Journal of Neuropathology & Experimental Neurology
ISSN / EISSN : 0022-3069 / 1554-6578
Published by: Oxford University Press (OUP) (10.1093)
Total articles ≅ 11,916
Latest articles in this journal
Published: 21 October 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 953-964; https://doi.org/10.1093/jnen/nlac094
3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability across centers is unclear. We calculated regional percentage areas occupied by tau pathological inclusions from the middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) from cases from the University of Pennsylvania and the University of California San Diego with AD, LBD+tau, PSP, or CBD (n = 150) using QuPath. In both cohorts, AD and LBD+tau had the highest grey and white matter tau burden in the STC (p ≤ 0.04). White matter tau burden was relatively higher in 4R-tauopathies than 3R/4R-tauopathies (p < 0.003). Grey and white matter tau were correlated in all diseases (R2=0.43–0.79, p < 0.04) with the greatest increase of white matter per unit grey matter tau observed in PSP (p < 0.02 both cohorts). Grey matter tau negatively correlated with MMSE in AD and LBD+tau (r = −4.4 to −5.4, p ≤ 0.02). These data demonstrate the feasibility of cross-institutional digital histology studies that generate finely grained measurements of pathology which can be used to support biomarker development and models of disease progression.
Published: 20 October 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 988-995; https://doi.org/10.1093/jnen/nlac095
The brain of a 58-year-old woman was included as a civilian control in an ongoing autopsy study of military traumatic brain injury (TBI). The woman died due to a polysubstance drug overdose, with Coronavirus Disease 2019 (COVID-19) serving as a contributing factor. Immunohistochemical stains for β-amyloid (Aβ), routinely performed for the TBI study, revealed numerous, unusual neocortical Aβ deposits. We investigated the autopsied brains of 10 additional young patients (<60 years old) who died of COVID-19, and found similar Aβ deposits in all, using two different Aβ antibodies across three different medical centers. The deposits failed to stain with Thioflavin-S. To investigate whether or not these deposits formed uniquely to COVID-19, we applied Aβ immunostains to the autopsied brains of COVID-19-negative adults who died with acute respiratory distress syndrome and infants with severe cardiac anomalies, and also biopsy samples from patients with subacute cerebral infarcts. Cortical Aβ deposits were also found in these cases, suggesting a link to hypoxia. The fate of these deposits and their effects on function are unknown, but it is possible that they contribute to the neurocognitive sequelae observed in some COVID-19 patients. Our findings may also have broader implications concerning hypoxia and its role in Aβ deposition in the brain.
Published: 20 October 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 975-987; https://doi.org/10.1093/jnen/nlac093
Transactive response DNA-binding protein 43 kDa (TDP-43) proteinopathy is the hallmark of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). LATE-NC is a common copathology with Alzheimer disease neuropathologic change (ADNC). Data from the National Alzheimer’s Coordinating Center were analyzed to compare clinical features and copathologies of autopsy-confirmed ADNC with versus without comorbid LATE-NC. A total of 735 participants with ADNC alone and 365 with ADNC with LATE-NC were included. Consistent with prior work, brains with LATE-NC had more severe ADNC, more hippocampal sclerosis, and more brain arteriolosclerosis copathologies. Behavioral symptoms and cognitive performance on neuropsychological tests were compared, stratified by ADNC severity (low/intermediate vs high). Participants with ADNC and LATE-NC were older, had higher ADNC burden, and had worse cognitive performance than participants with ADNC alone. In the low/intermediate ADNC strata, participants with comorbid LATE-NC had higher prevalence of behavioral symptoms (apathy, disinhibition, agitation, personality change). They also had worsened performance in episodic memory and language/semantic memory. Differences narrowed in the high ADNC strata, with worsened performance in only episodic memory in the comorbid LATE-NC group. The co-occurrence of LATE-NC with ADNC is associated with a different pattern of behavioral and cognitive performance than ADNC alone, particularly in people with low/intermediate ADNC burden.
