Relation of Motor Impairments to Neuropathologic Changes of Limbic-Predominant Age-Related TDP-43 Encephalopathy in Older Adults.

BACKGROUND AND OBJECTIVES: Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is common and is a major contributor to cognitive decline and Alzheimer dementia in older adults. The objective of the current study was to examine whether LATE-NC was also associated with declining motor function in older adults. METHODS: Participants were from 2 longitudinal clinical pathologic studies of aging who did not have dementia at the time of enrollment. Postmortem pathologic examination included immunohistochemical staining for TDP-43 in 8 brain regions, which was summarized as a dichotomous variable indicating advanced LATE-NC stages at which TDP-43 pathology had accumulated in the hippocampus, entorhinal, or neocortical regions. Annual motor testing included maximal inspiratory and expiratory pressures (summarized as respiratory muscle strength), grip and pinch strength (summarized as hand strength), finger tapping speed and the Purdue Pegboard Test (summarized as hand dexterity), and walking 8 feet and turning 360° (summarized as gait function). The severity of parkinsonism was also assessed and summarized as a global parkinsonism score. Global cognition was a summary of standardized scores of 19 neuropsychological tests. We used linear mixed-effect models to examine the associations of LATE-NC with longitudinal changes of motor decline and used multivariate random coefficient models to simultaneously examine the associations of LATE-NC with cognitive and motor decline. RESULTS: Among 1,483 participants (mean age at death 90.1 [SD = 6.4] years, 70% women, mean follow-up 7.4 [SD = 3.8] years), LATE-NC was present in 34.0% (n = 504). In separate linear mixed-effect models controlling for demographics and other brain pathologies, LATE-NC was associated with faster decline in respiratory muscle strength (estimate = -0.857, SE = 0.322, p = 0.008) and hand strength (estimate = -0.005, SE = 0.002, p = 0.005) but was not related to hand dexterity, gait function, or parkinsonism. In multivariate random coefficient models including respiratory muscle strength, hand strength, and global cognition as the outcomes, LATE-NC remained associated with a faster respiratory muscle strength decline rate (estimate = -0.021, SE = 0.009, p = 0.023), but the association with hand strength was no longer significant (estimate = -0.002, SE = 0.003, p = 0.390). DISCUSSION: Motor impairment, specifically respiratory muscle weakness, may be an unrecognized comorbidity of LATE-NC that highlights the potential association of TDP-43 proteinopathy with noncognitive phenotypes in aging adults.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Recurrent IgG4-Related Meningeal Disease of the Cervicothoracic Spine: A Case Report and Review of the Literature.

Background: IgG4-related disease is a rare, recently recognized chronic inflammatory disease. IgG4-related hypertrophic pachymeningitis (IgG4-RHP) of the central nervous system predominantly involves the cranial meninges. Spinal involvement remains rare. Objective: We report a case of recurrent cervicothoracic IgG4-RHP and review the surgical literature. Methods and Materials: A 35-year-old woman presented with a 6-month history of neck and right shoulder pain, progressive right triceps weakness and paresthesias in the right C8 and T1 dermatomes. MRI demonstrated a T2 hypointense epidural soft tissue mass extending from C6-T1. The patient underwent C6-T1 laminoforaminotomy and partial resection with near complete symptom resolution. Histopathology was consistent with diagnosis of IgG4-RHP. Eighteen months postoperatively, she experienced symptom recurrence necessitating re-operation and adjuvant postoperative prednisone with complete resolution at 40-months' follow-up. Results and Conclusions: Of the now nineteen confirmed cases of IgG4-RHP, fifteen underwent surgery. A majority achieved partial resection. Three surgical patients did not receive adjuvant therapy with symptomatic recurrence between 2 and 18 months.

Atypical Teratoid/Rhabdoid Tumor of the Conus Medullaris.

INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare tumor of the central nervous system, especially when involving the spinal column or spinal cord. CASE PRESENTATION: We present a case of a 5-year-old girl with progressive bilateral lower extremity pain found to have a discrete nodular lesion of the conus with mild heterogeneous enhancement. Surgical decompression and resection demonstrated a pathologic tumor consistent with AT/RT with loss of INI1 protein on immunohistochemistry. DISCUSSION AND CONCLUSION: AT/RT lesions of the conus medullaris are exceedingly rare and associated with extensive disease. We report a rare case of AT/RT with selective involvement of the conus medullaris, as well as describe the surgical, radiographic, and pathologic findings of this tumor.

Increased Expression of Vascular Endothelial Growth Factor-D Following Brain Injury.

