Postmortem Brain Imaging in Alzheimer's Disease and Related Dementias: The South Texas Alzheimer's Disease Research Center Repository.

BACKGROUND: Neuroimaging bears the promise of providing new biomarkers that could refine the diagnosis of dementia. Still, obtaining the pathology data required to validate the relationship between neuroimaging markers and neurological changes is challenging. Existing data repositories are focused on a single pathology, are too small, or do not precisely match neuroimaging and pathology findings. OBJECTIVE: The new data repository introduced in this work, the South Texas Alzheimer's Disease research center repository, was designed to address these limitations. Our repository covers a broad diversity of dementias, spans a wide age range, and was specifically designed to draw exact correspondences between neuroimaging and pathology data. METHODS: Using four different MRI sequences, we are reaching a sample size that allows for validating multimodal neuroimaging biomarkers and studying comorbid conditions. Our imaging protocol was designed to capture markers of cerebrovascular disease and related lesions. Quantification of these lesions is currently underway with MRI-guided histopathological examination. RESULTS: A total of 139 postmortem brains (70 females) with mean age of 77.9 years were collected, with 71 brains fully analyzed. Of these, only 3% showed evidence of AD-only pathology and 76% had high prevalence of multiple pathologies contributing to clinical diagnosis. CONCLUSION: This repository has a significant (and increasing) sample size consisting of a wide range of neurodegenerative disorders and employs advanced imaging protocols and MRI-guided histopathological analysis to help disentangle the effects of comorbid disorders to refine diagnosis, prognosis and better understand neurodegenerative disorders.

Deep Learning Based Detection of Enlarged Perivascular Spaces on Brain MRI.

Deep learning has been demonstrated effective in many neuroimaging applications. However, in many scenarios, the number of imaging sequences capturing information related to small vessel disease lesions is insufficient to support data-driven techniques. Additionally, cohort-based studies may not always have the optimal or essential imaging sequences for accurate lesion detection. Therefore, it is necessary to determine which imaging sequences are crucial for precise detection. This study introduces a deep learning framework to detect enlarged perivascular spaces (ePVS) and aims to find the optimal combination of MRI sequences for deep learning-based quantification. We implemented an effective lightweight U-Net adapted for ePVS detection and comprehensively investigated different combinations of information from SWI, FLAIR, T1-weighted (T1w), and T2-weighted (T2w) MRI sequences. The experimental results showed that T2w MRI is the most important for accurate ePVS detection, and the incorporation of SWI, FLAIR and T1w MRI in the deep neural network had minor improvements in accuracy and resulted in the highest sensitivity and precision (sensitivity =0.82, precision =0.83). The proposed method achieved comparable accuracy at a minimal time cost compared to manual reading. The proposed automated pipeline enables robust and time-efficient readings of ePVS from MR scans and demonstrates the importance of T2w MRI for ePVS detection and the potential benefits of using multimodal images. Furthermore, the model provides whole-brain maps of ePVS, enabling a better understanding of their clinical correlates compared to the clinical rating methods within only a couple of brain regions.

Assessment of Risk Factors and Clinical Importance of Enlarged Perivascular Spaces by Whole-Brain Investigation in the Multi-Ethnic Study of Atherosclerosis.

