostral anterior cingulate cortex (rACC), insula, precuneus, and superior frontal cortex. Social measures included the WebCNP Emotion Recognition (KER40) and Emotion Differentiation Test (MED36) accuracy score (Gur et al., 2010), The Awareness of Social Inference Test Total Score (TASIT; McDonald et al., 2003), and Social Responsiveness Scale, 2nd Edition (SRS-2; Constantino & Gruber, 2012). Trauma exposure was assessed using the Structured Clinical Interview Diagnostic (controls n = 5; EOP n = 9; First et al., 2015). Pearson’s correlations and independent t-tests were used to examine the relationship between cortical measurements and social cognition. Additionally, PROCESS macro (Hayes, 2018) was used to examine if trauma history statistically moderated the relationship between cortical measurements and social cognition performance.

Significant group differences in SRS-2 scores were observed, as EOP participants scored 24.272 points higher than controls (t = 20.724, p < .001). Across both groups, there was a negative correlation between the SRS-2 score and precuneus volume (r = -.438, p = .011) and thickness (r = -.383, p = .028), TASIT total and superior frontal volume (r = -.349, p = .023), and KER40 and insular volume (r = -.437, p = .20). Further, the moderation analysis revealed that the relationships between precuneus volume and SRS-2 scores, precuneus thickness and MED36 scores, and rACC thickness and KER40 scores depended on experiencing trauma across both groups. Participants with trauma across groups had increased precuneus volume associated with higher SRS-2 scores (p = .0442). Experiencing trauma was also associated with lower precuneus cortical thickness and lower MED36 scores (p = .0172). Conversely, lack of trauma experience was associated with greater rACC thickness and higher KER40 scores (p = .0119).

Our findings indicate that past traumatic experiences may be a moderating factor in the relationship between atypical volume and thickness of social brain regions and social cognition. Overall, the significant interactions between trauma exposure and increased volume and thickness in both EOP and control participants were associated with increased impairment on social cognition measures. These findings emphasize the importance of accounting for the impact of early life adversities on brain development and how it may be relevant to social impairments, especially in individuals experiencing psychosis.

Olfactory function declines during normal aging; however, accelerated olfactory decline is observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). Moreover, olfactory deficits in pre-clinical AD are associated with future cognitive decline. Odor identification and memory deficits have been consistently reported in early stage AD indicating its potential sensitivity to AD pathophysiology in olfactory and limbic structures, yet few studies of olfaction have incorporated structural measures in a well-characterized cohort of older adults. In the current study we examined the association between odor identification impairment, cognition, and medial temporal lobe (MTL) sub-regions in cognitively unimpaired and impaired older adults.

We enrolled 140 participants (age=72.25±6.54, 56% female, years of education=16.30±2.63, 82% Caucasian, 15% Black/AA, 3% Multiracial) from the Penn Alzheimer’s Disease Research Center Clinical Cohort. Participants completed the Sniffin’ Sticks Odor Identification Test (SS-OIT), cognitive testing (NACC UDS2 or UDS3 and additional cognitive tests), and MRI scans (3T Siemens MAGNETOM Prisma MRI scanner). For the SS-OIT, participants were presented with 16 odorants using felt-tipped pen dispensers and asked to identify each odor from four multiple-choice options. Scores range from 0 to 16. Additionally, cognitive domains were created by averaging z-scores from tests within each domain: attention, memory, language, executive function, and visuospatial. This cohort was divided into participants with unimpaired cognition (n=96) and impaired cognition (MCI, dementia; n=44) using established normative data and consensus diagnosis. Linear regressions were performed to examine the association between SS-OIT score, each cognitive domain, and MTL measurements for unimpaired and impaired groups. For all analyses, we controlled for age, race, sex, education, smoking status, and hypertension and additionally for MOCA score and intracranial volume with MTL measurements.

In the unimpaired group, SS-OIT significantly associated with language (p<.05). In the impaired group, SS-OIT significantly associated with language and memory (p<.05). In the unimpaired group, SS-OIT significantly associated with right anterior hippocampal volume (p<.05). In the impaired group, significant associations were found between SS-OIT and right anterior hippocampal volume (p<.05) and left hippocampal mean thickness (p<.05). Additionally, SS-OIT significantly associated with left and right entorhinal cortex volume (p<.05) and mean thickness (p<.05).