Alterations in the expression of the vascular endothelial growth factors (VEGF) A and B occur during blood⁻brain barrier (BBB) breakdown and angiogenesis following a brain injury. In this study, the temporal and spatial expression of VEGF-D and VEGF receptors-2 and -3 (VEGFR-2 and VEGFR-3, respectively) was determined at the mRNA and protein level in the rat cortical cold-injury model over a period of 0.5 to 6 days post-injury. In order to relate endothelial VEGF-D protein expression with BBB breakdown, dual labeling immunofluorescence was performed using antibodies to VEGF-D and to fibronectin, a marker of BBB breakdown. In control rats, VEGF-D signal was only observed in scattered perivascular macrophages in the cerebral cortex. The upregulation of VEGF-D mRNA expression was observed in the injury site between days 0.5 to 4, coinciding with the periods of BBB breakdown and angiogenesis. At the protein level, intracerebral vessels with BBB breakdown to fibronectin in the lesion on days 0.5 to 4 failed to show endothelial VEGF-D. Between days 0.5 to 6, increased VEGF-D immunoreactivity was noted in the endothelium of pial vessels overlying the lesion site, in neutrophils, macrophages, and free endothelial cells within the lesion. The upregulation of VEGFR-2 and -3 mRNA and protein expression was observed early post-injury on day 0.5. Although there was concurrent expression of VEGF-A, VEGF-B, and VEGF-D post-injury, differences in their spatial expression during BBB breakdown and angiogenesis suggest that they had specific and separate roles in these processes.

TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD.

OBJECTIVE: To investigate the association of TAR DNA-binding protein 43 (TDP-43) pathology with memory, other cognitive domains, and dementia in community-dwelling elders without pathologic diagnoses of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). METHODS: Of 1,058 autopsied participants, 343 (32.4%) did not have pathologic diagnoses of AD or FTLD. Diagnosis of dementia was based on clinical evaluation and cognitive performance tests, which were used to create summary measures of global cognition and of 5 cognitive domains. TDP-43 pathology evaluated in 6 brain regions by immunohistochemistry was converted into a summary measure of TDP-43 severity. RESULTS: Of 343 participants, 135 (39.4%) had TDP-43 pathology with a mean TDP-43 severity score of 0.394 (SD 0.490). TDP-43 inclusions were confined to the amygdala (stage 1) in 43.7% of participants, 40% showed additional involvement of the hippocampus or entorhinal cortex (stages 2), while fewer (16.3%) showed additional TDP-43 pathology in the temporal and frontal cortices (stage 3). Severity of TDP-43 pathology was independently related to lower function in global cognition and episodic and semantic memory while increased odds of dementia was only a trend. When participants with hippocampal sclerosis (HS) were excluded from the models, TDP-43 pathology remained associated with lower episodic memory but relationships with global cognition, semantic memory, and dementia were attenuated. CONCLUSIONS: TDP-43 pathology in elders, without pathologic diagnoses of AD or FTLD, is common and independently associated with lower function in episodic memory, while its associations with global cognitive impairment and dementia are difficult to separate from HS.

Molecular Changes Associated with the Protective Effects of Angiopoietin-1 During Blood-Brain Barrier Breakdown Post-Injury.

Blood-brain barrier (BBB) breakdown to plasma proteins leads to vasogenic edema which when diffuse is a life threatening complication in many types of acute brain injury. In our previous studies, early BBB breakdown was associated with increased expression of endothelial caveolin-1α (Cav-1) protein and decreased expression of occludin. In order to attenuate these changes, the effects of intra-cortical angiopoietin-1 (Ang1), a potent anti-permeability factor, on BBB breakdown was assessed in the cold injury model at day 1 post-injury. Overall vascular permeability at the lesion site was assessed in Ang1 non-treated and treated cold-injured rats, using horseradish peroxidase (HRP) as a tracer and in individual vessels by dual labeling immunofluorescence for Cav-1 or occludin and fibronectin, a marker of BBB breakdown. In addition, Cav-1, occludin, Akt, and ERK1/2 expression at the lesion site was detected by immunoblotting. Non-treated cold-injured rats showed focal HRP leakage at the lesion site which was significantly decreased (P < 0.001) in the Ang1-treated group. Increased endothelial Cav-1 and decreased occludin immunoreactivity was observed in arterioles and corresponding-sized venules with BBB breakdown in the non-treated cold-injured rats, and similar expression of these proteins was detected at the lesion site by immunoblotting associated with increased expression of Akt and ERK2 proteins. These alterations were attenuated by Ang1 treatment which resulted in Cav-1, occludin, Akt, and ERK1/2 protein expression that was similar to that of the control groups as was the endothelial Cav-1 and occludin immunoreactivity in leaky vessels. These data suggest that Ang1 administered early post-injury has potential in attenuating the degree of vascular alterations and subsequent vasogenic edema.

