Neuropathological interpretation of stimulated Raman histology images of brain and spine tumors: part B

Intraoperative histopathological examinations are routinely performed to provide neurosurgeons with information about the entity of tumor tissue. Here, we quantified the neuropathological interpretability of stimulated Raman histology (SRH) acquired using a Raman laser imaging system in a routine clinical setting without any specialized training or prior experience. Stimulated Raman scattering microscopy was performed on 117 samples of pathological tissue from 73 cases of brain and spine tumor surgeries. A board-certified neuropathologist — novice in the interpretation of SRH — assessed image quality by scoring subjective tumor infiltration and stated a diagnosis based on the SRH images. The diagnostic accuracy was determined by comparison to frozen hematoxylin–eosin (H&E)-stained sections and the ground truth defined as the definitive neuropathological diagnosis. The overall SRH imaging quality was rated high with the detection of tumor cells classified as inconclusive in only 4.2% of all images. The accuracy of neuropathological diagnosis based on SRH images was 87.7% and was non-inferior to the current standard of fast frozen H&E-stained sections (87.3 vs. 88.9%, p = 0.783). We found a substantial diagnostic correlation between SRH-based neuropathological diagnosis and H&E-stained frozen sections (κ = 0.8). The interpretability of intraoperative SRH imaging was demonstrated to be equivalent to the current standard method of H&E-stained frozen sections. Further research using this label-free innovative alternative vs. conventional staining is required to determine to which extent SRH-based intraoperative decision-making can be streamlined in order to facilitate the advancement of surgical neurooncology.

Two Case Reports of Chorea-acanthocytosis and Review of Literature

Background: Chorea-acanthocytosis (ChAc), as the most common subtype of neuroacanthocytosis syndrome, is characterized by the presence of acanthocytes and neurological symptoms. It is thought to be caused by the VPS13A (vacuolar protein sorting-associated protein 13A) mutations. This article reports two confirmed cases of ChAc and summarizes some suggestive features, which provide direction for the diagnosis and treatment of acanthocytosis in the future.Case presentation: Here, we present two cases of ChAc diagnosed based on typical clinical symptoms, neuroimaging features, genetic findings of VPS13A, and response to the symptomatic treatment. Conclusions: Chorea-acanthocytosis is a rare neurodegenerative disease with various early clinical manifestations. The final diagnosis of the ChAc can be established by either genetic analysis or protein expression by Western blotting. Supportive treatments and nursing are helpful to improve the quality of the patient’s life. Nevertheless, it is imperative to investigate the impact of neuroimaging and neuropathological diagnosis in a larger group of ChAc in future studies.

Loss of putative GABAergic neurons in the ventrolateral medulla in multiple system atrophy

Study Objectives Multiple system atrophy (MSA) is associated with disturbances in cardiovascular, sleep and respiratory control. The lateral paragigantocellular nucleus (LPGi) in the ventrolateral medulla (VLM) contains GABAergic neurons that participate in control of rapid eye movement (REM) sleep and cardiovagal responses. We sought to determine whether there was loss of putative GABAergic neurons in the LPGi and adjacent regions in MSA. Methods Sections of the medulla were processed for GAD65/67 immunoreactivity in eight subjects with clinical and neuropathological diagnosis of MSA and in six control subjects. These putative GABAergic LPGi neurons were mapped based on their relationship to adjacent monoaminergic VLM groups. Results There were markedly decreased numbers of GAD-immunoreactive neurons in the LPGi and adjacent VLM regions in MSA. Conclusions There is loss of GABAergic neurons in the VLM, including the LPGi in patients with MSA. Whereas these findings provide a possible mechanistic substrate, given the few cases included, further studies are necessary to determine whether they contribute to REM sleep-related cardiovagal and possibly respiratory dysregulation in MSA.