This study reveals that lower odor identification performance is related to lower performance on measures of cognition and atrophy in MTL sub-regions in unimpaired and impaired older adults. Our findings support prior results demonstrating relationships between olfactory function, cognition, and MTL sub-regions. Specifically, olfactory function and episodic memory have been shown to follow similar patterns of decline in the course of AD, potentially reflecting AD pathology in shared regions of the MTL subserving episodic memory and olfactory function. Our findings demonstrate that reductions in both cortical thickness and grey matter volume of MTL regions are linked to olfactory deficits in individuals at risk for Alzheimer’s dementia. Future steps will include the analysis of longitudinal cognitive and imaging indices and the incorporation of fluid biomarker data.

The aim of the current longitudinal study was to use improved brain white matter integrity outcomes (better at resolving white matter complexity, hence with improved biological significance compared to traditional diffusion tensor imaging - DTI outcomes) while considering baseline age, cardiovascular diseases (CVD), and HIV disease markers impacts on the health of major white matter tracts in virally suppressed people Living with HIV infection (PLHIV) versus demographically, geographically, and life-style comparable HIVnegative controls. Furthermore, white-matter hyperintensity (WMH) and normal-appearing white matter (NAWM) volumes and microstructure were considered.

At baseline 48 HIV-controls and 84 virally suppressed PLHIV (mean age 55), and at 24-month follow-up, 40 HIV-controls and 75 virally suppressed PLHIV underwent an MRI scan (3T Phillips) collecting a high-resolution anatomical MRI, FLAIR, and a 32-direction diffusion imaging. The diffusion data were processed using mrtrix and intra-cranial volume-corrected outcomes included fibre density (FD), fibre cross-section (log was used; logFC) and a composite fibre density and cross-section (FDC). The volumetric data was first processed in Freesurfer 6.0, and WMH were segmented using the “pgs” U-Net neural network. Using mixed models, we examine the longitudinal mrtrix outcomes across major white matter tracts by HIV status, and associations with CVD (sum of the scaled scores of total cholesterol, HDL, Systolic BP, current smoking, and diabetes) and HIV disease (HIV duration, historical AIDS, nadir CD4, baseline CD4) markers. Additionally, we assessed the volume, and FDC in the periventricular and deep WMH, as well as NAWM, and the associations with CVD and HIV disease markers. We used FDR control procedure (alpha = 0.05), and all p-values reported are FDR adjusted.

Relative to controls, PLHIV showed significant reductions (p<.05 - p<.01) of FC, and FDC to a lesser extent, in multiple long cortical association tracts, and within striatal- and thalamic-frontoparietal connections. A small HIV by age interaction was only detected for FC of inferior longitudinal fasciculus (Beta = -0.004, SE = 0.002 p<.04). However, HIV duration (corrected for baseline age) was associated with worse FDC across multiple tracts (p<03 -p<.001). Baseline CD4 counts associated with lower FD in frontal association tracts (p<.05 -p<.005). Furthermore, WMH increased in size with time, age, and higher CVD risk factors, but not HIV status. In PLHIV, deep WMH and NAWM microstructure were both associated with worse CVD but not HIV disease markers.

The fine integrity of major white matter tracts is impacted by HIV status, HIV duration and baseline CD4, whereas WMH and NAWM volumes and microstructure are affected by CVD. Our study provides further evidence of the immuno-vascular underpinning of HIV neuropathogenesis in virally suppressed PLHIV. The convergence of these effects in aging PLHIV may lead to early neurodegeneration. Hence, improving CVD health and maintaining high CD4 is critical.

