Cerebrospinal Fluid Flow Extends to Peripheral Nerves.

Cerebrospinal fluid (CSF) is an aqueous solution responsible for nutrient delivery and waste removal for the central nervous system (CNS). The three-layer meningeal coverings of the CNS support CSF flow. Peripheral nerves have an analogous three-layer covering consisting of the epineurium, perineurium, and endoneurium. Peripheral axons, located in the inner endoneurium, are bathed in "endoneurial fluid" similar to CSF but of undefined origin. CSF flow in the peripheral nervous system has not been demonstrated. Here we show CSF flow extends beyond the CNS to peripheral nerves in a contiguous flowing system. Utilizing gold nanoparticles, we identified that CSF is continuous with the endoneurial fluid and reveal the endoneurial space as the likely site of CSF flow in the periphery. Nanogold distribution along entire peripheral nerves and within their axoplasm suggests CSF plays a role in nutrient delivery and waste clearance, fundamental aspects of peripheral nerve health and disease. One Sentence Summary: Cerebrospinal fluid unites the nervous system by extending beyond the central nervous system into peripheral nerves.

Central Nervous System Tumor Classification: An Update on the Integration of Tumor Genetics.

In 2016, the World Health Organization Classification of CNS Tumors introduced molecular abnormalities that refined tumor diagnoses. Around this time, the introduction of large scale genetic mutational analyses quickly advanced our knowledge of recurrent abnormalities in disease. In 2017, the C-IMPACT group was established to render expert consensus opinions regarding the application of molecular findings into central nervous system tumor diagnoses. C-IMPACT have presented their recommendations in 7 peer-reviewed publications; this article details those recommendations that are expected to be incorporated into the upcoming fifth edition of the World Health Organization classification.

Neuropathology of Alzheimer's Disease.

The key pathological hallmarks-extracellular plaques and intracellular neurofibrillary tangles (NFT)-described by Alois Alzheimer in his seminal 1907 article are still central to the postmortem diagnosis of Alzheimer's disease (AD), but major advances in our understanding of the underlying pathophysiology as well as significant progress in clinical diagnosis and therapy have changed the perspective and importance of neuropathologic evaluation of the brain. The notion that the pathological processes underlying AD already start decades before symptoms are apparent in patients has brought a major change reflected in the current neuropathological classification of AD neuropathological changes (ADNC). The predictable progression of beta-amyloid (Aß) plaque pathology from neocortex, over limbic structures, diencephalon, and basal ganglia, to brainstem and cerebellum is captured in phases described by Thal and colleagues. The progression of NFT pathology from the transentorhinal region to the limbic system and ultimately the neocortex is described in stages proposed by Braak and colleagues. The density of neuritic plaque pathology is determined by criteria defined by the Consortium to establish a registry for Alzheimer's diseases (CERAD). While these changes neuropathologically define AD, it becomes more and more apparent that the majority of patients present with a multitude of additional pathological changes which are possible contributing factors to the clinical presentation and disease progression. The impact of co-existing Lewy body pathology has been well studied, but the importance of more recently described pathologies including limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy (ARTAG) still needs to be evaluated in large cohort studies. In addition, it is apparent that vascular pathology plays an important role in the AD patient population, but a lack of standardized reporting criteria has hampered progress in elucidating the importance of these changes for clinical presentation and disease progression. More recently a key role was ascribed to the immune response to pathological protein aggregates, and it will be important to analyze these changes systematically to better understand the temporal and spatial distribution of the immune response in AD and elucidate their importance for the disease process. Advances in digital pathology and technologies such as single cell sequencing and digital spatial profiling have opened novel avenues for improvement of neuropathological diagnosis and advancing our understanding of underlying molecular processes. Finally, major strides in biomarker-based diagnosis of AD and recent advances in targeted therapeutic approaches may have shifted the perspective but also highlight the continuous importance of postmortem analysis of the brain in neurodegenerative diseases.

Inflammatory myofibroblastic tumor masquerading as an anterior choroidal artery fusiform aneurysm.

BACKGROUND: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. CASE DESCRIPTION: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. CONCLUSION: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.

Case Studies in Neuroscience: Neuropathology and diaphragm dysfunction in ventilatory failure from late-onset Pompe disease.