Intrasphenoidal Rathke's cleft cyst.

We report a rare patient with an intrasphenoidal Rathke's cleft cyst (RCC) and review the literature. RCC are benign epithelium lined cysts containing mucoid material, which typically occur in a location that is either entirely intrasellar, or intrasellar with suprasellar extension (intra-suprasellar). RCC in a completely extrasellar location are uncommon. An intrasphenoidal RCC is extremely rare with only two patients reported in the literature to date. Preoperative diagnosis is difficult due to the uncommon location and absence of any characteristic radiological features. However, it remains of utmost clinical relevance because it may limit the operative management to biopsy sampling of the cyst wall and drainage of the contents via the transsphenoidal route.

Cytologic features of the normal pineal gland on squash preparations.

As primary pineal lesions are extremely rare, many surgical pathologists are unfamiliar with normal pineal cytologic features. We describe cytologic features of the normal pineal gland in patients of varying ages and identify common diagnostic pitfalls. We performed a retrospective review of pineal gland biopsies performed at our institution, where approximately 30,000 surgical specimens are accessioned yearly, for the last 23 years. Only two pineal gland biopsies were found. Although both cases were initially diagnosed as low-grade gliomas on frozen section, the final diagnosis was benign pineal tissue based on light microscopy and immunohistochemistry results. Additionally, we performed squash preparations of five normal pineal gland autopsy specimens with Papanicolaou and Diff-Quik® (Dade Behring, Newark, DE) stains. Infant preparations were highly cellular smears composed of numerous, uniform, single cells with indistinct cytoplasm, small round-to-oval nuclei, fine chromatin, and absent nucleoli and calcifications. The vague microfollicular pattern mimicked a pineocytoma and the fine fibrillary background mimicked a glial neoplasm. Young adult smears were similar; however, microcalcifications were present with fewer background single cells. Older patients had much less cellular smears composed of small clusters of cells with fusiform-to-spindle nuclei, a fine chromatin pattern, and indistinct cytoplasmic borders. There were fewer background single cells and more microcalcifications. The cytologic features of the native pineal gland vary with age. Normal pineal tissue can be confused with a pineocytoma or low-grade glioma. Familiarity with normal pineal gland cytological features will help to avoid a potential misdiagnosis.

Rapidly progressive quadriparesis heralding disseminated coccidioidomycosis in an immunocompetent patient.

Coccidioides species are dimorphic fungi endemic to southwestern USA and northern Mexico. Disseminated coccidioidomycosis is rare with an estimated incidence of 1% in affected individuals and usually presents as meningitis when the central nervous system is involved. Spinal involvement with coccidioidomycosis, though not uncommon, predominantly manifests as osseous involvement leading to osteomyelitis and epidural abscess formation. Progressive quadriparesis as a presenting symptom secondary to intramedullary spinal cord coccidioidomycosis is very unusual and to our knowledge has not been described. We report a patient with disseminated coccidioidomycosis who presented with rapidly progressive quadriparesis due to cervical intramedullary spinal cord involvement. The absence of known coccidioidomycosis with atypical clinical presentation made the diagnosis elusive, requiring emergent cervical laminectomies with dural biopsy for decompression of the spinal cord and confirmation of the diagnosis. The patient eventually succumbed to the progressive course of the disease. Although rare, disseminated coccidioidomycosis can present as new, rapidly progressing quadriparesis in patients who have traveled to endemic areas. A high index of suspicion in such patients with appropriately directed laboratory investigations and consideration of early biopsy might unravel the diagnosis facilitating early antifungal treatment with the potential to minimize morbidity and mortality associated with disseminated coccidioidomycosis.

A rare intramedullary spinal cord metastasis from uterine leiomyosarcoma.

Leiomyosarcoma is a rare smooth-muscle-derived malignancy with a significant malignant potential. Systemic metastases are a common late complication of leiomyosarcoma typically to lungs, liver, brain and bones. We report a 44-year-old woman with a prior history of uterine leiomyosarcoma who presented to us with a cervicothoracic intramedullary lesion and recent onset of neurological deficits. She underwent surgery with histological confirmation of a diagnosis of metastatic leiomyosarcoma, which was followed by adjuvant radiation and chemotherapy. To our knowledge there is no prior report of intramedullary spinal cord metastases (ISCM) from a leiomyosarcoma in the English literature. We report the present patient in view of the rarity of ISCM and its clinical significance. Even though ISCM are unusual, they should be suspected in any patient with primary malignancy irrespective of the histology. The overall prognosis remains grim irrespective of the treatment modality chosen and recognition of the same is important in preoperative counseling and overall treatment approach.