Neuropsychologists have difficulty detecting cognitive decline in high-functioning older adults, in whom substantially greater neurological change may need to occur before performance on cognitive tests are low enough to indicate cognitive impairment. For high-functioning older adults, subjective cognitive concerns (SCC) may indicate decline that is not detected by the presence of low cognitive test scores but may be related to the absence of high scores and the presence of latent neurological changes. We hypothesized that high-functioning older adults with SCC would have fewer high scores than those without concerns, but a comparable number of low scores. These findings would indicate that objective decline has occurred but would not be detected by a traditional focus on low scores. We also hypothesized that SCC would be associated with lower frontoparietal network volume, thickness, and connectivity, indicating latent neurological change underlying subjective cognitive concerns.

Participants from an imaging sub-study of an ongoing longitudinal aging study were selected if they had high estimated premorbid functioning, defined as either (a) estimated intelligence >75th percentile on the North American Adult Reading Test (n=48) or (b) having a college degree (n=62). This resulted in 68 participants subdivided based on SCC, defined as one or more self-reported SCC on the Medical Outcomes Study Cognitive Functioning Scale (MOS-Cog). Participants with SCC (n=35; 73.9 years-old, SD=9.6, range: 60-95; 62.9% female; 94.3% White) and without SCC (n=33; 71.0 years-old, SD=7.2, range: 61-85, 75.8% female; 100% White) completed a neuropsychological test battery of memory and executive functions, including the Rey Auditory Verbal Learning Test, Trail Making Test Parts A and B, Controlled Oral Word Association Test, Digit Span, and Letter-Number Sequencing, and underwent structural MRI. MR images were analyzed for frontoparietal network volume, thickness, and connectivity.

Participants with and without SCC were compared on the number of low test scores (i.e., at or below the 16th percentile) and high test scores (i.e., at or above the 75th percentile), finding a comparable number of low scores, t=1.66, p=.103, d=.40, but a lower number of high scores among participants with SCC, t=2.95, p=.004, d=.71. Participants with SCC had lower bilateral mean frontoparietal network volumes (left: t=2.98, p=.004, d=.74; right: t=2.63, p=.011, d=.66) and cortical thickness (left: t=2.65, p=.010, d=.66; right: t=2.18, p=.033, d=.54), but did not differ from those without SCC in terms of network connectivity.

SCC have been reported as a potential risk factor for dementia in older adults. High-functioning older adults with SCC presented with fewer high scores than those without SCC but had a comparable number of low scores. Among high-functioning older adults, subjective cognitive decline may correspond with objective cognitive change not detected by the traditional emphasis on low scores, but rather the absence of high scores. SCC were also related to underlying changes in the volume and thickness of the frontoparietal network, but not connectivity. In high-functioning older adults, subjective cognitive decline may correspond with a reduction from high average functioning in some domains and underlying neurological changes.

Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).

Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 < 45 and RDS < 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.

All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications < 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z < -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).

Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.

Cognitive dysfunction is a common non-motor symptom of Parkinson’s disease (PD). Cognitive decline in PD is likely associated with dysfunction in the cholinergic system, which is affected by synuclein pathology early in the disease course. Recent studies have shown an association between reduced integrity of the basal forebrain (BF), which provides cholinergic innervation to most of cortex, and diminished cognitive functioning in PD. Specifically, those with PD and reduced cholinergic innervation also have higher rates of cognitive impairment. However, no study has directly investigated the relationship between basal forebrain integrity and cortical cholinergic levels. In the present study, we examined this relationship through measures of basal forebrain microstructural integrity and cholinergic nerve terminal density in cortical and subcortical gray matter.

Participants included 92 non-demented individuals with idiopathic PD (M:F=64:28; Age=67.0±7.1 yrs) who underwent structural MRI, diffusion MRI, and [18F] fluoroethoxybenzovesamicol (FEOBV) cholinergic PET imaging. We used a basal forebrain and region of interest defined by AssemblyNet, which uses ensembles of pretrained convolutional neural networks to create a full brain segmentation. Bilateral putamen from this atlas was also included as a control region. We measured microstructural integrity using free water fraction (FWF), a diffusion MRI-derived metric of extracellular water that associates with cellular density and neuroinflammation. For PET data, we computed the distribution volume ratio (DVR) by regions as defined by FreeSurfer. A factor analysis of DVR in all 88 FreeSurfer ROIs resulted in seven clusters of ROIs covering 1) widespread bilateral cortical regions (PC1); 2) subcortical and limbic regions (PC2); 3) bilateral cingulate regions (PC3); 4) left frontal regions (PC4); 5) right frontal and temporal regions (PC5); 6) cerebellum (PC6); and 7) bilateral entorhinal cortex and left temporal cortex (PC7). We performed seven separate regression analyses per ROI (controlling for age and disease duration) to evaluate the association between BF FWF and cholinergic levels in these regions. To determine if these ROIs showed unique associations with BF FWF, we then entered ROIs with a significant association with BF FWF as independent variables in a stepwise regression with forward selection with BF FWF as the dependent variable.