Importance: Enlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain. Objective: Toperform a whole-brain investigation of ePVSs in a large community-based cohort. Design, Setting, and Participants: This cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included. Main Outcomes and Measures: Enlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models. Results: In the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (ß = 3.59 × 10-3; 95% CI, 2.80 × 10-3 to 4.39 × 10-3), systolic blood pressure (ß = 8.35 × 10-4; 95% CI, 5.19 × 10-4 to 1.15 × 10-3), use of antihypertensives (ß = 3.29 × 10-2; 95% CI, 1.92 × 10-2 to 4.67 × 10-2), and negatively associated with Black race (ß = -3.34 × 10-2; 95% CI, -5.08 × 10-2 to -1.59 × 10-2). Thalamic ePVS volume was positively associated with age (ß = 5.57 × 10-4; 95% CI, 2.19 × 10-4 to 8.95 × 10-4) and use of antihypertensives (ß = 1.19 × 10-2; 95% CI, 6.02 × 10-3 to 1.77 × 10-2). Insular region ePVS volume was positively associated with age (ß = 1.18 × 10-3; 95% CI, 7.98 × 10-4 to 1.55 × 10-3). Brainstem ePVS volume was smaller in Black than in White participants (ß = -5.34 × 10-3; 95% CI, -8.26 × 10-3 to -2.41 × 10-3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (ß = 1.14 × 10-4; 95% CI, 3.38 × 10-5 to 1.95 × 10-4) and negatively associated with age (ß = -3.38 × 10-4; 95% CI, -5.40 × 10-4 to -1.36 × 10-4). Temporal region ePVS volume was negatively associated with age (ß = -1.61 × 10-2; 95% CI, -2.14 × 10-2 to -1.09 × 10-2), as well as Chinese American (ß = -2.35 × 10-1; 95% CI, -3.83 × 10-1 to -8.74 × 10-2) and Hispanic ethnicities (ß = -1.73 × 10-1; 95% CI, -2.96 × 10-1 to -4.99 × 10-2). Conclusions and Relevance: In this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers: Post Hoc Secondary Analysis of the SPRINT MIND Randomized Clinical Trial.

Importance: Little is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers. Objective: To investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF). Design, Setting, and Participants: The Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target <120 mm Hg) vs standard control (SBP target <140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022. Interventions: At baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment. Main Outcomes and Measures: The main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest). Results: At baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]). Conclusions and Relevance: This study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Congenital Babesiosis After Maternal Infection With Borrelia burgdorferi and Babesia microti.

We describe the cases of 2 infants with congenital babesiosis born to mothers with prepartum Lyme disease and subclinical Babesia microti infection. The infants both developed anemia, neutropenia, and thrombocytopenia, and 1 infant required red blood cell transfusion. Both infants recovered with treatment. Additional studies are warranted to define the optimal management strategy for pregnant women with early Lyme disease in geographic areas in which B microti infection is endemic.

Progressive Bidirectional Age-Related Changes in Default Mode Network Effective Connectivity across Six Decades.

The default mode network (DMN) is a set of regions that is tonically engaged during the resting state and exhibits task-related deactivation that is readily reproducible across a wide range of paradigms and modalities. The DMN has been implicated in numerous disorders of cognition and, in particular, in disorders exhibiting age-related cognitive decline. Despite these observations, investigations of the DMN in normal aging are scant. Here, we used blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) acquired during rest to investigate age-related changes in functional connectivity of the DMN in 120 healthy normal volunteers comprising six, 20-subject, decade cohorts (from 20-29 to 70-79). Structural equation modeling (SEM) was used to assess age-related changes in inter-regional connectivity within the DMN. SEM was applied both using a previously published, meta-analytically derived, node-and-edge model, and using exploratory modeling searching for connections that optimized model fit improvement. Although the two models were highly similar (only 3 of 13 paths differed), the sample demonstrated significantly better fit with the exploratory model. For this reason, the exploratory model was used to assess age-related changes across the decade cohorts. Progressive, highly significant changes in path weights were found in 8 (of 13) paths: four rising, and four falling (most changes were significant by the third or fourth decade). In all cases, rising paths and falling paths projected in pairs onto the same nodes, suggesting compensatory increases associated with age-related decreases. This study demonstrates that age-related changes in DMN physiology (inter-regional connectivity) are bidirectional, progressive, of early onset and part of normal aging.

Modeling the effective connectivity of the visual network in healthy and photosensitive, epileptic baboons.