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-h noninvasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-yr period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm2) and cervical motoneurons (soma size: 487 ± 189 µm2) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1,363 ± 677 µm2) and sacral motoneurons (soma size: 1,411 ± 633 µm2) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle.NEW & NOTEWORTHY This case study offered a unique opportunity to investigate longitudinal changes in phrenic neurophysiology in an individual with severe, ventilator-dependent, late-onset Pompe disease. Additional diaphragm and neural tissue histology upon autopsy confirmed significant neuromuscular degeneration, and it provided novel insights regarding rostral to caudal variability in the neuropathology. These findings suggest that a successful treatment approach for ventilator-dependent Pompe disease should target the central nervous system, in addition to skeletal muscle.

Orbital metastasis of squamous cell cervical cancer: A case report and review of literature.

Common sites of metastatic disease seen in cervical cancer most often include the lungs and liver. Orbital metastasis secondary to cervical carcinoma is a rare form of metastatic disease. We report a 73-year-old woman who presented with ocular symptoms found to be secondary to orbital metastasis of cervical cancer. She underwent palliative radiation to the orbit and pelvis followed by systemic chemotherapy with carboplatin, paclitaxel, and bevacizumab. Prompt intervention was able to salvage her vision and improve her quality of life significantly. We identified 5 similar reported cases in which orbital metastasis was diagnosed simultaneously at the time of cervical cancer diagnosis. In these five cases, patients were treated with a combination of radiation and chemotherapy. Our case demonstrates an unusual presentation of isolated orbital metastatic disease secondary to squamous cell carcinoma of the cervix. Physicians should be aware that cervical cancer may metastasize to the eye leading to vision loss, and prompt intervention may be able to salvage one's vision and improve quality of life.

Pediatric pathology all grown up - An interesting case of adult tethered spinal cord.

BACKGROUND: Cervical myelopathy in an adult is typically the result of degenerative disease or trauma. Dysraphism is rarely the cause. CASE DESCRIPTION: The authors report the case of a 35-year-old male drywall installer who presented with 2 years of progressive left upper extremity weakness, numbness, and hand clumsiness. Only upon detailed questioning did he mention that he had neck surgery just after birth, but he did not know what was done. He then also reported that he routinely shaved a patch of lower back hair, but denied bowel, bladder, or lower extremity dysfunction. Magnetic resonance imaging of the cervical spine demonstrated T2 hyperintensity at C4-C5 with dorsal projection of the neural elements into the subcutaneous tissues concerning for a retethered cervical myelomeningocele. Lumbar imaging revealed a diastematomyelia at L4. He underwent surgical intervention for detethering and repaired of the cervical myelomeningocele. Four months postoperatively, he had almost complete resolution of symptoms, and imaging showed a satisfactory detethering. The diastematomyelia remained asymptomatic and is being observed. CONCLUSION: Tethered cervical cord is a rare cause for myelopathy in the adult patient. In the symptomatic patient, surgical repair with detethering is indicated to prevent disease progression and often results in clinical improvement.

An Unusual Cause of Intracerebral Hemorrhage: Clinical Pearls Regarding Primary Angiitis of the Central Nervous System.

Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis. It is a diagnosis of exclusion and often diagnosed post mortem on pathologic evaluation. Cerebral angiography can be suggestive, but biopsy is required. Symptoms can vary from headache to focal cranial nerve deficits. On the more severe spectrum, patients can present with ischemic and vary rarely hemorrhagic stroke. We present in this case report key clinical pearls regarding suspected diagnosis. Younger patients with cortical hemorrhages may have PACNS instead of the more common cerebral amyloid angiopathy. Early suspicion may aid in initiating effective treatment as we highlight in the discussion.

Novel monoclonal antibodies targeting the RRM2 domain of human TDP-43 protein.

Transactive response DNA-binding protein of 43 kilodaltons (TDP-43) is a 414 amino acid protein that under physiologic conditions localizes to the nucleus and participates in the regulation of RNA metabolism through two RNA recognition motifs (RRM1 and RRM2). In neurodegenerative diseases, TDP-43 may become hyperphosphorylated, ubiquitinated, and aggregate into cytoplasmic inclusions. TDP-43 is now well-characterized as a pathologic protein of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). Additionally, a common TDP-43 proteinopathy arising outside of the context of ALS and FTLD-TDP has been recently described, termed "limbic predominant age-related TDP-43 encephalopathy (LATE)." In the current study, two novel mouse-derived monoclonal antibodies, 2G11 and 2H1, raised against an epitope within the RRM2 domain of TDP-43 (residues 198-216), were characterized for specificity and immunohistochemical application in human brain from cases of Alzheimer's disease (AD), Lewy Body Disease (LBD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobe degeneration with TDP-43 inclusions (FTLD-TDP). Immunoblot analysis of these antibodies in HEK293T cells revealed efficient detection of intact human TDP-43 protein, and in N2A cells showed no reactivity for mouse TDP-43. Immunohistochemically applied to formalin-fixed paraffin-embedded tissues, 2G11 and 2H1 robustly identified the classic inclusions of ALS and FTLD-TDP, and efficaciously provided a diagnosis of LATE in cases of AD and LBD. These novel antibodies label aberrant intracytoplasmic protein inclusions without relying on hyperphosphorylated epitopes, and provide elegant discrimination between TDP-43 and tau neurofibrillary tangles within neurodegenerative comorbidity.

Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer's disease.

The discovery of mutations associated with familial forms of Alzheimer's disease (AD), has brought imperative insights into basic mechanisms of disease pathogenesis and progression and has allowed researchers to create animal models that assist in the elucidation of the molecular pathways and development of therapeutic interventions. Position 717 in the amyloid precursor protein (APP) is a hotspot for mutations associated with autosomal dominant AD (ADAD) and the valine to isoleucine amino acid substitution (V717I) at this position was among the first ADAD mutations identified, spearheading the formulation of the amyloid cascade hypothesis of AD pathogenesis. While this mutation is well described in multiple kindreds and has served as the basis for the generation of widely used animal models of disease, neuropathologic data on patients carrying this mutation are scarce. Here we present the detailed clinical and neuropathologic characterization of an APP V717I carrier, which reveals important novel insights into the phenotypic variability of ADAD cases. While age at onset, clinical presentation and widespread parenchymal beta-amyloid (Aß) deposition are in line with previous reports, our case also shows widespread and severe cerebral amyloid angiopathy (CAA). This patient also presented with TDP-43 pathology in the hippocampus and amygdala, consistent with limbic predominant age-related TDP-43 proteinopathy (LATE). The APOE ε2/ε3 genotype may have been a major driver of the prominent vascular pathology seen in our case. These findings highlight the importance of neuropathologic examinations of genetically determined AD cases and demonstrate striking phenotypic variability in ADAD cases.

Generation and Characterization of Novel Monoclonal Antibodies Targeting p62/sequestosome-1 Across Human Neurodegenerative Diseases.

Human neurodegenerative diseases can be characterized as disorders of protein aggregation. As a key player in cellular autophagy and the ubiquitin proteasome system, p62 may represent an effective immunohistochemical target, as well as mechanistic operator, across neurodegenerative proteinopathies. In this study, 2 novel mouse-derived monoclonal antibodies 5G3 and 2A5 raised against residues 360-380 of human p62/sequestosome-1 were characterized via immunohistochemical application upon human tissues derived from cases of C9orf72-expansion spectrum diseases, Alzheimer disease, progressive supranuclear palsy, Lewy body disease, and multiple system atrophy. 5G3 and 2A5 reliably highlighted neuronal dipeptide repeat, tau, and α-synuclein inclusions in a distribution similar to a polyclonal antibody to p62, phospho-tau antibodies 7F2 and AT8, and phospho-α-synuclein antibody 81A. However, antibodies 5G3 and 2A5 consistently stained less neuropil structures, such as tau neuropil threads and Lewy neurites, while 2A5 marked fewer glial inclusions in progressive supranuclear palsy. Both 5G3 and 2A5 revealed incidental astrocytic tau immunoreactivity in cases of Alzheimer disease and Lewy body disease with resolution superior to 7F2. Through their unique ability to highlight specific types of pathological deposits in neurodegenerative brain tissue, these novel monoclonal p62 antibodies may provide utility in both research and diagnostic efforts.

Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology.

Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer's disease (AD) and Parkinson's disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.

Unique α-synuclein pathology within the amygdala in Lewy body dementia: implications for disease initiation and progression.

The protein α-synuclein (αsyn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson's disease (PD). It is unclear why diseases such as LBD may develop widespread αsyn pathology, while in Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB) the αsyn aggregates remain localized. The amygdala contains αsyn aggregates in both LBD and in AD/ALB; to understand why αsyn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized αsyn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil αsyn aggregates, astrocytic αsyn, and αsyn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of αsyn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of αsyn pathology. Similar to carboxy-truncated αsyn, it was demonstrated herein that the presence of aggregation prone A53T αsyn is sufficient to drive misfolding of wild-type αsyn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in αsyn pathology that may be a determinant of disease progression.

Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils.

α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed αS fibrils in hemizygous M20+/- transgenic mice expressing wild type human αS and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS αS pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by αS inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing αS pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce αS pathology following neonatal brain inoculation in transgenic mice expressing A53T human αS (M83 line), but not in transgenic expressing wild type human αS (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human αS fibrils in hemizygous M83+/- transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA αS seeds that can induce pathology.

Dissecting α-synuclein inclusion pathology diversity in multiple system atrophy: implications for the prion-like transmission hypothesis.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of insoluble, aggregated α-synuclein (αS) pathological inclusions. Multiple system atrophy (MSA) presents with extensive oligodendroglial αS pathology and additional more limited neuronal inclusions while most of the other synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies (DLB), develop αS pathology primarily in neuronal cell populations. αS biochemical alterations specific to MSA have been described but thorough examination of these unique and disease-specific protein deposits is further warranted especially given recent findings implicating the prion-like nature of synucleinopathies perhaps with distinct strain-like properties. Taking advantage of an extensive panel of antibodies that target a wide range of epitopes within αS, we investigated the distinct properties of the various types of αS inclusion present in MSA brains with comparison to DLB. Brain biochemical fractionation followed by immunoblotting revealed that the immunoreactive profiles were significantly more consistent for DLB than for MSA. Furthermore, epitope-specific immunohistochemistry varied greatly between different types of MSA αS inclusions and even within different brain regions of individual MSA brains. These studies highlight the importance of using a battery of antibodies for adequate appreciation of the various pathology in this distinct synucleinopathy. In addition, it can be posited that if the spread of pathology in MSA undergoes prion-like mechanisms, "strains" of αS aggregated conformers must be inherently unstable and readily mutable, perhaps resulting in a more stochastic progression process.

SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.

Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the in vivo accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

Deep Brain Stimulation associated gliosis: A post-mortem study.

BACKGROUND: DBS is a well-established therapy for patients with PD and is an emerging therapy for other neuropsychiatric disorders. Despite the rise in DBS usage, relatively little is known about the tissue and cellular responses to DBS. PURPOSE: To examine post-mortem effects of DBS leads by objectively quantifying gliosis around the distal DBS lead tip. METHODS: The UF DBS Brain Bank repository currently has 64 brains, of which 18 cases met criteria for this study. RESULTS: The average patient age was 54.88 ±â€¯13.43 years (mean ±â€¯SD), male:female ratio was 3:1, average disease duration was 20.70 ±â€¯6.36 years and average DBS duration was 7.26 ±â€¯6.36 years. Microscopic evaluation revealed tissue reaction and astrocytic responses to the lead. Significant fibrosis was seen in n = 2 brains and prominent microglial response in n = 1. Mean gliotic collar measured from H&E and GFAP staining was 122.5 µm and 162.5 µm, respectively. Mean gliotic thickness at the DBS electrode lead tip was 119.13 ±â€¯64.29 µm for patients receiving DBS for 0-5 years, 127.85 ±â€¯94.34 µm for 5-10 years and 111.73 ±â€¯114.18 µm for patients with DBS >10 years. Kruskal-Wallis one-way analysis of variance (ANOVA) revealed no statistically significant differences between DBS duration and amount of gliosis. CONCLUSIONS: This study revealed that approximately three out of four post-mortem DBS cases exhibited pathological evidence of a glial collar or scar present at the ventral DBS lead tip. The amount of gliosis was not significantly associated with duration of DBS. Future studies should include serial sectioning across all DBS contacts with correlation to the volume of tissue activation and to the clinical outcome.

An Incidental Diffuse Midline Glioma Found at Autopsy.

This case shows an unexpected midline glioma found at autopsy. Two siblings were riding on a single bicycle on the side of a road. The 13-year-old brother was seated and steering the bicycle, while the 14-year-old sister held onto the back. The bicycle veered left into traffic and was struck by a vehicle. The siblings were admitted to the local Level 1 trauma center, but both later succumbed to injuries. Autopsies were performed on the children, including brains for neuropathologic evaluation. The brother was found to have an infiltrating astrocytoma located in the left middle cerebellar peduncle, with extension to the pons and medulla. His hospital course included several imaging studies using CT and MRI modalities. However, this lesion was not identified until the postmortem neuropathologic examination. This rare case shows the continued need for postmortem autopsy and the current limitations of medical imaging.