BF FWF was significantly and negatively associated with cholinergic levels in PC1 (AR2=.042, ß=-0.208, p=.04), PC3 (AR2=.044, ß=-0.206, p=.03), PC4 (AR2=.056, ß=-0.239, p=.02), and PC7 (ß=-0.215, p=.04). BF FWF trended towards a negative association with cholinergic levels in PC5 (AR2=.045, ß=-0.168, p=.09) and PC6 (ß=-0.188, p=.09). Putamen FWF did not significantly associate with any of the ROIs. In the follow-up stepwise regression, only PC4 contributed significantly to the overall model (AR2=.061, ß=-0.261, p=.02).

Basal forebrain FWF was inversely related to cholinergic levels in regions that are directly innervated by the basal forebrain (e.g., cingulate cortex, left frontal cortex, and bilateral entorhinal cortex). Future research should directly investigate the relationship between basal forebrain integrity, cortical cholinergic levels, and cognition. Separating the basal forebrain into specific nuclei would also be beneficial, as different nuclei may have differing associations with specific hemispheric cholinergic pathways and cognition.

Cognitive deficits in first-episode psychosis (FEP) are well documented, particularly aspects of cognitive control, which is one of the primary hypothesized functions of the frontoparietal network (FPN). The clinical features of psychotic disorders are known to differ between men and women, but little work has systematically studied neurobiological differences between the sexes, particularly in FEP. The current study aimed to examine sexual dimorphisms in structural integrity of the frontoparietal network (FPN) and its role in cognitive control in FEP.

A total of 111 FEP patients (68 male, 43 female) and 55 healthy control participants (35 male, 20 female) from the Human Connectome Project for Early Psychosis underwent T1-weighted magnetic resonance imaging and neuropsychological testing were included in the study. Regions of interest (ROIs) included: left and right superior frontal gyrus, left and right middle frontal gyrus, left inferior frontal gyrus, left and right inferior parietal gyrus, right caudate and left thalamus. Using high-dimensional brain mapping procedures, surface shape of the caudate and thalamus was characterized using Large Deformation Diffeomorphic Metric Mapping, and cortical thickness of frontal and parietal regions was estimated using the FreeSurfer toolkit. Cognitive control was assessed using the Fluid Cognition Composite score from the NIH Toolbox Cognition Battery. Multivariate ANOVA models tested group differences, separated by sex, in cortical thickness ROIs, in addition to a whole-brain vertex-wise analysis. Vertex-wise statistical surface t-maps evaluated differences in subcortical surface shape, and Pearson correlations tested relationships between brain regions and Fluid Cognition performance.

Results of deep brain region comparisons between schizophrenia males (SCZM) and schizophrenia females (SCZF) groups revealed significant outward deformation at the tail of the right caudate and significant inward deformation along the dorsal aspects of the right caudate. Additionally, significant inward deformation in multiple nuclei of the left thalamus were revealed. Significant negative relationships between Fluid Cognition and the left superior/middle frontal gyrus (r = -0.24, p = 0.05) in the male FEP group were observed. Additionally, significant positive relationships between Fluid Cognition and left inferior frontal gyrus (r = 0.35, p = 0.02) and left inferior parietal gyrus (r = 0.35, p = 0.02) in the female FEP group were found.

Overall, findings revealed significant brain differences of the FPN in deep-brain structures only, including abnormal caudal and thalamic shape, in male FEP compared to female FEP, providing evidence of the importance to examine sex differences in deep-brain regions at the first episode. Differential brain relationships with cognitive control also highlight sex-specific presentations that may aid in clinical management and further characterization of the illness in early stages.

