Persistence of Hyper-Ramified Microglia in Porcine Cortical Gray Matter after Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major contributor to morbidity and mortality in the United States as several million people visit the emergency department every year due to TBI exposures. Unfortunately, there is still no consensus on the pathology underlying mild TBI, the most common severity sub-type of TBI. Previous preclinical and post-mortem human studies have detailed the presence of diffuse axonal injury following TBI, suggesting that white matter pathology is the predominant pathology of diffuse brain injury. However, the inertial loading produced by TBI results in strain fields in both gray and white matter. In order to further characterize gray matter pathology in mild TBI, our lab used a pig model (n = 25) of closed-head rotational acceleration-induced TBI to evaluate blood-brain barrier disruptions, neurodegeneration, astrogliosis, and microglial reactivity in the cerebral cortex out to 1 year post-injury. Immunohistochemical staining revealed the presence of a hyper-ramified microglial phenotype-more branches, junctions, endpoints, and longer summed process length-at 30 days post injury (DPI) out to 1 year post injury in the cingulate gyrus (p < 0.05), and at acute and subacute timepoints in the inferior temporal gyrus (p < 0.05). Interestingly, we did not find neuronal loss or astroglial reactivity paired with these chronic microglia changes. However, we observed an increase in fibrinogen reactivity-a measure of blood-brain barrier disruption-predominately in the gray matter at 3 DPI (p = 0.0003) which resolved to sham levels by 7 DPI out to chronic timepoints. Future studies should employ gene expression assays, neuroimaging, and behavioral assays to elucidate the effects of these hyper-ramified microglia, particularly related to neuroplasticity and responses to potential subsequent insults. Further understanding of the brain's inflammatory activity after mild TBI will hopefully provide understanding of pathophysiology that translates to clinical treatment for TBI.

Neuronal somatic plasmalemmal permeability and dendritic beading caused by head rotational traumatic brain injury in pigs-An exploratory study.

Closed-head traumatic brain injury (TBI) is induced by rapid motion of the head, resulting in diffuse strain fields throughout the brain. The injury mechanism(s), loading thresholds, and neuroanatomical distribution of affected cells remain poorly understood, especially in the gyrencephalic brain. We utilized a porcine model to explore the relationships between rapid head rotational acceleration-deceleration loading and immediate alterations in plasmalemmal permeability within cerebral cortex, sub-cortical white matter, and hippocampus. To assess plasmalemmal compromise, Lucifer yellow (LY), a small cell-impermeant dye, was delivered intraventricularly and diffused throughout the parenchyma prior to injury in animals euthanized at 15-min post-injury; other animals (not receiving LY) were survived to 8-h or 7-days. Plasmalemmal permeability preferentially occurred in neuronal somata and dendrites, but rarely in white matter axons. The burden of LY+ neurons increased based on head rotational kinematics, specifically maximum angular velocity, and was exacerbated by repeated TBI. In the cortex, LY+ cells were prominent in both the medial and lateral gyri. Neuronal membrane permeability was observed within the hippocampus and entorhinal cortex, including morphological changes such as beading in dendrites. These changes correlated with reduced fiber volleys and synaptic current alterations at later timepoints in the hippocampus. Further histological observations found decreased NeuN immunoreactivity, increased mitochondrial fission, and caspase pathway activation in both LY+ and LY- cells, suggesting the presence of multiple injury phenotypes. This exploratory study suggests relationships between plasmalemmal disruptions in neuronal somata and dendrites within cortical and hippocampal gray matter as a primary response in closed-head rotational TBI and sets the stage for future, traditional hypothesis-testing experiments.

