CNS tumor with BCOR internal tandem duplication.

CNS tumor with BCOR internal tandem duplication is a recently proposed malignant tumor. The patient was an 18-month-old boy with torticollis and vomiting due to cerebellar hemispheric mass with extension to cerebellopontine angle and foramen magnum. Histopathologic examination of the tumor showed a moderately cellular tumor with microcystic formation, myxoid change, and atypical rosettes resembling Homer Wright rosettes. Illumina TruSight RNA Pan-Cancer NGS of the tumor genome revealed BCOR gene exon 15 internal tandem duplications.

Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy.

LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, however, scattered cytochrome c oxidase-negative staining and electron dense mitochondrial inclusions were observed. Primary cultured fibroblasts from the siblings showed normal levels of mtDNA and mitochondrial transcripts, and normal activities of oxidative phosphorylation complexes I through V. Interestingly, fibroblasts of both siblings showed glucose-repressed oxygen consumption compared to their mother, whereas galactose and palmitic acid utilization were similar. Notably, the siblings' fibroblasts had reduced pyruvate dehydrogenase (PDH) activity and elevated intracellular lactate:pyruvate ratios, whereas plasma ratios were normal. We demonstrated that in the siblings' fibroblasts, PDH dysfunction was caused by increased levels of the phosphorylated E1α subunit of PDH, which inhibits enzyme activity. Blocking E1α phosphorylation activated PDH and reduced intracellular lactate concentrations. In addition, overexpressing wild-type LonP1 in the siblings' fibroblasts down-regulated phosphoE1α. Furthermore, in vitro studies demonstrated that purified LonP1-P761L failed to degrade phosphorylated E1α, in contrast to wild-type LonP1. We propose a novel mechanism whereby homozygous expression of the LonP1-P761L variant leads to PDH deficiency and energy metabolism dysfunction, which promotes severe neurologic impairment and neurodegeneration.

Paediatric atypical choroid plexus papilloma: is adjuvant therapy necessary?

INTRODUCTION: Choroid Plexus Tumours (CPTs) account for 1-4% of all brain tumours in children. Atypical choroid plexus papillomas (aCPPs) are a subset of these tumours, defined over a decade ago, yet no consensus exists on the optimal approach to their management. METHODS: We conducted a retrospective analysis of all patients treated for CPTs at the Hospital for Sick Children between January 1, 2000, and December 31, 2018, and focused on patients with aCPP. Data extracted from the patient records for analysis included: demographic and clinical features, radiological imaging, surgical and adjuvant therapies, key pathological features, immunohistochemical staining for TP53 and tumour karyotype. Six of seven aCPP samples were profiled using Illumina HumanMethylationEPIC arrays and the top 10,000 most variably methylated probes were visualized using tSNE. Copy number inferencing was also performed. RESULTS: Twenty-nine patients were diagnosed with CPT, seven of whom had a diagnosis of aCPP as confirmed by histological review. Methylation profiling demonstrated that aCPPs clustered with both choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). Complete resection of the tumour was pursued in all cases of aCPP and no patient received adjuvant therapy. All aCPP patients were alive at last follow up. CONCLUSIONS: This limited case series suggests that paediatric aCPP can be successfully managed with surgical resection alone, followed by a 'watch and wait' approach thus avoiding adjuvant therapies. A deeper understanding of the biology of aCPP is required to identify objective markers which can help provide robust risk stratification and inform treatment strategies.

Chronic traumatic encephalopathy neuropathology might not be inexorably progressive or unique to repetitive neurotrauma.