White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players.

240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%.

In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference).

These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI.

Previous research established that white matter hyperintensities (WMH), a biomarker of small vessel cerebrovascular disease, are strong predictors of cognitive function in older adults and associated with clinical presentation of Alzheimer’s disease (AD), particularly when distributed in posterior brain regions. Secondary prevention clinical trials, such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, target amyloid accumulation in asymptomatic amyloid positive individuals, but it is unclear the extent to which small vessel cerebrovascular disease accounts for performance on the primary cognitive outcomes in these trials. The purpose of this study was to examine the relationship between regional WMH volume and performance on the Preclinical Alzheimer Cognitive Composite (PACC) among participants screened for participation in the A4 trial. We also determined whether the association between WMH and cognition is moderated by amyloid positivity status.

We assessed demographic, amyloid PET status, cognitive screening, and raw MRI data for participants in the A4 trial and quantitated regional (by cerebral lobe) WMH volumes from T2-weighted FLAIR in amyloid positive and amyloid negative participants at screening. Cognition was assessed using PACC scores, a z-score sum of four cognitive tests: The Mini-Mental State Examination (MMSE), the Free and Cued Selective Reminding Test, Logical Memory Test, and Digit Symbol Substitution Test. We included 1329 amyloid positive and 329 amyloid negative individuals (981 women; mean age=71.79 years; mean education=16.58 years) at the time of the analysis. The sample included Latinx (n=50; 3%), non-Latinx (n=1590; 95.9%), or unspecified ethnicity (n=18; 1.1%) individuals who identified as American Indian/Alaskan Native (n=7; 0.4%), Asian (n=38; 2.3%), Black/African American (n=41; 2.5%), White (n=1551 ; 93.5%), or unspecified (n=21; 1.3%) race. We first examined the associations of total and regional WMH volume and amyloid positivity on PACC scores (the primary cognitive outcome measure for A4) using separate general linear models and then determined whether amyloid positivity status and regional WMH statistically interacted for those WMH regions that showed significant main effects.

Both increased WMH, in the frontal and parietal lobes particularly, and amyloid positivity were independently associated with poorer performance on the PACC, with similar magnitude. In subsequent models, WMH volume did not interact with amyloid positivity status on PACC scores.

Regionally distributed WMH are independently associated with cognitive functioning in typical participants enrolled in a secondary prevention clinical trial for AD. These effects are of similar magnitude to the effects of amyloid positivity on cognition, highlighting the extent to which small vessel cerebrovascular disease potentially drives AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered explicitly when evaluating outcomes in trials, both as potential effect modifiers and as possible targets for intervention or prevention. The findings from this study cannot be generalized widely, as the participants are not representative of the overall population.

The present study explored how individual differences and development of gray matter architecture in inferior frontal gyri (IFG), anterior cingulate (ACC), and inferior parietal lobe (IPL) relate to development of response inhibition as measured by both the Stop Signal Task (SST) and the Go/No-Go (GNG) task in a longitudinal sample of healthy adolescents and young adults. Reliability of behavioral and neural measures was also explored.

A total of 145 individuals contributed data from the second through fifth timepoints of an accelerated longitudinal study focused on adolescent brain and behavioral development at the University of Minnesota. At baseline, participants were 9 to 23 years of age and were typically-developing. Assessment waves were spaced approximately 2 years apart. Behavioral measures of response inhibition collected at each assessment included GNG Commission Errors (CE) and the SST Stop Signal Reaction Time (SSRT). Structural T1 MRI scans were collected on a Siemens 3 T Tim Trio and processed with the longitudinal Freesurfer 6.0 pipeline to yield cortical thickness (CT) and surface area values. Regions of interest based on the Desikan-Killiany-Tourville atlas included IFG regions (pars opercularis (PO) and pars triangularis (PT)), ACC and IPL. The cuneus and global brain measures were evaluated as control regions. Retest stability of all measures was calculated using the psych package in R. Mixed linear effects modeling using the lme4 R package identified whether age-based trajectories for SSRTs and GNG CEs best fit linear, quadratic, or inverse curve. Then, disaggregated between- and within-subjects effects of regional cortical architecture measures were added to longitudinal behavioral models to identify individual differences and developmental effects, respectively.

