Importance of the lumbar paraspinal muscles on the maintenance of global sagittal alignment after lumbar pedicle subtraction osteotomy.

OBJECTIVE: There are limited data about the influence of the lumbar paraspinal muscles on the maintenance of sagittal alignment after pedicle subtraction osteotomy (PSO) and the risk factors for sagittal realignment failure. The authors aimed to investigate the influence of preoperative lumbar paraspinal muscle quality on the postoperative maintenance of sagittal alignment after lumbar PSO. METHODS: Patients who underwent lumbar PSO with preoperative lumbar MRI and pre- and postoperative whole-spine radiography in the standing position were included. Spinopelvic measurements included pelvic incidence, sacral slope, pelvic tilt, L1-S1 lordosis, T4-12 thoracic kyphosis, spinosacral angle, C7-S1 sagittal vertical axis (SVA), T1 pelvic angle, and mismatch between pelvic incidence and L1-S1 lordosis. Validated custom software was used to calculate the percent fat infiltration (FI) of the psoas major, as well as the erector spinae and multifidus (MF). A multivariable linear mixed model was applied to further examine the association between MF FI and the postoperative progression of SVA over time, accounting for repeated measures over time that were adjusted for age, sex, BMI, and length of follow-up. RESULTS: Seventy-seven patients were recruited. The authors' results demonstrated significant correlations between MF FI and the maintenance of corrected sagittal alignment after PSO. After adjustment for the aforementioned parameters, the model showed that the MF FI was significantly associated with the postoperative progression of positive SVA over time. A 1% increase from the preoperatively assessed total MF FI was correlated with an increase of 0.92 mm in SVA postoperatively (95% CI 0.42-1.41, p < 0.0001). CONCLUSIONS: This study included a large patient cohort with midterm follow-up after PSO and emphasized the importance of the lumbar paraspinal muscles in the maintenance of sagittal alignment correction. Surgeons should assess the quality of the MF preoperatively in patients undergoing PSO to identify patients with severe FI, as they may be at higher risk for sagittal decompensation.

Relationship between facet joint osteoarthritis and lumbar paraspinal muscle atrophy: a cross-sectional study.

OBJECTIVE: The paraspinal muscles play an essential role in the stabilization of the lumbar spine. Lumbar paraspinal muscle atrophy has been linked to chronic back pain and degenerative processes within the spinal motion segment. However, the relationship between the different paraspinal muscle groups and facet joint osteoarthritis (FJOA) has not been fully explored. METHODS: In this cross-sectional study, the authors analyzed adult patients who underwent lumbar spinal surgery between December 2014 and March 2023 for degenerative spinal conditions and had preoperative MRI and CT scans. The fatty infiltration (FI) and functional cross-sectional area (fCSA) of the psoas, erector spinae, and multifidus muscles were assessed on axial T2-weighted MR images at the level of the upper endplate of L4 based on established studies and calculated using custom-made software. Intervertebral disc degeneration at each lumbar level was evaluated using the Pfirrmann grading system. The grades from each level were summed to report the cumulative lumbar Pfirrmann grade. Weishaupt classification (0-3) was used to assess FJOA at all lumbar levels (L1 to S1) on preoperative CT scans. The total lumbar FJOA score was determined by adding the Weishaupt grades of both sides at all 5 levels. Correlation and linear regression analyses were conducted to assess the relationship between FJOA and paraspinal muscle parameters. RESULTS: A total of 225 patients (49.7% female) with a median age of 61 (IQR 54-70) years and a median BMI of 28.3 (IQR 25.1-33.1) kg/m2 were included. After adjustment for age, sex, BMI, and the cumulative lumbar Pfirrmann grade, only multifidus muscle fCSA (estimate -4.69, 95% CI -6.91 to -2.46; p < 0.001) and FI (estimate 0.64, 95% CI 0.33-0.94; p < 0.001) were independently predicted by the total FJOA score. A similar relation was seen with individual Weishaupt grades of each lumbar level after controlling for age, sex, BMI, and the Pfirrmann grade of the corresponding level. CONCLUSIONS: Atrophy of the multifidus muscle is significantly associated with FJOA in the lumbar spine. The absence of such correlation for the erector spinae and psoas muscles highlights the unique link between multifidus muscle quality and the degeneration of the spinal motion segment. Further research is necessary to establish the causal link and the clinical implications of these findings.

Repetitive mild closed-head injury induced synapse loss and increased local BOLD-fMRI signal homogeneity.

Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries, requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild closed-head injury (rmTBI) and chronic variable stress (CVS) mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [ 18 F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an i ncrease in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.

Asymmetrical atrophy of the paraspinal muscles in patients undergoing unilateral lumbar medial branch radiofrequency neurotomy.

ABSTRACT: Lumbar medial branch radiofrequency neurotomy (RFN), a common treatment for chronic low back pain due to facet joint osteoarthritis (FJOA), may amplify paraspinal muscle atrophy due to denervation. This study aimed to investigate the asymmetry of paraspinal muscle morphology change in patients undergoing unilateral lumbar medial branch RFN. Data from patients who underwent RFN between March 2016 and October 2021 were retrospectively analyzed. Lumbar foramina stenosis (LFS), FJOA, and fatty infiltration (FI) functional cross-sectional area (fCSA) of the paraspinal muscles were assessed on preinterventional and minimum 2-year postinterventional MRI. Wilcoxon signed-rank tests compared measurements between sides. A total of 51 levels of 24 patients were included in the analysis, with 102 sides compared. Baseline MRI measurements did not differ significantly between the RFN side and the contralateral side. The RFN side had a higher increase in multifidus FI (+4.2% [0.3-7.8] vs +2.0% [-2.2 to 6.2], P = 0.005) and a higher decrease in multifidus fCSA (-60.9 mm2 [-116.0 to 10.8] vs -19.6 mm2 [-80.3 to 44.8], P = 0.003) compared with the contralateral side. The change in erector spinae FI and fCSA did not differ between sides. The RFN side had a higher increase in multifidus muscle atrophy compared with the contralateral side. The absence of significant preinterventional degenerative asymmetry and the specificity of the effect to the multifidus muscle suggest a link to RFN. These findings highlight the importance of considering the long-term effects of lumbar medial branch RFN on paraspinal muscle health.

Relationship between neuroimaging and cognition in frontotemporal dementia: An FDG-PET and structural MRI study.

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative condition with a prevalence comparable to Alzheimer's disease for patients under 65 years of age. Limited studies have examined the association between cognition and neuroimaging in FTD using different imaging modalities. METHODS: We examined the association of cognition using Montreal Cognitive Assessment (MoCA) with both gray matter (GM) volume and glucose metabolism using magnetic resonance imaging and fluorodeoxyglucose (FDG)-PET in 21 patients diagnosed with FTD. Standardized uptake value ratio (SUVR) using the brainstem as a reference region was the primary outcome measure for FDG-PET. Partial volume correction was applied to PET data to account for disease-related atrophy. RESULTS: Significant positive associations were found between whole-cortex GM volume and MoCA scores (r = 0.46, p = .04). The association between whole-cortex FDG SUVR and MoCA scores was not significant (r = 0.37, p = .09). GM volumes of the frontal cortex (r = 0.54, p = .01), caudate (r = 0.62, p<.01), and insula (r = 0.57, p<.01) were also significantly correlated with MoCA, as were SUVR values of the insula (r = 0.51, p = .02), thalamus (r = 0.48, p = .03), and posterior cingulate cortex (PCC) (r = 0.47, p = .03). CONCLUSIONS: Whole-cortex atrophy is associated with cognitive dysfunction, and this association is larger than for whole-cortex hypometabolism as measured with FDG-PET. At the regional level, focal atrophy and/or hypometabolism in the frontal cortex, insula, PCC, thalamus, and caudate seem to be important for the decline of cognitive function in FTD. Furthermore, these results highlight how functional and structural changes may not overlap and might contribute to cognitive dysfunction in FTD in different ways.

An overview of preclinical models of traumatic brain injury (TBI): relevance to pathophysiological mechanisms.