Significant Overlap of α-Synuclein, Amyloid-β, and Phospho-Tau Pathologies in Neuropathological Diagnosis of Lewy-related Pathology: Evidence from China Human Brain Bank

Background: Lewy-related pathology (LRP), primarily comprised of α-synuclein, is a typical neuropathological change that has been identified in many neurodegenerative disorders such as Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies. Objective: To investigate the distribution of LRP in the China Human Brain Bank, the co-occurrence of neuropathologic features of Alzheimer’s disease (AD) in LRP cases, and LRP-related cognitive dysfunction. Methods: LRP neuropathological diagnosis was performed in 180 postmortem brains. AD neuropathological diagnosis was then performed in the 21 neuropathologically-diagnosed LRP cases. Antemortem cognitive functioning evaluation (Everyday Cognitive, ECog) was assessed for brain donors by the immediate kin of the donor within 24 hours after death. Results: 12% (21 in 180) postmortem brains were neuropathologically diagnosed as LRP cases. 86% (18 in 21) aged above 80, 81% (17 in 21) LRP cases combined with AD neuropathology, and 62% (13 in 21) combined with both the intermediate or high-level amyloid-β and phospho-tau pathologies. ECog scores showed significant differences between the groups of LRP brainstem-predominant type and LRP diffuse neocortical type, and between groups of AD and the combined LRP (diffuse neocortical type)-AD. Conclusion: The overlap of neocortical α-synuclein, amyloid-β, phospho-tau, and neuritic plaques in LRP suggested the potential interplay among the common characteristics of proteinopathies in the late stage of neuropathological development of LRP in human brains. The anatomic progression of LRP, the process of α-synuclein spreading from the brainstem to limbic and neocortical regions, might aggravate the deterioration of cognitive function in addition to that effect of AD.

Alzheimer’s Disease Neuropathological Comorbidities are Common in the Younger-Old

Background: Clinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the rate of cognitive decline. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. Objective: As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown; our objective is to provide this information. Methods: We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association intermediate or high AD Neuropathological Change levels, excluding those with known autosomal dominant AD-related mutations. Results: Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20%in the 70s and beyond. Lewy body disease is the most common comorbidity at younger ages but actually is less common at later ages, while for most others, their prevalence increases with age. Conclusion: Alzheimer’s disease neuropathological comorbidities are highly prevalent even in the younger-old.

Clinicopathological investigation of the background of cognitive decline in elderly schizophrenia

Objective: We have often observed dementia symptoms or severe neurocognitive decline in the long-term course of schizophrenia. While there are epidemiological reports that patients with schizophrenia are at an increased risk of developing dementia, there are also neuropathological reports that the prevalence of Alzheimer’s disease (AD) in schizophrenia is similar to that in normal controls. It is difficult to distinguish, based solely on the clinical symptoms, whether the remarkable dementia symptoms and cognitive decline seen in elderly schizophrenia are due to the course of the disease itself or a concomitant neurocognitive disease. Neuropathological observation is needed for discrimination. Methods: We conducted a neuropathological search on three cases of schizophrenia that developed cognitive decline or dementia symptoms after a long illness course of schizophrenia. The clinical symptoms of total disease course were confirmed retrospectively in the medical record. We have evaluated neuropathological diagnosis based on not only Hematoxylin–Eosin and Klüver–Barrera staining specimens but also immunohistochemical stained specimens including tau, β-amyloid, pTDP-43 and α-synuclein protein throughout clinicopathological conference with multiple neuropathologists and psychiatrists. Results: The three cases showed no significant pathological findings or preclinical degenerative findings, and poor findings consistent with symptoms of dementia were noted. Conclusion: Although the biological background of dementia symptoms in elderly schizophrenic patients is still unclear, regarding the brain capacity/cognitive reserve ability, preclinical neurodegeneration changes in combination with certain brain vulnerabilities due to schizophrenia itself are thought to induce dementia syndrome and severe cognitive decline.