Both response inhibition metrics demonstrated fair reliability and were best fit by an inverse age trajectory. Neural measures demonstrated excellent retest stability (all ICCs > 0.834). Age-based analyses of regional CT identified heterogeneous patterns of development, including linear trajectories for ACC and inverse age trajectories for bilateral PT. Individuals with thinner left PO showed worse performance on both response inhibition tasks. SSRTs were related to individual differences in right PO thickness and surface area. A developmental pattern was observed for right PT cortical thickness, where thinning over time was related to better GNG performance. Lower surface area of the right PT was related to worse GNG performance. No individual differences or developmental patterns were observed for the ACC, IPL, cuneus, or global metrics.

This study examined the adolescent development of response inhibition and its association with cortical architecture in the IFG, ACC and IPL. Separate response inhibition tasks demonstrated similar developmental patterns with steepest improvements in early adolescence and relationships with left PO thickness, but each measure had unique relationships with other IFG regions. This study indicates that a region of the IFG, the par opercularis, relates to both individual difference and developmental change in response inhibition. These patterns suggest brain-behavior association that could be further explored in functional imaging studies and that may index, in vulnerable individuals, risk for psychopathology.

Cognitive training has shown promise for improving cognition in older adults. Aging involves a variety of neuroanatomical changes that may affect response to cognitive training. White matter hyperintensities (WMH) are one common age-related brain change, as evidenced by T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) MRI. WMH are associated with older age, suggestive of cerebral small vessel disease, and reflect decreased white matter integrity. Higher WMH load associates with reduced threshold for clinical expression of cognitive impairment and dementia. The effects of WMH on response to cognitive training interventions are relatively unknown. The current study assessed (a) proximal cognitive training performance following a 3-month randomized control trial and (b) the contribution of baseline whole-brain WMH load, defined as total lesion volume (TLV), on pre-post proximal training change.

Sixty-two healthy older adults ages 65-84 completed either adaptive cognitive training (CT; n=31) or educational training control (ET; n=31) interventions. Participants assigned to CT completed 20 hours of attention/processing speed training and 20 hours of working memory training delivered through commercially-available Posit Science BrainHQ. ET participants completed 40 hours of educational videos. All participants also underwent sham or active transcranial direct current stimulation (tDCS) as an adjunctive intervention, although not a variable of interest in the current study. Multimodal MRI scans were acquired during the baseline visit. T1- and T2-weighted FLAIR images were processed using the Lesion Segmentation Tool (LST) for SPM12. The Lesion Prediction Algorithm of LST automatically segmented brain tissue and calculated lesion maps. A lesion threshold of 0.30 was applied to calculate TLV. A log transformation was applied to TLV to normalize the distribution of WMH. Repeated-measures analysis of covariance (RM-ANCOVA) assessed pre/post change in proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures in the CT group compared to their ET counterparts, controlling for age, sex, years of education and tDCS group. Linear regression assessed the effect of TLV on post-intervention proximal composite and sub-composite, controlling for baseline performance, intervention assignment, age, sex, years of education, multisite scanner differences, estimated total intracranial volume, and binarized cardiovascular disease risk.

RM-ANCOVA revealed two-way group*time interactions such that those assigned cognitive training demonstrated greater improvement on proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures compared to their ET counterparts. Multiple linear regression showed higher baseline TLV associated with lower pre-post change on Processing Speed Training sub-composite (ß = -0.19, p = 0.04) but not other composite measures.

These findings demonstrate the utility of cognitive training for improving postintervention proximal performance in older adults. Additionally, pre-post proximal processing speed training change appear to be particularly sensitive to white matter hyperintensity load versus working memory training change. These data suggest that TLV may serve as an important factor for consideration when planning processing speed-based cognitive training interventions for remediation of cognitive decline in older adults.

The objective of the study was to examine longitudinal changes in the white matter tracts with diffusion tensor imaging (DTI), neuropsychological performance, and the associate between the two in adults with a mild traumatic brain injury (mTBI).