Axonal Tract Reconstruction Using a Tissue-Engineered Nigrostriatal Pathway in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) affects 1-2% of people over 65, causing significant morbidity across a progressive disease course. The classic PD motor deficits are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in the loss of their long-distance axonal projections that modulate striatal output. While contemporary treatments temporarily alleviate symptoms of this disconnection, there is no approach able to replace the nigrostriatal pathway. We applied microtissue engineering techniques to create a living, implantable tissue-engineered nigrostriatal pathway (TE-NSP) that mimics the architecture and function of the native pathway. TE-NSPs comprise a discrete population of dopaminergic neurons extending long, bundled axonal tracts within the lumen of hydrogel micro-columns. Neurons were isolated from the ventral mesencephalon of transgenic rats selectively expressing the green fluorescent protein in dopaminergic neurons with subsequent fluorescent-activated cell sorting to enrich a population to 60% purity. The lumen extracellular matrix and growth factors were varied to optimize cytoarchitecture and neurite length, while immunocytochemistry and fast-scan cyclic voltammetry (FSCV) revealed that TE-NSP axons released dopamine and integrated with striatal neurons in vitro. Finally, TE-NSPs were implanted to span the nigrostriatal pathway in a rat PD model with a unilateral 6-hydroxydopamine SNpc lesion. Immunohistochemistry and FSCV established that transplanted TE-NSPs survived, maintained their axonal tract projections, extended dopaminergic neurites into host tissue, and released dopamine in the striatum. This work showed proof of concept that TE-NSPs can reconstruct the nigrostriatal pathway, providing motivation for future studies evaluating potential functional benefits and long-term durability of this strategy. This pathway reconstruction strategy may ultimately replace lost neuroarchitecture and alleviate the cause of motor symptoms for PD patients.

Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.

Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD + AD = 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD = 17). We find novel evidence for selective impairment of PIGD burden in LBD + AD vs LBD-AD (OR = 1.95, 95%CI = 1.02-3.70, p = 0.04) and a direct association of increasing CSF tau/Aß1-42 ratio with increasing PIGD disability in the total cohort (ß = 0.23, SE = 0.08, p = 0.01). This unique biomarker stratification approach suggests AD co-pathology may contribute to PIGD motor signs in LBD.

Gait abnormalities and non-motor symptoms predict abnormal dopaminergic imaging in presumed drug-induced Parkinsonism.

Drug-induced parkinsonism (DIP) can be clinically indistinguishable from degenerative parkinsonism, and bedside assessments are needed to differentiate between these conditions. We examined 34 U.S. Veterans with DIP using 123I-FP-CIT (DAT-SPECT) to identify underlying nigrostriatal degeneration. Participants were 94% male with mean age of 64.5 ± 7.1 years. DAT-SPECT was abnormal in 12/34 (35%). Comparing normal and abnormal imaging groups, there were no differences in age, sex, race/ethnicity, psychiatric diagnosis, motor severity, or RBD Screening Questionnaire scores. Those with underlying neurodegeneration reported significantly more non-motor symptoms (NMS), worse olfactory function on the University of Pennsylvania Smell Identification Test, and greater turning duration/steps on the instrumented Timed Up and Go. Area under the curve (AUC) combining poor olfaction and total NMS burden was 0.84 (CI 0.71-0.97), while AUC for turn steps was 0.91 (CI 0.81-1.00). Gait impairment, hyposmia, and NMS may be useful alone and in combination to identify DIP patients with underlying dopaminergic degeneration.

Predictors of multi-domain cognitive decline following DBS for treatment of Parkinson's disease.

BACKGROUND: Statistically and clinically significant cognitive declines are observed in a small subset of individuals with Parkinson's Disease (PD) following treatment with Deep Brain Stimulation (DBS). OBJECTIVES: We examine the association between multi-domain cognitive decline (MCD) and demographic and baseline clinical variables and the incidence of serious adverse events (SAE) arising within a six-month interval following DBS for PD. METHOD: Study participants with PD who displayed MCD at 6-month follow-up evaluation after DBS (n = 18) were contrasted with individuals with PD from the same study who did not show cognitive decline after DBS (n = 146). Logistic regression analyses were employed to assess relationship between predictors, including age (>70 years old), pre-DBS cognitive screening test performance, SAE, and MCD. MCD+ and MCD-groups were also compared on other baseline clinical and demographic variables. RESULTS: MCD showed modest association with older age and lower baseline neurocognitive screening performance, whereas the groups did not differ on most other baseline clinical and demographic variables. SAEs during the study interval were the most robust predictor of MCD in the DBS group. A variety of SAEs were documented in study participants experiencing MCD after DBS surgery, including, but not limited to, infections and small intracranial hemorrhages. CONCLUSIONS: Older age and lower baseline cognition measured prior to treatment are associated with MCD measured at six-months after DBS. SAE occurring following DBS surgery are also predictive of MCD. These predictors may reflect aspects of "frailty" in advanced PD. Risk factors for SAE warrant careful consideration in clinical trials.