A 40-year-old male with an intraventricular tumor. Combined tanycytic ependymoma and subependymoma.

Combined tumors showing histologic features of both ependymoma and subependymoma have been described. In this report we present a case of combined tanycytic ependymoma with foci of subependymoma (WHO grade II), occurring in a 40 year-old male, which arose in the wall of the lateral ventricle. The tanycytic ependymoma component showed elongated fibrillary cells with a fascicular pattern of growth, while the subependymoma component showed clustered cell bodies surrounded by a fibrillary stroma with a microcystic appearance.We consider the present case to be an unusual example of tanycytic ependymoma; which to the best of our knowledge has not been associated with a subependymoma.

Isolated spinal neurosarcoidosis: An enigmatic intramedullary spinal cord pathology-case report and review of the literature.

Isolated spinal cord neurosarcoidosis (NS) in the absence of systemic disease or intracranial involvement is exceptionally rare. Adjunctive laboratory tests though useful may not be reliable and the absence of any pathognomonic radiological features makes the diagnosis difficult. As spinal cord NS may be a presenting feature of systemic sarcoidosis which may be occult on routine workup, (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) may be of value in unraveling this systemic involvement avoiding biopsying the spinal cord. A case of truly isolated NS is described with review of literature on this enigmatic pathology. Long segment intramedullary signal changes with focal parenchymal along with dural/meningeal enhancement in the absence of significant cervical stenosis in a young patient of northern European or African-American decent is very suggestive of NS and although may be presumably treated with steroids; there should be a low threshold for spinal cord biopsy especially in the absence of response to steroids to confirm isolated spinal cord NS in a patient with clinical neurological deterioration.

Pathology and new players in the pathogenesis of brain edema.

Brain edema continues to be a major cause of mortality after diverse types of brain pathologies such as major cerebral infarcts, hemorrhages, trauma, infections and tumors. The classification of edema into vasogenic, cytotoxic, hydrocephalic and osmotic has stood the test of time although it is recognized that in most clinical situations there is a combination of different types of edema during the course of the disease. Basic information about the types of edema is provided for better understanding of the expression pattern of some of the newer molecules implicated in the pathogenesis of brain edema. These molecules include the aquaporins, matrix metalloproteinases and growth factors such as vascular endothelial growth factors A and B and the angiopoietins. The potential of these agents in the treatment of edema is discussed. Since many molecules are involved in the pathogenesis of brain edema, effective treatment cannot be achieved by a single agent but will require the administration of a "magic bullet" containing a variety of agents released at different times during the course of edema in order to be successful.

Muscle and nerve involvement in granulomatous mycosis fungoides.

Occasional cases of peripheral neuropathy have been reported in classic mycosis fungoides. A rare variant of mycosis fungoides is the granulomatous form. We describe the occurrence of myopathy and peripheral neuropathy in a young woman who had skin lesions since the age of 12 years. At the age of 20 years they were diagnosed as granulomatous mycosis fungoides. The skin lesions resolved with interferon therapy and radiation. She then presented with cardiac and pulmonary symptoms and signs that were initially thought to be due to sarcoidosis or systemic vasculitis. A nerve and muscle biopsy showed granulomatous mycosis fungoides. To our knowledge, involvement of muscle and nerve by granulomatous mycosis fungoides has not been reported previously. Early reports suggested a favorable prognosis for the granulomatous subtype of mycosis fungoides. Based on a literature review and the course in our case, however, granulomatous mycosis fungoides seems to be an indicator of aggressive disease and ultimately a poor prognosis.

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis.

A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1beta, TNF-alpha and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1beta, TNF-alpha, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1beta was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-alpha was expressed to a lesser extent than IL-1beta, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrate the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.

Rapid expansion of a previously asymptomatic subependymoma. Case report.

This 39-year-old man presented with a 6-month history of occipital headaches. Magnetic resonance imaging revealed an irregularly shaped fourth ventricle mass. One month after his initial presentation, he was admitted to the hospital with significant tumor expansion and clinical deterioration. A posterior fossa craniectomy was performed and the mass was resected. Histopathological analysis of this tumor showed central necrosis with associated edema in an otherwise typical and benign-appearing subependymoma. To the authors' knowledge, this is the first reported case of rapid, nonhemorrhagic expansion associated with necrosis in a previously asymptomatic subependymoma.