Sixteen adult patients (age = 38.5(12.8); 75% female) seeking medical care at an emergency department for their first mTBI and 15 healthy adults (age = 30.5(11.3); 33% female) from the community were recruited. DTI and the neuropsychological evaluation were performed at 7 days and 4-months post-injury. The neuropsychological evaluation consisted of the CNS Vital Signs computerized neurocognitive test battery and 2 trials of the Paced Auditory Serial-Addition Test.

Results showed a significant decrease in fractional anisotropy (FA) and an increase in radial diffusivity (RD) of the right uncinate fasciculus as well as a significant decrease in FA and axial diffusivity (AD) of the right inferior fronto-occipital fasciculus over the 4-month follow-up period in the mTBI group compared to the Control group.

The FA of multiple white matter tracts at baseline were positively associated with working memory, sustained attention, and complex attention at baseline in the mTBI group but not the Control group. The global mean cerebral diffusivity for FA at baseline was positively associated with working memory and sustained attention at 4-months post-injury.

The current findings of abnormal white matter suggest an oxidative stress reaction as a result of mTBI altering the diffusivity of some white matter tracts. Furthermore, the disruption of the white matter tracts at baseline may serve as a biomarker for identifying mTBI and those who may have prolonged cognitive difficulties in working memory and attention as a result of the mTBI.

Multiple Sclerosis (MS) affects up to 500,000 adults in the United States, with cognitive impairment present in 45%-65% of people. Studies showed hippocampal atrophy in MS, but the underlying mechanisms remain unknown. Inflammation has been proposed to play a significant role, and associations between systemic inflammatory biomarkers and hippocampal atrophy have been shown in other neurological conditions. However, research exploring serum biomarker and volumetric associations in MS are lacking. Given that conventional imaging methods lack resolution for hippocampal internal architecture (HIA), new protocols were developed. We used the High-Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) method to visualize the HIA subfields. We investigated the relationship between subfield volumes generated from HR-MICRA scans and systemic serum biomarkers in MS.

Patients with MS were recruited (N= 34, mean age= 54.6, 35.3% Black) underwent Magnetic Resonance Imaging (MRI), and serum biomarkers were obtained, specifically chosen for their potential role in MS. Inflammatory biomarkers included; granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- a (TNF- a), and growth factors; vascular endothelial growth factor (VEGF); insulin-like growth factor-1 (IGF-1), and brain derived growth factor (BDNF). Imaging was performed in a Siemens Prisma 3T scanner with a 64-channel head coil using the HR-MICRA method. Hippocampal subfields were calculated using the Automated Segmentation of Hippocampal Subfields (ASHS) package. We used the Magdeburg Young Adult 7T Atlas for sub-hippocampal structures and Penn Temporal Lobe Epilepsy T1-MRI Whole Hippocampus ASHS Atlas for general hippocampal structure and segmentation. Pearson's product-moment analyses provided correlations between biomarkers and hippocampal subfield volumes for each cerebral hemisphere. A statistical significance level of p < 0.05 was used for all analyses.

Correlations emerged between left hemisphere Cornu Ammonis (CA) 2 and G-CSF (r = -.384; p = .025); IL-10 (r = -.342; p = .048); VEGF (r = -.371; p= .031); and CA3 with IL-10 (r = -.488, p = .003); G-CSF (r = -.386; p= .024); VEGF (r = -.352; p= .041). Dentate gyrus correlated with MMP-9 (r =.416; p=.014); IL-10 (r = -.365; p =.034). BDNF was correlated with right hemisphere CA1 (r = -.417, p = .014), CA2 (r = -.497; p= .003) and CA3 (r = -.451; p=.007).

In our sample of persons with MS, left hemisphere hippocampal subfield volumes were negatively correlated with inflammatory biomarkers, supporting previous reports linking inflammation to reduced brain volumes in other neurological conditions. In the right hemisphere, we found negative correlations between HIA and BDNF, suggesting a neuroprotective function for BDNF in this neurodegenerative disease. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between HIA and systemic serum biomarkers in MS.