In the 20th century, chronic traumatic encephalopathy (CTE) was conceptualized as a neurological disorder affecting some active and retired boxers who had tremendous exposure to neurotrauma. In recent years, the two research groups in the USA who have led the field have asserted definitively that CTE is a delayed-onset and progressive neurodegenerative disease, with symptoms appearing in midlife or decades after exposure. Between 2005 and 2012 autopsy cases of former boxers and American football players described neuropathology attributed to CTE that was broad and diverse. This pathology, resulting from multiple causes, was aggregated and referred to, in toto, as the pathology 'characteristic' of CTE. Preliminary consensus criteria for defining the neuropathology of CTE were forged in 2015 and published in 2016. Most of the macroscopic and microscopic neuropathological findings described as characteristic of CTE, in studies published before 2016, were not included in the new criteria for defining the pathology. In the past few years, there has been steadily emerging evidence that the neuropathology described as unique to CTE may not be unique. CTE pathology has been described in individuals with no known participation in collision or contact sports and no known exposure to repetitive neurotrauma. This pathology has been reported in individuals with substance abuse, temporal lobe epilepsy, amyotrophic lateral sclerosis, multiple system atrophy, and other neurodegenerative diseases. Moreover, throughout history, some clinical cases have been described as not being progressive, and there is now evidence that CTE neuropathology might not be progressive in some individuals. Considering the current state of knowledge, including the absence of a series of validated sensitive and specific biomarkers, CTE pathology might not be inexorably progressive or specific to those who have experienced repetitive neurotrauma.

DNA damage as a marker of brain damage in individuals with history of concussions.

Mild traumatic brain injury (mTBI) is common in many populations, including athletes, veterans, and domestic abuse victims. mTBI can cause chronic symptoms, including depression, irritability, memory problems, and attention deficits. A history of repetitive mTBI has been epidemiologically associated with developing early-onset dementia and neurodegenerative diseases and, in particular, is thought to be the underlying cause of chronic traumatic encephalopathy (CTE)-a progressive tauopathy diagnosed by the presence of perivascular hyperphosphorylated tau protein (p-tau) in the depths of cortical sulci. However, the scarce and focal pathology often seen in CTE does not correlate with the severity of symptoms experienced by patients. This paper proposes accumulation of γH2AX, a marker of double-stranded DNA damage, as a novel pathological marker to identify brain damage post-mTBI. We present two cases of men with history of mTBI. Immunohistochemistry revealed extensive DNA damage throughout the frontal cortex, hippocampus, and brainstem areas. Furthermore, gene expression profiling showed increases of ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2), two serine/threonine kinases recruited in response to double-strand breaks in the DNA damage response pathway. These cases highlight the complex pathophysiology of head trauma, and suggest DNA damage as the molecular mechanism behind mTBI-induced pathology and symptoms.

Clinical Predictors at Diagnosis of Low-Risk Histopathology in Unilateral Advanced Retinoblastoma.

PURPOSE: Attempted eye salvage for unilateral (cT2b/group D) retinoblastoma may risk tumor spread compared with primary enucleation. Identification of clinical features predictive of low histopathologic risk support safe trial salvage. DESIGN: Retrospective, noncomparative single-institutional observational case series. PARTICIPANTS: Children with unilateral cT2b/group D retinoblastoma managed with primary enucleation at the Hospital for Sick Children, Toronto, Canada, January 2008 through February 2018. METHODS: Data included clinical features (intraocular pressure, optic nerve obscuration, macular involvement, tumor seeding, and serous retinal detachment [RD] >1 quadrant), timing to enucleation, histopathologic features, and follow-up. MAIN OUTCOME MEASURES: Primary outcome was low-risk (LR; pT1/pT2) versus high-risk (HR; pT3/pT4) histopathologic features with clinicopathologic correlations. Secondary outcomes were positive predictive (probability that certain clinical features would predict LR histopathologic features) and negative predictive values (probability that absence of these clinical features would predict HR histopathologic features). RESULTS: Thirty-eight eyes were eligible and showed vitreous seeding and normal intraocular pressure. The median diagnosis to enucleation interval was 4 days (range, 0-14 days). Histopathologic analysis diagnosed 4 (10.5%) HR and 34 (89.5%) LR eyes. High-risk eyes demonstrated massive choroidal invasion (4/38) or trans-scleral, extraocular, and postlaminar optic nerve invasion (1/38). Clinical findings included macular involvement (31/38), complete optic nerve obscuration (27/38), and RD (28/38). The proportion of eyes with HR histopathologic features was 13% (4/31; 95% confidence interval [CI], 1%-25%) with macular involvement, 15% (4/27; 95% CI, 1%-28%) with complete optic nerve obscuration, and 14% (4/28; 95% CI, 1%-27%) with RD. The predictability of LR histopathologic features was 100% with macular sparing (7/7; 95% CI, 47%-100%), optic nerve visibility (10/10; 95% CI, 63%-100%), and less than 1 quadrant of RD (10/10; 95% CI, 63%-100%). In 1 child lacking all 3 clinical LR predictive features with HR histopathologic features (pT3a), metastases developed and the patient died; other children are alive and well (mean follow-up, 65 months). CONCLUSIONS: Presence of macular sparing, optic nerve visibility, less than 1 quadrant of RD, or a combination thereof predicted LR histopathologic features at primary enucleation, suggesting safe trial eye salvage. No clinical sign predicted HR histopathologic features.

Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum.

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.

Intraosseous schwannoma of the occipital bone: a case report.

OBJECT: Intraosseous schwanomma of the calvarium METHODS: This paper reports the case of a 7-year-old boy who presented with an intraosseous schwanomma involving the occipital bone and provides a brief overview of the literature. RESULTS: The patient presented with a mass in the midline occipital region. Neuroimaging revealed a lytic lesion in the occipital bone with lack of enhancement on gadolinium MRI sequences. A gross total resection was performed, and histopathological analysis confirmed the diagnosis of schwannoma. CONCLUSION: Intraosseous schwanomma should be considered in the differential diagnosis of skull vault lesions in the pediatric population and can be successfully managed with surgical excision.

Microscopic and macroscopic infarct complicating pediatric epilepsy surgery.

OBJECTIVE: There is some suggestion that microscopic infarct could be associated with invasive monitoring, but it is unclear if the microscopic infarct is also visible on imaging and associated with neurologic deficits. The aims of this study were to assess the rates of microscopic and macroscopic infarct and other major complications of pediatric epilepsy surgery, and to determine if these complications were higher following invasive monitoring. METHODS: We reviewed the epilepsy surgery data from a tertiary pediatric center, and collected data on microscopic infarct on histology and macroscopic infarct on postoperative computed tomography (CT) or magnetic resonance imaging (MRI) done one day after surgery and major complications. RESULTS: Three hundred fifty-two patients underwent surgical resection and there was one death. Forty-two percent had invasive monitoring. Thirty patients (9%) had microscopic infarct. Univariable analyses showed that microscopic infarct was higher among patients with invasive monitoring relative to no invasive monitoring (20% vs. 0.5%, respectively, p < 0.001). Eighteen patients (5%) had macroscopic infarct on CT or MRI. Univariable analysis showed no significant difference in macroscopic infarct between invasive monitoring and no invasive monitoring (8% vs. 3%, respectively, p = 0.085). One patient with microscopic infarct had transient right hemiparesis, and two with both macroscopic and microscopic infarct had unexpected persistent neurologic deficits. Thirty-two major complications (9.1%) were reported, with no difference in major complications between invasive monitoring and no invasive monitoring (10% vs. 7%, p = 0.446). In the multivariable analysis, invasive monitoring increased the odds of microscopic infarct (odds ratio [OR] 15.87, p = 0.009), but not macroscopic infarct (OR 2.6, p = 0.173) or major complications (OR 1.4, p = 0.500), after adjusting for age at surgery, sex, age at seizure onset, operative type, and operative location. SIGNIFICANCE: Microscopic infarct was associated with invasive monitoring, and none of the patients had permanent neurologic deficits. Macroscopic infarct was not associated with invasive monitoring, and two patients with macroscopic infarct had persistent neurologic deficits.

Minimal change multiple system atrophy: an aggressive variant?

BACKGROUND: Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus. METHODS: Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases. RESULTS: More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases. CONCLUSIONS: Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA. © 2015 International Parkinson and Movement Disorder Society.

Alimentary, my dear Watson? The challenges of enteric α-synuclein as a Parkinson's disease biomarker.

