Automated MRI Segmentation of Brainstem Nuclei Critical to Consciousness

While substantial progress has been made in mapping the connectivity of cortical networks responsible for conscious awareness, neuroimaging analysis of subcortical arousal networks that modulate arousal (i.e., wakefulness) has been limited by a lack of a robust segmentation procedures for brainstem arousal nuclei. Automated segmentation of brainstem arousal nuclei is an essential step toward elucidating the physiology of arousal in human consciousness and the pathophysiology of disorders of consciousness. We created a probabilistic atlas of brainstem arousal nuclei built on diffusion MRI scans of five ex vivo human brain specimens scanned at 750 μm isotropic resolution. Labels of arousal nuclei used to generate the probabilistic atlas were manually annotated with reference to nucleus-specific immunostaining in two of the five brain specimens. We then developed a Bayesian segmentation algorithm that utilizes the probabilistic atlas as a generative model and automatically identifies brainstem arousal nuclei in a resolution- and contrast-agnostic manner. The segmentation method displayed high accuracy in both healthy and lesioned in vivo T1 MRI scans and high test-retest reliability across both T1 and T2 MRI contrasts. Finally, we show that the segmentation algorithm can detect volumetric changes and differences in magnetic susceptibility within brainstem arousal nuclei in Alzheimer's disease and traumatic coma, respectively. We release the probabilistic atlas and Bayesian segmentation tool in FreeSurfer to advance the study of human consciousness and its disorders.

Inherent differences in tissue magnetic susceptibility produce inhomogeneities in the static magnetic field which give rise to an additional dephasing of the transverse magnetization in gradient-echo images. The enhanced dephasing of the signal results in an increase of the apparent relaxation rate 1/T2* and a corresponding decrease in signal intensity. These effects have been used to explain the regional loss of marrow signal intensity in the appendicular skeleton, where in the presence of trabecular bone in the proximal tibia there is an enhanced loss of signal compared to the tibial shaft where there is no trabeculation. It has been postulated that differences in tissue magnetic susceptibility arising due to the marrow--trabeculae interface give rise to magnetic field inhomogeneities and a reduced T2*. In this study computer simulations are used to determine whether susceptibility differences comparable to that between trabecular bone and tissue relate to the reduction of tissue T2* and whether the reduction in T2* is also related to the concentration and magnitude of susceptibility differences. In addition the effects of the spatial distribution of these particulate discontinuities in susceptibility on the measured relaxation time T2* are also estimated. This model demonstrates that 1/T2* increases as the number density and magnitude of such susceptibility differences increase. In a pixel of linear dimension L consisting of material simulating tissue water, the presence of circular point susceptibility differences of dimension 0.001 L with magnetic susceptibility equivalent to trabecular bone, 1/T2*, increases at a rate of 1.60 x 10(-2) s-1/N for N ranging from 25-2500. Differences in magnetic susceptibility that are less than that between soft tissue and trabecular bone are also modeled and the simulations demonstrate that differences in magnetic susceptibility, much lower than that between trabecular bone and tissue equivalent interfaces, also produce a relaxation rate enhancement in gradient-echo images.

This study adopted diffusion tensor imaging to detect alterations in the diffusion parameters of the white matter fiber in Alzheimer’s disease (AD) and used quantitative susceptibility mapping to detect changes in magnetic susceptibility. However, whether the changes of susceptibility values due to excessive iron in the basal ganglia have correlations with the alterations of the diffusion properties of the white matter in patients with AD are still unknown. We aim to investigate the correlations among magnetic susceptibility values of the basal ganglia, diffusion indexes of the white matter, and cognitive function in patients with AD. Thirty patients with AD and nineteen healthy controls (HCs) were recruited. Diffusion indexes of the whole brain were detected using tract-based spatial statistics. The caudate nucleus, putamen, and globus pallidus were selected as regions of interest, and their magnetic susceptibility values were measured. Compared with HCs, patients with AD showed that there were significantly increased axial diffusivity (AxD) in the internal capsule, superior corona radiata (SCR), and right anterior corona radiata (ACR); increased radial diffusivity (RD) in the right anterior limb of the internal capsule, ACR, and genu of the corpus callosum (GCC); and decreased fractional anisotropy (FA) in the right ACR and GCC. The alterations of RD values, FA values, and susceptibility values of the right caudate nucleus in patients with AD were correlated with cognitive scores. Besides, AxD values in the right internal capsule, ACR, and SCR were positively correlated with the magnetic susceptibility values of the right caudate nucleus in patients with AD. Our findings revealed that the magnetic susceptibility of the caudate nucleus may be an MRI-based biomarker of the cognitive dysfunction of AD and abnormal excessive iron distribution in the basal ganglia had adverse effects on the diffusion properties of the white matter.

