Evidence of mutant huntingtin and tau-related pathology within neuronal grafts in Huntington's disease cases.

A number of post-mortem studies conducted in transplanted Huntington's disease (HD) patients from various trials have reported the presence of pathological and misfolded proteins, in particular mutant huntingtin (mHtt) and phosphorylated tau neuropil threads, in the healthy grafted tissue. Here, we extended these observations with histological analysis of post-mortem tissue from three additional HD patients who had received similar striatal allografts from the fetal tissue transplantation trial conducted in Los Angeles in 1998. Immunohistochemical staining was performed using anti-mHtt antibodies, EM48 and MW7, as well as anti-hyperphosphorylated tau antibodies, AT8 and CP13. Immunofluorescence was used to assess the colocalization of EM48+ mHtt aggregates with the neuronal marker MAP2 and/or the extracellular matrix protein phosphacan in both the host and grafts. We confirmed the presence of mHtt aggregates within grafts of all three cases as well as tau neuropil threads in the grafts of two of the three transplanted HD patients. Phosphorylated tau was also variably expressed in the host cerebral cortex of all three subjects. While mHtt inclusions were present within neurons (immunofluorescence co-localization of MAP2 and EM48) as well as within the extracellular matrix of the host (immunofluorescence co-localization of phosphacan and EM48), their localization was limited to the extracellular matrix in the grafted tissue. This study corroborates previous findings that both mHtt and tau pathology can be found in the host and grafts of HD patients years post-grafting.

Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics.

BACKGROUND: Traumatic brain injury (TBI) often results in diverse molecular responses, challenging traditional proteomic studies that measure average changes at tissue levels and fail to capture the complexity and heterogeneity of the affected tissues. Spatial proteomics offers a solution by providing insights into sub-region-specific alterations within tissues. This study focuses on the hippocampal sub-regions, analyzing proteomic expression profiles in mice at the acute (1 day) and subacute (7 days) phases of post-TBI to understand subregion-specific vulnerabilities and long-term consequences. METHODS: Three mice brains were collected from each group, including Sham, 1-day post-TBI and 7-day post-TBI. Hippocampal subregions were extracted using Laser Microdissection (LMD) and subsequently analyzed by label-free quantitative proteomics. RESULTS: The spatial analysis reveals region-specific protein abundance changes, highlighting the elevation of FN1, LGALS3BP, HP, and MUG-1 in the stratum moleculare (SM), suggesting potential immune cell enrichment post-TBI. Notably, established markers of chronic traumatic encephalopathy, IGHM and B2M, exhibit specific upregulation in the dentate gyrus bottom (DG2) independent of direct mechanical injury. Metabolic pathway analysis identifies disturbances in glucose and lipid metabolism, coupled with activated cholesterol synthesis pathways enriched in SM at 7-Day post-TBI and subsequently in deeper DG1 and DG2 suggesting a role in neurogenesis and the onset of recovery. Coordinated activation of neuroglia and microtubule dynamics in DG2 suggest recovery mechanisms in less affected regions. Cluster analysis revealed spatial variations post-TBI, indicative of dysregulated neuronal plasticity and neurogenesis and further predisposition to neurological disorders. TBI-induced protein upregulation (MUG-1, PZP, GFAP, TJP, STAT-1, and CD44) across hippocampal sub-regions indicates shared molecular responses and links to neurological disorders. Spatial variations were demonstrated by proteins dysregulated in both or either of the time-points exclusively in each subregion (ELAVL2, CLIC1 in PL, CD44 and MUG-1 in SM, and SHOC2, LGALS3 in DG). CONCLUSIONS: Utilizing advanced spatial proteomics techniques, the study unveils the dynamic molecular responses in distinct hippocampal subregions post-TBI. It uncovers region-specific vulnerabilities and dysregulated neuronal processes, and potential recovery-related pathways that contribute to our understanding of TBI's neurological consequences and provides valuable insights for biomarker discovery and therapeutic targets.