Olfaction as an early marker of Parkinson's disease and Alzheimer's disease.

Olfactory impairment is a common and early sign of Parkinson's disease (PD) and Alzheimer's disease (AD), the two most prevalent neurodegenerative conditions in the elderly. This phenomenon corresponds to pathologic processes emerging in the olfactory system prior to the onset of typical clinical manifestations. Clinically available tests can establish hyposmia through odor identification assessment, discrimination, and odor detection threshold. There are significant efforts to develop preventative or disease-modifying therapies that slow down or halt the progression of PD and AD. Due to the convenience and low cost of its assessment, olfactory impairment could be used in these studies as a screening instrument. In the clinical setting, loss of smell may also help to differentiate PD and AD from alternative causes of Parkinsonism and cognitive impairment, respectively. Here, we discuss the pathophysiology of olfactory dysfunction in PD and AD and how it can be assessed in the clinical setting to aid in the early and differential diagnosis of these disorders.

Restoring lost nigrostriatal fibers in Parkinson's disease based on clinically-inspired design criteria.

Parkinson's disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation. An alternative approach is pathway reconstruction, which aims to rebuild the entire structure of neurons and axonal fibers of the nigrostriatal pathway in a way that matches its anatomy and physiology. This type of repair could be more capable of reestablishing the signaling mechanisms that ensure proper dopamine release in the striatum and regulation of other motor circuit regions in the brain. In this manuscript, we conduct a review of the literature related to pathway reconstruction as a treatment for Parkinson's disease, delve into the limitations of these studies, and propose the requisite design criteria to achieve this goal at a human scale. We then present our tissue engineering-based platform to fabricate hydrogel-encased dopaminergic axon tracts in vitro for later implantation into the brain to replace and reconstruct the pathway. These tissue-engineered nigrostriatal pathways (TE-NSPs) can be characterized and optimized for cell number and phenotype, axon growth lengths and rates, and the capacity for synaptic connectivity and dopamine release. We then show original data of advances in creating these constructs matching clinical design criteria using human iPSC-derived dopaminergic neurons and a hyaluronic acid hydrogel. We conclude with a discussion of future steps that are needed to further optimize human-scale TE-NSPs and translate them into clinical products.

Diverse changes in microglia morphology and axonal pathology during the course of 1 year after mild traumatic brain injury in pigs.

Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1-year post-injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1-year post-injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

OBJECTIVE: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology. METHODS: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF ß-amyloid1-42 (Aß42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aß42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes. RESULTS: Patients with LBD + AD performed worse on BNT than patients with LBD - AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, p < 0.05) and p-tau (ρ = -0.26, p = 0.05) but not Aß42 (p > 0.1). CONCLUSION: Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Psychometric Properties of the Clinical Dementia Rating Scale Sum of Boxes in Parkinson's Disease.