Background: Traumatic brain injury (TBI) is a major cause of morbidity and mortality, affecting millions annually worldwide. Although the majority of TBI patients return to premorbid baseline, a subset of patient can develop persistent and often debilitating neurocognitive and behavioral changes. The etiology of TBI within the clinical setting is inherently heterogenous, ranging from sport related injuries, fall related injuries and motor vehicle accidents in the civilian setting, to blast injuries in the military setting. Objective: Animal models of TBI, offer the distinct advantage of controlling for injury modality, duration and severity. Furthermore, preclinical models of TBI have provided the necessary temporal opportunity to study the chronic neuropathological sequelae of TBI, including neurodegenerative sequelae such as tauopathy and neuroinflammation within the finite experimental timeline. Despite the high prevalence of TBI, there are currently no disease modifying regimen for TBI, and the current clinical treatments remain largely symptom based. The preclinical models have provided the necessary biological substrate to examine the disease modifying effect of various pharmacological agents and have imperative translational value. Methods: The current review will include a comprehensive survey of well-established preclinical models, including classic preclinical models including weight drop, blast injury, fluid percussion injury, controlled cortical impact injury, as well as more novel injury models including closed-head impact model of engineered rotational acceleration (CHIMERA) models and closed-head projectile concussive impact model (PCI). In addition to rodent preclinical models, the review will include an overview of other species including large animal models and Drosophila. Results: There are major neuropathological perturbations post TBI captured in various preclinical models, which include neuroinflammation, calcium dysregulation, tauopathy, mitochondrial dysfunction and oxidative stress, axonopathy, as well as glymphatic system disruption. Conclusion: The preclinical models of TBI continue to offer valuable translational insight, as well as essential neurobiological basis to examine specific disease modifying therapeutic regimen.

Combined Use of Guanfacine and N-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury.

Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.

The Relationship of Cerebrospinal Fluid Biomarkers and Cognitive Performance in Frontotemporal Dementia.

Objective: Currently available literature on the relationships between cerebrospinal fluid (CSF) biomarkers and cognitive performance in frontotemporal dementia (FTD) is very limited and inconclusive. In this study, we investigated the association of cognition, as measured with Montreal Cognitive Assessment (MoCA), with CSF levels of total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and amyloid ß 1-42 (Aß1-42) in a group of patients with FTD and Alzheimer's disease (AD). Methods: We conducted a retrospective cohort study with participants selected from the electronic records of patients seen at Yale New Haven Hospital's Memory Clinic, CT, USA. We included 61 patients, 28 with FTD (mean age=64.1) and 33 with AD (mean age=66.8). Results: T-tau levels negatively and significantly correlated with total MoCA scores as well as the different MoCA index scores in both the FTD (r=-0.469, p<0.05) and AD (r=-0.545, p<0.01) groups. There were no significant associations with MoCA scores and p-tau181 levels in patients with FTD (r=-0.224, p>0.05), unlike patients with AD, who exhibited significant correlations (r=-0.549, p<0.01). Also, Aß1-42 levels were not significantly correlated with MoCA scores in either of the FTD and AD groups. Conclusion: CSF concentrations of t-tau are inversely correlated to cognitive performance in patients with FTD and both t-tau and p-tau181 in AD. These findings provide valuable insights into the relationship between clinical cognitive performance and tau-related pathology in FTD.

Relationship between Neuroimaging and Cognition in Frontotemporal Dementia: A [18 F]FDG PET and Structural MRI Study.

Background: Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous condition with a prevalence comparable to Alzheimer's Disease for patients under sixty-five years of age. Gray matter (GM) atrophy and glucose hypometabolism are important biomarkers for the diagnosis and evaluation of disease progression in FTD. However, limited studies have systematically examined the association between cognition and neuroimaging in FTD using different imaging modalities in the same patient group. Methods: We examined the association of cognition using Montreal Cognitive Assessment (MoCA) with both GM volume and glucose metabolism using structural magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography scanning ([18F]FDG PET) in 21 patients diagnosed with FTD. Standardized uptake value ratio (SUVR) using the brainstem as a reference region was the primary outcome measure for [18F]FDG PET. Partial volume correction was applied to PET data to account for disease-related atrophy. Results: Significant positive associations were found between whole-cortex GM volume and MoCA scores (r = 0.461, p = 0.035). The association between whole-cortex [18F]FDG SUVR and MoCA scores was not Significant (r = 0.374, p = 0.094). GM volumes of the frontal cortex (r = 0.540, p = 0.011), caudate (r = 0.616, p = 0.002), and insula (r = 0.568, p = 0.007) were also Significantly correlated with MoCA, as were SUVR values of the insula (r = 0.508, p = 0.018), thalamus (r = 0.478, p = 0.028), and posterior cingulate cortex (PCC) (r = 0.472, p = 0.030). Discussion: Whole-cortex atrophy is associated with cognitive dysfunction, and this effect is larger than for cortical hypometabolism as measured with [18F]FDG PET. At the regional level, focal atrophy and/or hypometabolism in the frontal lobe, insula, PCC, thalamus, and caudate seem to imply the importance of these regions for the decline of cognitive function in FTD. Furthermore, these results highlight how functional and structural changes may not overlap and might contribute to cognitive dysfunction in FTD in different ways. Our findings provide insight into the relationships between structural, metabolic, and cognitive changes due to FTD.