Single Level Spondylolisthesis Associated Sagittal Plane Imbalance Corrected by Pre-Psoas Interbody Fusion Using Anterior Column Release with 30° Expandable Hyperlordotic Cage.

Background: Loss of lumbar lordosis caused by single level degenerative spondylolisthesis can trigger significant sagittal plane imbalance and failure to correct lumbopelvic parameters during lumbar fusion can lead to poor outcome or worsening deformity. Anterior column release (ACR) through a pre-psoas approach allows the placement of a hyperlordotic cage (HLC) to improve lumbar lordosis, but it is unclear if the amount of cage lordosis affects radiological outcomes in real-life patient conditions. Methods: Three patients were treated with ACR and 30° expandable HLC for positive sagittal imbalance secondary to single-level spondylolisthesis. Patients reported baseline and post-operative Oswestry Disability Index (ODI) and Numeric Pain Score (NRS). Radiographic parameters of sagittal balance included lumbar lordosis (LL), sagittal vertical axis (SVA) and pelvic incidence-lumbar lordosis mismatch (PI-LL). Results: Surgical indications were sagittal plane imbalance caused by L4-L5 degenerative spondylolisthesis (n = 2) and L3-L4 spondylolisthesis secondary to adjacent segmental degeneration (n = 1). Average post-operative length of stay was 3 days (range 2-4) and estimated blood loss was 266 mL (range 200-300). NRS and ODI improved in all patients. All experienced improvements in LL (x¯preop = 33°, x¯postop = 56°), SVA (x¯preop = 180 mm, x¯postop = 61 mm) and PI-LL (x¯preop = 26°, x¯postop = 5°). Conclusion: ACR with expandable HLC can restore sagittal plane balance associated with single-level spondylolisthesis. Failure to perform ACR with HLC placement during pre-psoas interbody fusion may result in under correction of lordosis and poorer outcome for these patients.

Luminex-based quantification of Alzheimer's disease neuropathologic change in formalin-fixed post-mortem human brain tissue.

The vast majority of archived research and clinical pathological specimens are stored in the form of formalin fixed, paraffin-embedded (FFPE) tissues, but, unlike fresh frozen tissue samples, highly quantitative measures in FFPE tissues are limited to immunohistochemical and immunofluorescence thresholding image analysis studies, cell counting, and ordinal ranking systems. This poses a significant obstacle for clinical investigations that aim to correlate diagnostic markers of neurodegenerative diseases like Alzheimer's disease (AD) with parameters like age, gender, drug exposures, genotype, disease stage, co-morbidities, or environmental factors. To overcome this limitation, we have developed Luminex-based techniques and protocols for the quantification of amyloid ß and hyperphosphorylated Tau in FFPE brain sections. We validated the Luminex assay in FFPE sections from prefrontal cortex, hippocampus, and neostriatum from 30 cases that underwent prior neuropathological diagnostic assessment of AD following the current NIA-AA recommendations for AD: 10 cases diagnosed as not or low, 10 cases as intermediate, and 10 cases as high AD neuropathologic change. Consistent with the neuropathologic assessment, Luminex assay detected high amounts of amyloid beta in the frontal cortex and striatum, and high amounts of hyperphosphorylated Tau in the frontal cortex and hippocampus, of cases with high AD neuropathologic change. This assay can be expanded to detect diverse antigenic targets of interest, as we show here with IBA1 and GFAP. This novel approach supports multiplexed highly quantitative, molecularly specific neuropathology measures to further explore mechanisms of neurodegeneration in AD.

Tracing the path of disruption: 13C isotope applications in traumatic brain injury-induced metabolic dysfunction.