The baboon provides a model of photosensitive, generalized epilepsy. This study compares cerebral blood flow responses during intermittent light stimulation (ILS) between photosensitive (PS) and healthy control (CTL) baboons using H 2 (15) O-PET. We examined effective connectivity associated with visual stimulation in both groups using structural equation modeling (SEM). Eight PS and six CTL baboons, matched for age, gender and weight, were classified on the basis of scalp EEG findings performed during the neuroimaging studies. Five H 2 (15) O-PET studies were acquired alternating between resting and activation (ILS at 25 Hz) scans. PET images were acquired in 3D mode and co-registered with MRI. SEM demonstrated differences in neural connectivity between PS and CTL groups during ILS that were not previously identified using traditional activation analyses. First-level pathways consisted of similar posterior-to-anterior projections in both groups. While second-level pathways were mainly lateralized to the left hemisphere in the CTL group, they consisted of bilateral anterior-to-posterior projections in the PS baboons. Third- and fourth-level pathways were only evident in PS baboons. This is the first functional neuroimaging study used to model the photoparoxysmal response (PPR) using a primate model of photosensitive, generalized epilepsy. Evidence of increased interhemispheric connectivity and bidirectional feedback loops in the PS baboons represents electrophysiological synchronization associated with the generation of epileptic discharges. PS baboons demonstrated decreased model stability compared to controls, which may be attributed to greater variability in the driving response or PPRs, or to the influence of regions not included in the model.

Functional activation and effective connectivity differences in adolescent marijuana users performing a simulated gambling task.

Background. Adolescent marijuana use is associated with structural and functional differences in forebrain regions while performing memory and attention tasks. In the present study, we investigated neural processing in adolescent marijuana users experiencing rewards and losses. Fourteen adolescents with frequent marijuana use (>5 uses per week) and 14 nonuser controls performed a computer task where they were required to guess the outcome of a simulated coin flip while undergoing magnetic resonance imaging. Results. Across all participants, "Wins" and "Losses" were associated with activations including cingulate, middle frontal, superior frontal, and inferior frontal gyri and declive activations. Relative to controls, users had greater activity in the middle and inferior frontal gyri, caudate, and claustrum during "Wins" and greater activity in the anterior and posterior cingulate, middle frontal gyrus, insula, claustrum, and declive during "Losses." Effective connectivity analyses revealed similar overall network interactions among these regions for users and controls during both "Wins" and "Losses." However, users and controls had significantly different causal interactions for 10 out of 28 individual paths during the "Losses" condition. Conclusions. Collectively, these results indicate adolescent marijuana users have enhanced neural responses to simulated monetary rewards and losses and relatively subtle differences in effective connectivity.

The neural changes in connectivity of the voice network during voice pitch perturbation.

Voice control is critical to communication. To date, studies have used behavioral, electrophysiological and functional data to investigate the neural correlates of voice control using perturbation tasks, but have yet to examine the interactions of these neural regions. The goal of this study was to use structural equation modeling of functional neuroimaging data to examine network properties of voice with and without perturbation. Results showed that the presence of a pitch shift, which was processed as an error in vocalization, altered connections between right STG and left STG. Other regions that revealed differences in connectivity during error detection and correction included bilateral inferior frontal gyrus, and the primary and pre motor cortices. Results indicated that STG plays a critical role in voice control, specifically, during error detection and correction. Additionally, pitch perturbation elicits changes in the voice network that suggest the right hemisphere is critical to pitch modulation.

Investigating the functional heterogeneity of the default mode network using coordinate-based meta-analytic modeling.

The default mode network (DMN) comprises a set of regions that exhibit ongoing, intrinsic activity in the resting state and task-related decreases in activity across a range of paradigms. However, DMN regions have also been reported as task-related increases, either independently or coactivated with other regions in the network. Cognitive subtractions and the use of low-level baseline conditions have generally masked the functional nature of these regions. Using a combination of activation likelihood estimation, which assesses statistically significant convergence of neuroimaging results, and tools distributed with the BrainMap database, we identified core regions in the DMN and examined their functional heterogeneity. Meta-analytic coactivation maps of task-related increases were independently generated for each region, which included both within-DMN and non-DMN connections. Their functional properties were assessed using behavioral domain metadata in BrainMap. These results were integrated to determine a DMN connectivity model that represents the patterns of interactions observed in task-related increases in activity across diverse tasks. Subnetwork components of this model were identified, and behavioral domain analysis of these cliques yielded discrete functional properties, demonstrating that components of the DMN are differentially specialized. Affective and perceptual cliques of the DMN were identified, as well as the cliques associated with a reduced preference for motor processing. In summary, we used advanced coordinate-based meta-analysis techniques to explicate behavior and connectivity in the default mode network; future work will involve applying this analysis strategy to other modes of brain function, such as executive function or sensorimotor systems.