Multi-modal MRI investigation of volumetric and microstructural changes inthe hippocampus and its subfields in mild cognitive impairment, Alzheimer's disease, anddementia with Lewy bodies

Topographical metal burden correlates with brain atrophy and clinical severity in Wilson's disease

Imaging studies of traumatic brain injury (TBI) have several major goals: to develop methods that detect neurotraumarelated brain abnormalities with high sensitivity and specificity, especially when routine neuroimaging is unrevealing; to identify prognostic biomarkers, including abnormalities that portend the development of adverse neurological, neuropsychiatric, and/or functional outcomes; and to advance our knowledge of task-associated brain function and dysfunction in a manner that elucidates the pathophysiology of TBI and its consequences. This quickly expanding literature, in general, suffers from a lack of consistency of techniques, methods of analysis, and subject exclusion and inclusion. These inconsistencies make it difficult to determine whether neuroimaging abnormalities identified in such studies are attributable to TBI, a co-occurring condition, a preinjury condition, or some combination of conditions. The crosssectional design of most such studies also precludes conclusions about the permanence or transience of the findings, and at best allows only inference on the meaning of abnormalities in terms of TBI-induced changes in brain structure and/or function. The study by Ponto et al. in this issue of the Journal of Neuropsychiatry and Clinical Neurosciences is a preliminary examination of veterans from Operation Iraqi Freedom/ Operation Enduring Freedom (OIF/OEF). Importantly, they assessed twomeasures of interest: evaluating a risk factor for Alzheimer disease (AD) (amyloid deposition) andmeasuring cerebral blood flow (CBF) in participants with and without a history of TBI (8 and 11 individuals, respectively). They found that amyloid burden was similar, but those with a TBI had lower CBF. Assessments of cognition, depression, and posttraumatic stress disorder (PTSD) did not differ between groups, and there was no indication of whether those two groups were symptomatically distinguishable. Several studies have demonstrated that TBI increases risk of developing AD. One hypothesized mechanism is that TBI promotes the deposition or inhibits clearance of amyloid. It is important to note that in studies of individuals looking for risk of AD, many individuals who demonstrate amyloid on positron emission tomography (PET) of the brain—using Pittsburgh compound B (PIB), for example—do not have and may not necessarily develop AD. Amyloid on [C]PIB PET therefore carries a relatively high false positive rate in relation to diagnosing AD or pre-AD status, and the presence of amyloid after TBI does not necessarily portend AD. By contrast, the absence of amyloid on PIB imaging studies may be useful as a marker of brain health and, possibly, reduced risk of AD (i.e., has negative predictive value for AD). In the Ponto et al. study, [C]PIB PET was used to evaluate amyloid burden and the hypothesis that amyloid burden (and, by implication, risk of amyloid-related neurodegeneration) is associated with TBI and time since injury. Their findings did not support this hypothesis: amyloid burden did not differ between those with and without histories of TBI, and the extent of amyloid burden was not in the pathological range in either group. They note that this finding is consistent with prior studies that failed to support the hypothesis that TBI is associated with progressive amyloid deposition. It is noteworthy that a risk factor for amyloid deposition in general and after TBI, APOE4 genotype, was not used as a risk stratifier in this study and may be relevant to the dynamics of amyloid deposition and clearance after TBI. If the participants in this study underrepresent APOE4 carriers relative to the general population, it is possible that this may decrease the likelihood of Ponto et al. finding an association between TBI and amyloid burden. The [C]PIB PET study did not show neurotraumarelated abnormalities and may not provide information that guides us to predict those that may be more vulnerable to develop adverse cognitive outcomes. Interestingly, a recent study demonstrated increased Abeta burden in a group with moderate to severe TBI using the same PET methodology. Ponto et al. also measured cerebral blood flow (CBF) at rest and under increasing emotional stimuli. We do not know if these findings would be similar if they used a paradigm that involved cognition (of note, the authors state that CBF with a “driving paradigm” will be published later). Those with TBI had lower global CBF, but regional CBF without stimulationwas similar. Thosewithout TBI exhibited a U-shape gCBF response to stress (resting,low stress.high stress) while those with TBI had a “flat” response to stress. The authors interpreted this as a possible indication of impaired vascular responsivity after TBI. CBF studies have been used in the sports concussion literature, demonstrating impairment. However, the methodology differs, making comparisons problematic. For example,Meier et al. examined rCBF (not gCBF) during the early post-injury period and “at rest.” It is difficult to compare the acute effects of a TBI on CBF with that after several months ormore, especially considering the differing circumstances of the injury. However, the cerebro-cardiac connection may have significant implications in terms of physiology, symptoms, diagnosis,

Background: This study investigated the relation between cognition and the neural connection from injured cingulum to brainstem cholinergic nuclei in patients with traumatic brain injury (TBI), using diffusion tensor tractography (DTT).Methods: Among 353 patients with TBI, 20 chronic patients who showed discontinuation of both anterior cingulums from the basal forebrain on DTT were recruited for this study. The Wechsler Intelligence Scale and the Memory Assessment Scale (MAS; short-term, verbal, visual and total memory) were used for assessment of cognition. Patients were divided into two groups according to the presence of a neural connection between injured cingulum and brainstem cholinergic nuclei.Results: Eight patients who had a neural connection between injured cingulum and brainstem cholinergic nuclei showed better short-term memory on MAS than 12 patients who did not (p < 0.05). However, other results of neuropsychological testing showed no significant difference (p > 0.05).Conclusions: Better short-term memory in patients who had the neural connection between injured cingulum and brainstem cholinergic nuclei appears to have been attributed to the presence of cholinergic innervation to the cerebral cortex through the neural connection instead of the injured anterior cingulum. The neural connection appears to compensate for the injured anterior cingulum in obtaining cholinergic innervation.