Navigating the Complexities of Traumatic Encephalopathy Syndrome (TES): Current State and Future Challenges.

Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease that is associated with repetitive head impacts (RHI) in both civilian and military settings. In 2014, the research criteria for the clinical manifestation of CTE, traumatic encephalopathy syndrome (TES), were proposed to improve the clinical identification and understanding of the complex neuropathological phenomena underlying CTE. This review provides a comprehensive overview of the current understanding of the neuropathological and clinical features of CTE, proposed biomarkers of traumatic brain injury (TBI) in both research and clinical settings, and a range of treatments based on previous preclinical and clinical research studies. Due to the heterogeneity of TBI, there is no universally agreed-upon serum, CSF, or neuroimaging marker for its diagnosis. However, as our understanding of this complex disease continues to evolve, it is likely that there will be more robust, early diagnostic methods and effective clinical treatments. This is especially important given the increasing evidence of a correlation between TBI and neurodegenerative conditions, such as Alzheimer's disease and CTE. As public awareness of these conditions grows, it is imperative to prioritize both basic and clinical research, as well as the implementation of necessary safe and preventative measures.

Examining the Role of Paraspinal Musculature in Post-Operative Disability after Lumbar Fusion Surgery for Degenerative Spondylolisthesis.

STUDY DESIGN: Retrospective analysis of prospectively enrolled patients. OBJECTIVE: To evaluate the relationship between paraspinal muscle (PM) atrophy and Oswestry Disability Index (ODI) improvement after spinal fusion surgery for degenerative lumbar spondylolisthesis (DLS). BACKGROUND: Atrophy of the PM is linked to multiple spinal conditions, sagittal malalignment, and increased postoperative complications. However, only limited evidence for the effect on patient-reported outcomes exists. METHODS: Patients with DLS undergoing decompression and fusion surgery were analyzed. Patients with missing follow-up, no imaging, or inadequate image quality were excluded. The Oswestry Disability Index (ODI) was assessed preoperatively and two years postoperatively. A cross-sectional area of the PM was measured on a T2-weighted Magnetic Resonance Imaging (MRI) sequence at the upper endplate of L4. Based on the literature, a 10-point improvement cut-off was defined as the minimum clinically important difference (MCID). Patients with a baseline ODI below the MCID were excluded. Logistic regression was used to calculate the association between fatty infiltration (FI) of the PM and improvement in ODI, adjusted for age, sex, and body mass index (BMI). RESULTS: 133 patients were included in the final analysis, with only two lost to follow-up. The median age was 68 years (IQR 62 - 73). The median preoperative ODI was 23 (IQR 17 - 28), and 76.7% of patients showed improvement in their ODI score by at least 10 points. In the multivariable regression, FI of the erector spinae and multifidus increased the risk of not achieving clinically relevant ODI improvement (P=0.01 and P<0.001, respectively). No significant association was found for the psoas muscle (P=0.158). CONCLUSIONS: This study demonstrates that FI of the erector spinae and multifidus, is significantly associated with less likelihood of clinically relevant ODI improvement following decompression and fusion. Further research is needed to assess the effect of interventions.

Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID.

Sustained cognitive deficits are a common and debilitating feature of "long COVID", but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function. KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID.

Oxidative Stress in Traumatic Brain Injury.

Traumatic Brain Injury (TBI) remains a major cause of disability worldwide. It involves a complex neurometabolic cascade, including oxidative stress. The products of this manuscript is examining the underlying pathophysiological mechanism, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). This process in turn leads to secondary injury cascade, which includes lipid peroxidation products. These reactions ultimately play a key role in chronic inflammation and synaptic dysfunction in a synergistic fashion. Although there are no FDA approved antioxidant therapy for TBI, there is a number of antioxidant therapies that have been tested and include free radical scavengers, activators of antioxidant systems, inhibitors of free radical generating enzymes, and antioxidant enzymes. Antioxidant therapies have led to cognitive and functional recovery post TBI, and they offer a promising treatment option for patients recovering from TBI. Current major challenges in treatment of TBI symptoms include heterogenous nature of injury, as well as access to timely treatment post injury. The inherent benefits of antioxidant therapies include minimally reported side effects, and relative ease of use in the clinical setting. The current review also provides a highlight of the more studied anti-oxidant regimen with applicability for TBI treatment with potential use in the real clinical setting.