Clinical Diagnostic Accuracy of Early/Advanced Parkinson Disease: Updated Clinicopathologic Study

Objectives:Update data for diagnostic accuracy of a clinical diagnosis of Parkinson’s disease (PD) using neuropathological diagnosis as the gold standard.Methods:Data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) was used to determine the predictive value of a clinical PD diagnosis. Two clinical diagnostic confidence levels were used, Possible PD (PossPD, never treated or not responsive) and Probable PD (ProbPD, 2/3 cardinal clinical signs + responsive to dopaminergic medications). Neuropathological diagnosis was the gold standard.Results:Based on first visit to AZSAND, 15/54 (27.8%) PossPD cases and 138/163 (84.7%) ProbPD had confirmed PD. PD was confirmed in 24/34 (70.6%) ProbPD with <5 yrs and 114/128 (89.1%) with >5 yrs disease duration. Using the consensus final clinical diagnosis following death, 161/187 (86.1%) ProbPD had neuropathologically confirmed PD. Diagnostic accuracy for ProbPD improved if included motor fluctuations, dyskinesias, and hyposmia, and hyposmia for PossPD.Conclusions:This updated study confirmed lower clinical diagnostic accuracy for elderly, untreated or poorly responsive PossPD participants and for ProbPD with <5 yr disease duration, even when medication responsive. Caution continues to be needed when interpreting clinical studies of PD, especially studies of early disease, that do not have autopsy confirmation.Classification of Evidence:This study provides Class II evidence that a clinical diagnosis of probable PD at first visit identifies patients who will have pathologically confirmed PD with a sensitivity of 82.6% and specificity of 86.0%.

Human Autopsy-Derived Scalp Fibroblast Biobanking for Age-Related Neurodegenerative Disease Research

The Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program at Banner Sun Health Research Institute (BSHRI) is a longitudinal clinicopathological study with a current enrollment of more than 900 living subjects for aging and neurodegenerative disease research. Annual clinical assessments are done by cognitive and movement neurologists and neuropsychologists. Brain and body tissues are collected at a median postmortem interval of 3.0 h for neuropathological diagnosis and banking. Since 2018, the program has undertaken banking of scalp fibroblasts derived from neuropathologically characterized donors with Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. Here, we describe the procedure development and cell characteristics from 14 male and 15 female donors (mean ± SD of age: 83.6 ± 12.2). Fibroblasts from explant cultures were banked at passage 3. The results of mRNA analysis showed positive expression of fibroblast activation protein, vimentin, fibronectin, and THY1 cell surface antigen. We also demonstrated that the banked fibroblasts from a postmortem elderly donor were successfully reprogramed to human-induced pluripotent stem cells (hiPSCs). Taken together, we have demonstrated the successful establishment of a human autopsy-derived fibroblast banking program. The cryogenically preserved cells are available for request at the program website of the BSHRI.

The Role of Liquid Biopsies in Pediatric Brain Tumors

Early detection and serial therapeutic monitoring for pediatric brain tumors are essential for diagnosis and therapeutic intervention. Currently, neuropathological diagnosis relies on biopsy of tumor tissue and surgical intervention. There is a great clinical need for less invasive methods to molecularly characterize the tumor and allow for more reliable monitoring of patients during treatment and to identify patients that might potentially benefit from targeted therapies, particularly in the setting where diagnostic tissue cannot be safely obtained. In this literature review, we highlight recent studies that describe the use of circulating tumor DNA, circulating tumor cells, circulating RNA and microRNA, and extracellular vesicles as strategies to develop liquid biopsies in pediatric central nervous system tumors. Liquid biomarkers have been demonstrated using plasma, urine, and cerebrospinal fluid. The use of liquid biopsies to help guide diagnosis, determine treatment response, and analyze mechanisms of treatment resistance is foreseeable in the future. Continued efforts to improve signal detection and standardize liquid biopsy procedures are needed for clinical application.