Cerebral metabolic dysfunction is a critical pathological hallmark observed in the aftermath of traumatic brain injury (TBI), as extensively documented in clinical investigations and experimental models. An in-depth understanding of the bioenergetic disturbances that occur following TBI promises to reveal novel therapeutic targets, paving the way for the timely development of interventions to improve patient outcomes. The 13C isotope tracing technique represents a robust methodological advance, harnessing biochemical quantification to delineate the metabolic trajectories of isotopically labeled substrates. This nuanced approach enables real-time mapping of metabolic fluxes, providing a window into the cellular energetic state and elucidating the perturbations in key metabolic circuits. By applying this sophisticated tool, researchers can dissect the complexities of bioenergetic networks within the central nervous system, offering insights into the metabolic derangements specific to TBI pathology. Embraced by both animal studies and clinical research, 13C isotope tracing has bolstered our understanding of TBI-induced metabolic dysregulation. This review synthesizes current applications of isotope tracing and its transformative potential in evaluating and addressing the metabolic sequelae of TBI.

Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology.

We present open-source tools for 3D analysis of photographs of dissected slices of human brains, which are routinely acquired in brain banks but seldom used for quantitative analysis. Our tools can: (i) 3D reconstruct a volume from the photographs and, optionally, a surface scan; and (ii) produce a high-resolution 3D segmentation into 11 brain regions per hemisphere (22 in total), independently of the slice thickness. Our tools can be used as a substitute for ex vivo magnetic resonance imaging (MRI), which requires access to an MRI scanner, ex vivo scanning expertise, and considerable financial resources. We tested our tools on synthetic and real data from two NIH Alzheimer's Disease Research Centers. The results show that our methodology yields accurate 3D reconstructions, segmentations, and volumetric measurements that are highly correlated to those from MRI. Our method also detects expected differences between post mortem confirmed Alzheimer's disease cases and controls. The tools are available in our widespread neuroimaging suite "FreeSurfer" ( https://surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools ).

Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology.

We present open-source tools for three-dimensional (3D) analysis of photographs of dissected slices of human brains, which are routinely acquired in brain banks but seldom used for quantitative analysis. Our tools can: (1) 3D reconstruct a volume from the photographs and, optionally, a surface scan; and (2) produce a high-resolution 3D segmentation into 11 brain regions per hemisphere (22 in total), independently of the slice thickness. Our tools can be used as a substitute for ex vivo magnetic resonance imaging (MRI), which requires access to an MRI scanner, ex vivo scanning expertise, and considerable financial resources. We tested our tools on synthetic and real data from two NIH Alzheimer's Disease Research Centers. The results show that our methodology yields accurate 3D reconstructions, segmentations, and volumetric measurements that are highly correlated to those from MRI. Our method also detects expected differences between post mortem confirmed Alzheimer's disease cases and controls. The tools are available in our widespread neuroimaging suite 'FreeSurfer' (https://surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools).

Every year, thousands of human brains are donated to science. These brains are used to study normal aging, as well as neurological diseases like Alzheimer's or Parkinson's. Donated brains usually go to 'brain banks', institutions where the brains are dissected to extract tissues relevant to different diseases. During this process, it is routine to take photographs of brain slices for archiving purposes. Often, studies of dead brains rely on qualitative observations, such as 'the hippocampus displays some atrophy', rather than concrete 'numerical' measurements. This is because the gold standard to take three-dimensional measurements of the brain is magnetic resonance imaging (MRI), which is an expensive technique that requires high expertise ­ especially with dead brains. The lack of quantitative data means it is not always straightforward to study certain conditions. To bridge this gap, Gazula et al. have developed an openly available software that can build three-dimensional reconstructions of dead brains based on photographs of brain slices. The software can also use machine learning methods to automatically extract different brain regions from the three-dimensional reconstructions and measure their size. These data can be used to take precise quantitative measurements that can be used to better describe how different conditions lead to changes in the brain, such as atrophy (reduced volume of one or more brain regions). The researchers assessed the accuracy of the method in two ways. First, they digitally sliced MRI-scanned brains and used the software to compute the sizes of different structures based on these synthetic data, comparing the results to the known sizes. Second, they used brains for which both MRI data and dissection photographs existed and compared the measurements taken by the software to the measurements obtained with MRI images. Gazula et al. show that, as long as the photographs satisfy some basic conditions, they can provide good estimates of the sizes of many brain structures. The tools developed by Gazula et al. are publicly available as part of FreeSurfer, a widespread neuroimaging software that can be used by any researcher working at a brain bank. This will allow brain banks to obtain accurate measurements of dead brains, allowing them to cheaply perform quantitative studies of brain structures, which could lead to new findings relating to neurodegenerative diseases.