BACKGROUND: A composite measure that assesses both cognitive and functional abilities in Parkinson's disease (PD) would be useful for diagnosing mild cognitive impairment (MCI) and PD dementia (PDD) and as an outcome measure in randomized controlled trials. The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) was designed to assess both cognition and basic-instrumental activities of daily living in Alzheimer's disease but has not yet been validated in PD. OBJECTIVE: To validate the CDR-SOB as a composite cognitive-functional measure for PD patients, as well as to assess its sensitivity to change. METHODS: The CDR-SOB and a comprehensive cognitive and functional battery was administered to 101 PD patients at baseline (39 normal cognition [NC], 41 MCI and 21 PDD by expert consensus panel), and re-administered to 64 patients after 1-2 years follow-up (32 NC and 32 cognitive impairment [CI] at baseline). RESULTS: Cross-sectionally, CDR-SOB and domain scores were correlated with corresponding neuropsychological or functional measures and were significantly different between cognitive subgroups both at baseline and at follow-up. In addition, CDR-SOB ROC curves distinguished between normal cognition and dementia with high sensitivity, but did not distinguish well between NC and MCI. Longitudinal changes in the CDR-SOB and domain scores were not significant and were inconsistent in predicting change in commonly-used cognitive and functional tests. CONCLUSION: The CDR-SOB detects dementia-level cognitive impairment in PD but may not be appropriate for predicting longitudinal combined cognitive-functional changes in patients without significant cognitive impairment at baseline.

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

Tau pathology associates with in vivo cortical thinning in Lewy body disorders.

OBJECTIVES: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). METHODS: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aß1-42  > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBD-AD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aß, and alpha-synuclein using digital histopathology in five representative neocortical regions. RESULTS: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBD-AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Aß or alpha-synuclein pathology. INTERPRETATION: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.

Subjective Cognitive Complaint in Parkinson's Disease Patients With Normal Cognition: Canary in the Coal Mine?

OBJECTIVE: The objective of this study was to determine the frequency and impact of subjective cognitive complaint (SCC) in Parkinson's disease (PD) patients with normal cognition. METHODS: Patients with PD with expert consensus-determined normal cognition at baseline were asked a single question regarding the presence of SCC. Baseline (N = 153) and longitudinal (up to 4 follow-up visits during a 5-year period; N = 121) between-group differences in patients with PD with (+SCC) and without (-SCC) cognitive complaint were examined, including cognitive test performance and self-rated and informant-rated functional abilities. RESULTS: A total of 81 (53%) participants reported a cognitive complaint. There were no between-group differences in global cognition at baseline. Longitudinally, the +SCC group declined more than the -SCC group on global cognition (Mattis Dementia Rating Scale-2 total score, F1,431 = 5.71, P = 0.02), processing speed (Symbol Digit Modalities Test, F1,425 = 7.52, P = 0.006), and executive function (Trail Making Test Part B, F1,419 = 4.48, P = 0.04), although the results were not significant after correction for multiple testing. In addition, the +SCC group was more likely to progress to a diagnosis of cognitive impairment over time (hazard ratio = 2.61, P = 0.02). The +SCC group also demonstrated significantly lower self-reported and knowledgeable informant-reported cognition-related functional abilities at baseline, and declined more on an assessment of global functional abilities longitudinally. CONCLUSIONS: Patients with PD with normal cognition, but with SCC, report poorer cognition-specific functional abilities, and are more likely to be diagnosed with cognitive impairment and experience global functional ability decline long term. These findings suggest that SCC and worse cognition-related functional abilities may be sensitive indicators of initial cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

A Review of the Relationship Between Vitamin D and Parkinson Disease Symptoms.