Traumatic brain injury may increase risk of young onset dementia

Microglia in Alzheimer's Disease

<h3>Objective:</h3> We sought to investigate incidence and trends of falls and Traumatic brain injury (TBI) in Alzheimer Disease (AD) cohort, and impact on mortality using a large administrative database <h3>Background:</h3> Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, with significant health-care burden. AD patients are more likely to fall and experience traumatic brain injury (TBI) than those without. However, there are no recent population based epidemiological studies to guide designing preventive strategies. <h3>Design/Methods:</h3> Hospitalizations with AD or TBI and age&gt;64 years were extracted from the Nationwide Inpatient Sample (NIS) 2006–2011. A subset of those with falls was identified using provided e-codes. Appropriate weights were attached to approximate national estimates. <h3>Results:</h3> Total hospitalizations from 2006–2011 was 62,949,73; out of which, 15.5% had AD with mean age = 83±7 years and 63.8% females, compared to mean age 78±8 and 56.3% females otherwise. TBI incidence in AD was 1.4% vs. 0.9% in non-AD (p&lt;0.0001). Fall incidence in AD was 11.5% vs. 6.7% in non-AD (p&lt;0.0001), and falls contributed to TBI in 68% cases. Fall incidence in AD increased from 10.5% (2006) to 12.1% (2011) (p&lt;0.0001). TBI incidence in AD with falls also increased from 7.7% (2006) to 10.0% (2011) (p&lt;0.0001). Overall in-hospital mortality was 4.7% in AD vs. 4.5% in non-AD (p&lt;0.0001). Mortality with TBI in AD was 6.9% vs. 4.7% in non-AD (p&lt;0.0001). In AD with falls cohort, mortality with TBI was 7.5% vs. 2.5% without TBI. <h3>Conclusions:</h3> There is a greater incidence of falls and TBI in AD compared to without AD, which is increasing yearly. Falls contribute to majority of TBI incidence in AD. TBI and falls also increase mortality incidence in AD. These findings necessitate investigation into their causes, impact on healthcare, and design of preventive strategies. <b>Disclosure:</b> Dr. Tahir has nothing to disclose. Dr. Al Jarrah has nothing to disclose. Dr. Khawaja has nothing to disclose. Dr. Izzy has nothing to disclose.

Discerning neurodegenerative and aging genetic influences on hippocampal subfields trajectories in the Alzheimer’s disease continuum

Discerning neurodegenerative and aging genetic influences on hippocampal subfields trajectories in the Alzheimer’s disease continuum

Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as ‘tauopathies’, by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Traumatic brain injury (TBI) afflicts 70 million people worldwide annually and is the 3rd overall risk factor for developing Alzheimer's disease (AD), behind genetics and aging. In patients with AD, a history of TBI is associated with a 3-4 year earlier onset of cognitive impairment. TBI and AD share many pathologies, including blood brain barrier dysfunction, neuroinflammation, and protein aggregation. Yet, the underlying mechanism of this relationship is not understood, and there are no treatments that protect patients from accelerated AD after TBI. We recently reported that tau, a microtubule binding protein essential for neuronal health, is acetylated after TBI. Acetylation impairs tau binding to microtubules, leading to its mis-localization into the cell soma and pathological aggregation. Acetylated tau is also elevated early in AD, and acetylated tau was significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesize that TBI-induced tau acetylation drives the acceleration of AD. To study this phenomenon, we developed a mouse model of TBI that accelerates AD-like pathology and cognitive impairment in 5xFAD mice, and amyloid-driven AD model. Our unique model of multimodal TBI produces a complex and reproducible brain injury with neurodegeneration and neurobehavioral impairment, beginning with acute axonal degeneration and persisting chronically with blood-brain barrier degradation and nerve cell death. This model of TBI also produces the same systemic metabolic alterations that are reported in TBI patients. TBI causes learning deficits in young 5xFAD mice that are not seen in either sham-injured 5xFAD mice or in wild type littermates subjected to TBI. TBI also accelerates amyloid deposition in 5xFAD mice. We hypothesize that TBI will also worsen blood brain barrier function in 5xFAD mice. Importantly, 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Preliminary data suggests that treatment with the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the enzyme that acetylates tau, reduces acetylated tau and rescues behavior deficits after TBI in 5xFAD mice.