Spontaneous resolution of syringomyelia following pregnancy and parturition in a patient with type I chiari malformation: A case and systematic review.

BACKGROUND: Spontaneous resolution of syringomyelia has rarely been reported in the literature. Rarer still are cases wherein this process is associated with pregnancy and parturition. We review theories on syringomyelia development and spontaneous resolution to better understand the role pregnancy and parturition may play in both processes. METHODS: We present a 30-year-old female with MRI-confirmed spontaneous syrinx regression following caesarean delivery of a full-term pregnancy. We additionally review the literature to identify previously reported cases of spontaneous syrinx regression both independent of and associated with pregnancy. RESULTS: Including the present case, 39 cases describing spontaneous regression of syringomyelia have been reported in the literature, of which only four are associated with pregnancy and parturition. 75% of all reported cases were associated with type I Chiari malformation, though several disorders of the craniocervical junction and spinal canal were implicated. Complete syrinx regression was achieved in 33.3% of cases and 5% of cases described recurrence of syringomyelia following the spontaneous resolution. CONCLUSION: Syringomyelia likely develops due to disturbance of the physiologic flow of cerebrospinal fluid around the craniocervical junction and the obex. Several mechanisms including fissuring of the spinal cord parenchyma and reduction of subarachnoid scarring are likely involved in this process. In the setting of pregnancy, additional mechanisms surrounding the increased intraabdominal forces imparted by a growing fetus, Valsalva-like strain experienced during labor, and hemodynamic changes that occur to accommodate gestation are likely implicated. Nevertheless, patients should continue to be monitored periodically for syrinx recurrence.

Patient-reported outcome measures in spine surgery: A systematic review.

Background: Steadily increasing expenditure in the United States health-care system has led to a shift toward a value-based model that focuses on quality of care and cost-effectiveness. Operations involving the spine rank among some of the most common and expensive procedures performed in operating rooms nationwide. Patient-reported outcomes measures (PROMs) are a useful tool for reporting levels of outcome and analyzing patient recovery but are both under-utilized and nonstandardized in spine surgery. Methods: We conducted a systematic review of the literature using the PubMed database, focusing on the most commonly utilized PROMs for spine disease as well as spinal deformity. The benefits and drawbacks of these PROMs were then summarized and compared. Results: Spine-specific PROMs were based on the class of disease. The most frequently utilized PROMs were the Neck Disability Index and the modified Japanese Orthopaedic Association scale; the Oswestry Disability Index and the Roland-Morris Disability Questionnaire; and the Scoliosis Research Society 22-item questionnaire (SRS-22) for cervicothoracic spine disease, lumbar spine disease, and spinal deformity, respectively. Conclusion: We found limited, though effective, use of PROMs targeting specific classes of disease within spine surgery. Therefore, we advocate for increased use of PROMs in spine surgery, in both the research and clinical settings. PROM usage can help physicians assess subjective outcomes in standard ways that can be compared across patients and institutions, more uniquely tailor treatment to individual patients, and engage patients in their own medical care.

Papillary tumor of the pineal region in pediatric populations: An additional case and systematic review of a rare tumor entity.

Papillary tumors of the pineal region (PTPR) are a rare tumor entity first described in 2003, later codified in the 2007 WHO tumor classification system. PTPRs most commonly occur in the third and fourth decades, with exceedingly rare presentations in pediatric populations. Herein, we present an additional case of a 10-year-old female found to have PTPR in conjunction with Trisomy 21 managed successfully with cerebrospinal fluid diversion and gross total resection (GTR). Three years after resection she has returned to baseline without recurrence. We also performed a comprehensive review of the current literature discussing the diagnosis, treatment, and pathophysiologic correlations in children. Diagnosis and management of PTPRs is a topic that is increasingly garnering attention in the literature given the recent characterization of this tumor entity. However, relatively little is known about the presentation of PTPRs in pediatric populations. In adults, PTPRs have been linked with several chromosomal and genetic abnormalities; however this correlation is limited in pediatric literature. Although GTR is the mainstay for treatment, the application of adult treatment protocols may not be advisable due to age and the developmental changes of the CNS in children.