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging.

The development of novel PET imaging agents for synaptic vesicle glycoprotein 2A (SV2A) allowed for the in vivo detection of synaptic density changes, which are correlated with the progression and severity of a variety of neuropsychiatric diseases. While multiple ongoing clinical investigations using SV2A PET are expanding its applications rapidly, preclinical SV2A PET imaging in animal models is an integral component of the translation research and provides supporting and complementary information. Herein, we overview preclinical SV2A PET studies in animal models of neurodegenerative disorders and discuss the opportunities and practical challenges in small animal SV2A PET imaging. At the Yale PET Center, we have conducted SV2A PET imaging studies in animal models of multiple diseases and longitudinal SV2A PET allowed us to evaluate synaptic density dynamics in the brains of disease animal models and to assess pharmacological effects of novel interventions. In this article, we discuss key considerations when designing preclinical SV2A PET imaging studies and strategies for data analysis. Specifically, we compare the brain imaging characteristics of available SV2A tracers, i.e., [11C]UCB-J, [18F]SynVesT-1, [18F]SynVesT-2, and [18F]SDM-16, in rodent brains. We also discuss the limited spatial resolution of PET scanners for small brains and challenges of kinetic modeling. We then compare different injection routes and estimate the maximum throughput (i.e., number of animals) per radiotracer synthesis by taking into account the injectable volume for each injection method, injected mass, and radioactivity half-lives. In summary, this article provides a perspective for designing and analyzing SV2A PET imaging studies in small animals.

A Case of Possible Chronic Traumatic Encephalopathy and Alzheimer's Disease in an Ex-Football Player.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a debilitating neurodegenerative disease, which is often the sequelae of repetitive head trauma. Although the definitive diagnosis of CTE is made postmortem, there are proposed clinical algorithms aimed at identifying characteristic features of CTE, based on a combination of clinical history, serum, cerebrospinal fluid and neuroimaging biomarkers. There are promising new advances in positron emission tomography neuroimaging, including tau specific ligands, which will potentially provide a robust assessment as well as an exploratory tool of the disease semiology and progression. CASE REPORT: Here is a unique case of an ex-football player, who suffered multiple prior traumatic brain injuries throughout his career, and presented to our clinic with significant episodic memory, visuospatial and executive functioning deficits, as well as comorbid mood and behavioral changes in the absence of prior psychiatric history or substance use. His clinical presentation and biomarkers were consistent with a suspected diagnosis of CTE comorbid with Alzheimer disease, which comprises a significant portion of overall CTE cases. CONCLUSION: This case report presents a patient with a subtle case of dementia, which could be easily mistaken for behavioral variant frontotemporal dementia or primary progressive aphasia. This in turn highlights the importance of detailed longitudinal history taking, as well as rigorous biomarker studies.

Coronavirus disease 2019 and neurodegenerative disease: what will the future bring?

PURPOSE OF REVIEW: Over 70 million people worldwide, including those with neurodegenerative disease (NDD), have been diagnosed with coronavirus disease 2019 (COVID-19) to date. We review outcomes in patients with NDD and COVID-19 and discuss the hypothesis that due to putative commonalities of neuropathogenesis, COVID-19 may unmask or trigger NDD in vulnerable individuals. RECENT FINDINGS: Based on a systematic review of published literature, patients with NDD, including dementia, Parkinson's disease, and multiple sclerosis (MS) make up a significant portion of hospitalized COVID-19 patients. Such patients are likely to present with altered mental status or worsening of their preexisting neurological symptoms. Patients with NDD and poor outcomes often have high-risk comorbid conditions, including advanced age, hypertension, diabetes, obesity, and heart/lung disease. Patients with dementia including Alzheimer's disease are at higher risk for hospitalization and death, whereas those with preexisting Parkinson's disease are not. MS patients have good outcomes and disease modifying therapies do not increase the risk for severe disease. Viral infections and attendant neuroinflammation have been associated with the pathogenesis of Alzheimer's disease, Parkinson's disease, and MS, suggesting that COVID-19 may have the potential to incite or accelerate neurodegeneration. SUMMARY: Since patients with Alzheimer's disease are at higher risk for hospitalization and death in the setting of COVID-19, additional precautions and protective measures should be put in place to prevent infections and optimize management of comorbidities in this vulnerable population. Further studies are needed to determine whether COVID-19 may lead to an increased risk of developing NDD in susceptible individuals.