Vitamin D is a fat-soluble secosteroid that exerts its effects by binding to the vitamin D receptor (VDR), through which it directly and indirectly modulates the expression of hundreds to thousands of genes. While originally known for its role in regulating calcium homeostasis and metabolism, vitamin D is now associated with many other health conditions, including Parkinson's disease (PD). A high prevalence of vitamin D deficiency has been noted in PD for at least the past two decades. These findings, along with the discovery that the VDR and 1α-hydroxylase, the enzyme that converts vitamin D to its active form, are highly expressed in the substantia nigra, led to the hypothesis that inadequate levels of circulating vitamin D may lead to dysfunction or cell death within the substantia nigra. Studies investigating the relationship between vitamin D status and PD, however, have been inconsistent. Two prospective studies examined the association between mid-life vitamin D levels and risk of PD and produced conflicting results-one demonstrated an increased risk for PD with lower mid-life vitamin D levels, and the other showed no association between vitamin D and PD risk. One of the most consistent findings in the literature is the inverse association between serum vitamin D level and motor symptom severity in cross-sectional studies. While these data suggest that vitamin D may modify the disease, another likely explanation is confounding due to limited mobility. Fall risk has been associated with vitamin D in PD, but more study is needed to determine if supplementation decreases falls, which has been demonstrated in the general population. The association between vitamin D and non-motor symptoms is less clear. There is some evidence that vitamin D is associated with verbal fluency and verbal memory in PD. Studies in PD have also shown associations between vitamin D status and mood, orthostatic hypotension and olfactory impairment in PD. While more research is needed, given the numerous potential benefits and limited risks, vitamin D level assessment in PD patients and supplementation for those with deficiency and insufficiency seems justified.

Neurons in Subcortical Oculomotor Regions Are Vulnerable to Plasma Membrane Damage after Repetitive Diffuse Traumatic Brain Injury in Swine.

Oculomotor deficits, such as insufficiencies in accommodation, convergence, and saccades, are common following traumatic brain injury (TBI). Previous studies in patients with mild TBI attributed these deficits to insufficient activation of subcortical oculomotor nuclei, although the exact mechanism is unknown. A possible cause for neuronal dysfunction in these regions is biomechanically induced plasma membrane permeability. We used our established porcine model of head rotational TBI to investigate whether cell permeability changes occurred in subcortical oculomotor areas following single or repetitive TBI, with repetitive injuries separated by 15 min, 3 days, or 7 days. Swine were subjected to sham conditions or head rotational acceleration in the sagittal plane using a HYGE pneumatic actuator. Two hours prior to the final injury, the cell-impermeant dye Lucifer Yellow was injected into the ventricles to diffuse throughout the interstitial space to assess plasmalemmal permeability. Animals were sacrificed 15 min after the final injury for immunohistological analysis. Brain regions examined for cell membrane permeability included caudate, substantia nigra pars reticulata, superior colliculus, and cranial nerve oculomotor nuclei. We found that the distribution of permeabilized neurons varied depending on the number and spacing of injuries. Repetitive injuries separated by 15 min or 3 days resulted in the most permeability. Many permeabilized cells lost neuron-specific nuclear protein reactivity, although no neuronal loss occurred acutely after injury. Microglia contacted and appeared to begin phagocytosing permeabilized neurons in repetitively injured animals. These pathologies within oculomotor areas may mediate transient dysfunction and/or degeneration that may contribute to oculomotor deficits following diffuse TBI.

Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs.

BACKGROUND: Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs. METHODS: This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days post-injury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus. RESULTS: There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = <  0.001 each) and 30 DPI in posterior (8.3% increase; p = <  0.0001) hippocampus. We also found dramatic increases in synapsin staining around mossy cells at 7 DPI in both anterior (74.7% increase in synapsin labeling; p = <  0.0001) and posterior (82.7% increase; p = < 0.0001) hippocampus. Interestingly, these morphological and synaptic alterations correlated with a significant change in microglia in proximity to mossy cells at 7 DPI in anterior and at 30 DPI in the posterior hippocampus. For broader context, while we found that there were significant increases in microglia density in the granule cell layer at 30 DPI (anterior and posterior) and 1 YPI (posterior only) and in the molecular layer at 1 YPI (anterior only), we found no significant changes in overall microglial density in the hilus at any of the time points evaluated post-injury. CONCLUSIONS: The alterations of mossy cell size and synaptic inputs paired with changes in microglia density around the cells demonstrate the susceptibility of hilar mossy cells after even mild TBI. This subtle hilar mossy cell pathology may play a role in aberrant hippocampal function post-TBI, although additional studies are needed to characterize potential physiological and cognitive alterations.

Emerging regenerative medicine and tissue engineering strategies for Parkinson's disease.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease, affecting 1-2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway-a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.