Complete ophthalmoplegia secondary to idiopathic intracranial hypertension managed successfully with dural sinus stenting: A case and systematic review.

Idiopathic Intracranial Hypertension (IIH) typically occurs in obese (BMI >30 kg/m2) females of childbearing age in the absence of any apparent intracranial space-occupying lesion. Patients typically present with headache, nausea, vomiting, tinnitus, and blurry vision secondary to increased intracranial pressure, with more severe cases involving cranial neuropathies and ophthalmological manifestations. Complete ophthalmoplegia is a rare event in IIH. In such cases, aggressive management with pharmacological, endovascular, and surgical intervention is essential to hasten recovery and limit long-term neurological and visual deficits. Herein, we present a rare case of a patient with IIH associated with third, fourth, and sixth cranial nerve palsies, resulting in complete unilateral ophthalmoplegia, who underwent dural sinus stenting and 2.5-year follow-up revealed complete resolution with full extraocular movements. We also perform a systematic literature review of complete and partial ophthalmoplegia secondary to IIH, highlighting the associated presentations, pathophysiology, management, and outcomes.

Effects of the COVID-19 Pandemic on Operative Volume and Residency Training at Two Academic Neurosurgery Centers in New Orleans.

BACKGROUND: Medical subspecialties including neurosurgery have seen a dramatic shift in operative volume in the wake of the coronavirus disease 2019 (COVID-19) pandemic. The goal of this study was to quantify the effects of the COVID-19 pandemic on operative volume at 2 academic neurosurgery centers in New Orleans, Louisiana, USA from equivalent periods before and during the COVID-19 pandemic. METHODS: A retrospective review was conducted analyzing neurosurgical case records for 2 tertiary academic centers from March to June 2020 and March to June 2019. The records were reviewed for variables including institution and physician coverage, operative volume by month and year, cases per subspecialty, patient demographics, mortality, and morbidity. RESULTS: Comparison of groups showed a 34% reduction in monthly neurosurgical volume per institution during the pandemic compared with earlier time points, including a 77% decrease during April 2020. There was no change in mortality and morbidity across institutions during the pandemic. CONCLUSIONS: The COVID-19 pandemic has had a significant impact on neurosurgical practice and will likely continue to have long-term effects on patients at a time when global gross domestic products decrease and relative health expenditures increase. Clinicians must anticipate and actively prepare for these impacts in the future.

Neurological Impact of Coronavirus Disease of 2019: Practical Considerations for the Neuroscience Community.

BACKGROUND: The coronavirus disease of 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently been designated a pandemic by the World Health Organization, affecting 2.7 million individuals globally as of April 25, 2020, with more than 187,000 deaths. An increasing body of evidence has supported central nervous system involvement. METHODS: We conducted a review of the reported data for studies concerning COVID-19 pathophysiology, neurological manifestations, and neuroscience provider recommendations and guidelines. RESULTS: Central nervous system manifestations range from vague nonfocal complaints to severe neurological impairment associated with encephalitis. It is unclear whether the neurological dysfunction results from direct viral injury or systemic disease. The virus could affect brainstem pathways that lead to indirect respiratory dysfunction, in addition to direct pulmonary injury. Necessary adaptations in patient management, triage, and diagnosis are evolving in light of the ongoing scientific and clinical findings. CONCLUSIONS: The present review has consolidated the current body of data regarding the neurological impact of coronaviruses, discussed the reported neurological manifestations of COVID-19, and highlighted the recommendations for patient management. Specific recommendations pertaining to clinical practice for neurologists and neurosurgeons have also been provided.

Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort.

Alzheimer's disease neuropathologic change (ADNC) is defined by progressive accumulation of ß-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.