Modeling motor connectivity using TMS/PET and structural equation modeling.

Structural equation modeling (SEM) was applied to positron emission tomographic (PET) images acquired during transcranial magnetic stimulation (TMS) of the primary motor cortex (M1(hand)). TMS was applied across a range of intensities, and responses both at the stimulation site and remotely connected brain regions covaried with stimulus intensity. Regions of interest (ROIs) were identified through an activation likelihood estimation (ALE) meta-analysis of TMS studies. That these ROIs represented the network engaged by motor planning and execution was confirmed by an ALE meta-analysis of finger movement studies. Rather than postulate connections in the form of an a priori model (confirmatory approach), effective connectivity models were developed using a model-generating strategy based on improving tentatively specified models. This strategy exploited the experimentally imposed causal relations: (1) that response variations were caused by stimulation variations, (2) that stimulation was unidirectionally applied to the M1(hand) region, and (3) that remote effects must be caused, either directly or indirectly, by the M1(hand) excitation. The path model thus derived exhibited an exceptional level of goodness (chi(2)=22.150, df=38, P=0.981, TLI=1.0). The regions and connections derived were in good agreement with the known anatomy of the human and primate motor system. The model-generating SEM strategy thus proved highly effective and successfully identified a complex set of causal relationships of motor connectivity.

Infections and apparent life-threatening events.

The need for routine sepsis evaluation in patients who have experienced an apparent life-threatening event but lack signs of infection remains controversial. To assess their risk of a serious occult bacterial infection, records were reviewed of 95 infants in whom infections were discovered during their inpatient evaluation after an apparent life-threatening event. Noted for each patient was the presence of any suggestive findings that would have prompted a physician to consider the given type of infection in the differential diagnosis. Thirty patients had bacterial infections; all but 5 had suggestive findings. The exceptions included 1 patient with pneumonia and 4 with urinary tract infections. None of the remaining 25 patients had occult bacterial infections. In patients with an apparent life-threatening event who appear well and lack signs suggestive of a serious bacterial infection, it may be possible to forego routine sepsis evaluation beyond a chest radiograph and urine culture without risking a serious missed diagnosis.

Neuroanatomical correlates of phonological processing of Chinese characters and alphabetic words: a meta-analysis.

We used the activation likelihood estimation (ALE) method to quantitatively synthesize data from 19 published brain mapping studies of phonological processing in reading, six with Chinese and 13 with alphabetic languages. It demonstrated high concordance of cortical activity across multiple studies in each written language system as well as significant differences of activation likelihood between languages. Four neural systems for the phonological processing of Chinese characters included: (1) a left dorsal lateral frontal system at Brodmann area (BA) 9; (2) the dorsal aspect of left inferior parietal system; (3) a bilateral ventral-occipitotemporal system including portions of fusiform gyrus and middle occipital gyrus; and (4) a left ventral prefrontal system covering the superior aspect of inferior frontal gyrus. For phonological processing of written alphabetic words, cortical areas identified here are consistent with the three neural systems proposed previously in the literature: (1) a ventral prefrontal system involving superior portions of left inferior frontal gyrus; (2) a left dorsal temporoparietal system including mid-superior temporal gyri and the ventral aspect of inferior parietal cortex (supramarginal region); and (3) a left ventral occipitotemporal system. Contributions of each of these systems to phonological processing in reading were discussed, and a covariant learning hypothesis is offered to account for the findings that left middle frontal gyrus is responsible for addressed phonology in Chinese whereas left temporoparietal regions mediate assembled phonology in alphabetic languages. Language form, cognitive process, and learning strategy drive the development of functional neuroanatomy.

Congenital tuberculosis with facial nerve palsy.

Congenital tuberculosis is unusual, and central nervous system involvement is even more rare. We report a case of congenital tuberculosis presenting with facial palsy and purulent otorrhea.