Published: 18 October 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 996-1001; https://doi.org/10.1093/jnen/nlac091
Glioblastoma (GBM) is a highly heterogenous tumor. Though several well-defined histological patterns of GBMs are known, these are infrequent, and the molecular correlates of several of these histological patterns are not well understood. We identified 31 adult-type infiltrating grade 4 gliomas with unusual histology in our institutional archives from 2016 to 2020, including tumors with a preponderant component of giant cell (n = 15), gemistocytes (n = 6), spindle cells (n = 5), small cells (n = 3), and ependymoma-like features (n = 2). We performed molecular and cytogenetic profiles of IDH-wildtype GBMs with unusual histology and compared to 48 tumors with conventional histology. We found that the majority (85%) of giant cell GBM had increased numbers of whole chromosome loss and genomic haploidization compared to conventional GBMs and other variants. Furthermore, we identified a genetically confirmed GBM with prominent ependymal features, indicating that glial tumors with ependymal features should be considered in the differential diagnosis of GBM. We also identified 6 IDH-mutant grade 4 astrocytomas with unusual histology and similar molecular and cytogenetic profiles to conventional appearing grade 4 IDH-mutant astrocytomas. These findings emphasize the role of molecular/cytogenetic analyses in the diagnostic clarification of GBMs with unusual histological patterns, refine the classification of unusual GBMs, and potentially pave the way for personalized therapies.
Published: 3 October 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 1037-1039; https://doi.org/10.1093/jnen/nlac092
Published: 30 September 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 1008-1017; https://doi.org/10.1093/jnen/nlac089
Meningioma is the most common intracranial neoplasm, yet there is no effective therapy for recurrent/refractory meningiomas after surgery and radiation. Prostate-specific membrane antigen (PSMA) is an enzyme upregulated on endothelial cells of multiple neoplasms and is being investigated as a theranostic target. Until now, PSMA has not been studied in meningiomas. We aimed to verify PSMA endothelial expression in meningiomas, detect tumor grade variability, and investigate the relationship of PSMA signal with tumor recurrence. We analyzed 96 archival meningiomas including 58 de novo and 38 recurrent specimens. All specimens were stained routinely and immunostained for CD31 and PSMA. Slides were scanned and analyzed producing raw data for images of PSMA, CD31, PSMA/CD31, and PSMA/vasculature. PSMA expression was seen within 98.9% of meningioma samples. In the total cohort, higher-grade tumors had increased expression of raw PSMA and PSMA/CD31, and PSMA/vasculature ratios compared to grade 1 tumors. PSMA expression and PSMA/vasculature ratios (p = 0.0015) were higher in recurrent versus de novo tumors among paired samples. ROC curves demonstrated PSMA/CD31, PSMA/vasculature, and raw CD31 as indicators of tumor recurrence. Thus, PSMA is expressed within endothelial cells of meningiomas, is increased with tumor grade and recurrence, and persists with prior irradiation.
Published: 26 September 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 1029-1032; https://doi.org/10.1093/jnen/nlac087
Published: 22 September 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 1033-1036; https://doi.org/10.1093/jnen/nlac086
Published: 22 September 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 1018-1025; https://doi.org/10.1093/jnen/nlac085
Immune-mediated neuropathies are a heterogenous group of inflammatory peripheral nerve disorders. They can be classified according to the domain where the autoimmune process begins: the internode, paranode, or node. However, conventional diagnostic tools, electrodiagnosis (EDX), and autoantibody testing do not fully address this issue. In this institutional cohort study, we investigated the value of dermal myelinated fiber analysis for target domain-based classification. Twenty-seven consecutive patients with immune-mediated neuropathies underwent skin biopsies. The sections were stained with antibodies representative of myelinated fiber domains and were scanned using a confocal microscope. Clinical and pathological features of each patient were reviewed comprehensively. Quantitative morphometric parameters were subjected to clustering analysis, which stratified patients into 3 groups. Cluster 1 (“internodopathy”) was characterized by prominent internodal disruption, intact nodes and paranodes, demyelinating EDX pattern, and absence of nodal-paranodal antibodies. Cluster 2 (“paranodopathy”) was characterized by paranodal disruption and corresponding antibodies. Morphological changes were restricted to the nodes in cluster 3; we designated this cluster as “nodopathy.” This report highlights the utility of skin biopsy as a diagnostic aid to gain pathogenic insight and classify patients with immune-mediated neuropathies.
Published: 19 September 2022
Journal of Neuropathology and Experimental Neurology, Volume 81, pp 771-772; https://doi.org/10.1093/jnen/nlac081
Butler et al studied 159 case of chronic traumatic encephalopathy (CTE) and report that in the dorsolateral frontal cortex neuronal phosphorylated tau was significantly higher than astrocytic tau across all layers. Neuronal tau found mostly at the depth of sulci, including the pathognomonic perivascular distribution seen in CTE, was associated with age, years of repetitive head injury exposure and CTE severity. On the other hand, astrocytic tau was located primarily in the subpial regions and represents findings most consistent with aging-related tau astrogliopathy (ARTAG). The study supports the premise that neuronal tau is the major underlying pathological correlate of CTE.see page 773