Increased Behavioral Deficits and Inflammation in a Mouse Model of Co-Morbid Traumatic Brain Injury and Post-Traumatic Stress Disorder.

Comorbid post-traumatic stress disorder with traumatic brain injury (TBI) produce more severe affective and cognitive deficits than PTSD or TBI alone. Both PTSD and TBI produce long-lasting neuroinflammation, which may be a key underlying mechanism of the deficits observed in co-morbid TBI/PTSD. We developed a model of co-morbid TBI/PTSD by combining the closed head (CHI) model of TBI with the chronic variable stress (CVS) model of PTSD and examined multiple behavioral and neuroinflammatory outcomes. Male C57/Bl6 mice received sham treatment, CHI, CVS, CHI then CVS (CHI → CVS) or CVS then CHI (CVS → CHI). The CVS → CHI group had deficits in Barnes maze or active place avoidance not seen in the other groups. The CVS → CHI, CVS and CHI → CVS groups displayed increased basal anxiety level, based on performance on elevated plus maze. The CVS → CHI had impaired performance on Barnes Maze, and Active Place Avoidance. These performance deficits were strongly correlated with increased hippocampal Iba-1 level an indication of activated MP/MG. These data suggest that greater cognitive deficits in the CVS → CHI group were due to increased inflammation. The increased deficits and neuroinflammation in the CVS → CHI group suggest that the order by which a subject experiences TBI and PTSD is a major determinant of the outcome of brain injury in co-morbid TBI/PTSD.

Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in.

There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD symptoms is known to reflect interaction between environmental and genetic risks. Mild traumatic brain injury (mTBI) is an environmental risk for dementia, including Alzheimer's, but there has been limited mechanistic analysis of mTBI contribution to AD. Here, we investigate the interplay between mTBI and Aß precursor protein gene mutation in AD pathogenesis. We employed a knock-in (KI) model of AD that expresses the Aß-containing exons from human APP bearing the Swedish and Iberian mutations, namely AppNL-F/NL-F mice. Without environmental risk, this genetic variation yields minimal mouse symptomatology. Anesthetized 4-month-old KI mice and their age-matched wild type (WT) controls were subjected to repeated mild closed head injury (rmCHI), once daily for 14 days. Anesthetized, uninjured genotype- and age-matched mice were used as sham controls. At 3- and 8-months post-injury, amyloid-ß, phospho-tau and Iba1 expression in the injured KI cortices were assessed. Our data reveal that rmCHI enhances accumulation of amyloid-ß and hyperphosphorylated tau inclusions, as well as neuroinflammation in AppNL-F/NL-F mice. Furthermore, novel object recognition and Morris water maze tests demonstrated that rmCHI greatly exacerbates persistent cognitive deficits in APPNL-F/NL-F mice. Therefore, study of gene-environment interaction demonstrates that combining risk factors provides a more robust model for AD, and that repeated mTBI substantially accelerates AD pathology in a genetically susceptible situation.

Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy.

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

Chronic Traumatic Encephalopathy: A Brief Overview.

Chronic Traumatic Encephalopathy (CTE) is a debilitating neurodegenerative disease, which has been increasingly reported in athletes, especially American football players, as well as military veterans in combat settings, commonly as a result of repetitive mild traumatic brain injuries (TBIs). CTE has a unique neuropathological signature comprised of accumulation of phosphorylated tau (p-tau) in sulci and peri-vascular regions, microgliosis, and astrocytosis. As per most recent disease classification, the disease manifests itself in four different stages, characterized by widespread tauopathy. Clinically, CTE has a more subtle presentation, as patients often present with two distinct phenotypes, with one subtype initially presenting with affective changes, and the other subtype with more cognitive impairment. On a genetic basis, there are no clear risk factor genes. Although ApoE4 carriers have been reported to suffer more severe outcome post TBI. As there are no disease modifying regimen for CTE, the newly developed TBI treatments, if administered in a time sensitive manner, can offer a potential viable option. Prevention is another key strategy that needs to be implemented in various sports and military settings. Providing education for safe practice techniques, such as safe tackling and hitting, and providing ready access to full neuropsychiatric assessment by team physician could have measurable benefits. The combination of advanced of research techniques including neuroimaging, as well as increasing public awareness of CTE, offers promising vistas for research advancement.