An accurate early diagnostic test for Parkinson's disease (PD) is a critical unmet need. Recently, independent groups using different histological techniques have reported that the presence of alpha-synuclein (α-syn) in colonic biopsy tissue is able to distinguish living patients with PD from those without the disease. In addition, a further study has suggested that the presence of α-syn in colonic biopsy tissue may be evident in early or even prodromal PD. However, several questions remain regarding the translation of these findings into using the assessment of α-syn deposition in the enteric nervous system as a diagnostic biomarker for prodromal PD. Here we address critical issues related to the location and quantification of enteric α-syn, detection of α-syn with currently available histological techniques, timing of detection of α-syn deposition, and, most crucially, whether enteric α-syn can distinguish those with PD from both healthy individuals and individuals with other related diseases. We conclude that, although enteric α-syn is a very exciting prospect, further studies will be vital to determine whether enteric α-syn deposition has the potential to be the biomarker for prodromal PD that the field so desperately seeks.

Brain pathology and symptoms linked to concussion history: beyond chronic traumatic encephalopathy.

Repeated head trauma acquired through sports injuries has been associated with the development of long-term disabling symptoms that negatively impact the quality of life. In this retrospective case series, 52 male former professional athletes involved in contact sports and with a history of multiple concussions were evaluated for chronic clinical symptoms and post-mortem neuropathological diagnoses. The clinical symptoms of 19 cases were examined in greater detail for symptom type, severity and duration. Information on neurological, psychiatric and physical symptoms, substance use profiles and concussion histories was obtained from the athletes' next of kin and assessed in relation to post-mortem neuropathological diagnoses. Cases were categorized into three different neuropathological groups: no major neuropathological findings, the presence of only chronic traumatic encephalopathy (CTE) and the diagnosis(es) of other neurodegenerative diseases. Age at death and the presence of DNA damage in the post-mortem brains were analysed for correlation with the clinical symptoms. In this case series, 14/52 (26.9%) cases (mean age 48.2 ± 11.4) had neuropathological evidence of low-stage/low-burden CTE. A total of 11/52 (21.2%) cases (mean age 38.7 ± 12.7) presented a similar profile and severity of behavioural symptoms to those with CTE, despite the lack of significant post-mortem neuropathological findings. A total of 27/52 (51.9%) cases (mean age 75.5 ± 8.7) presented with complex post-mortem neurodegenerative diagnoses, including Alzheimer's disease and other mixed pathologies, and clinical symptoms associated with language, memory and sensory dysfunction. The presence of DNA damage in the brain was found in all neuropathological groups, predominantly in the ependymal lining of ventricles, and phosphorylated histone H2AX staining was correlated with higher age at death (r = 0.59) and symptoms of language dysfunction (r = 0.56). Findings from our case series suggest that post-concussive symptoms are not driven by CTE. Our findings show that proteinopathies alone may not account for the complexity of the clinical manifestations and suggest the possibility of other drivers, such as DNA damage, as potentially useful markers of brain trauma. Broadening the search for biological markers that reflect the effects of brain injury, even when proteinopathy is not observed, and taking a symptom-driven approach are therefore advised.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Parkinson's disease, parkinsonism, and traumatic brain injury.

We review the relationship between traumatic brain injury (TBI) and the development of idiopathic Parkinson's disease (PD) or secondary parkinsonism. Limited by methodological issues such as recall bias and confounding risk factors, epidemiological studies on the association between TBI and idiopathic PD have so far yielded mixed results. While clinical reports describe parkinsonism - often with lesions in the substantia nigra - secondary to traumatic brain injury, these do not represent cases of idiopathic PD. In laboratory studies, animal models of traumatic brain injury demonstrate neuronal loss in the substantia nigra, altered dopaminergic metabolism, or altered synuclein pathology. While parkinsonism does occur secondary to TBI, the relationship between TBI and subsequent idiopathic PD remains controversial.

Semiquantitative proteomic analysis of human hippocampal tissues from Alzheimer's disease and age-matched control brains.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia affecting people over 65 years of age. The hallmarks of AD are the extracellular deposits known as amyloid ß plaques and the intracellular neurofibrillary tangles, both of which are the principal players involved in synaptic loss and neuronal cell death. Tau protein and Aß fragment 1-42 have been investigated so far in cerebrospinal fluid as a potential AD biomarkers. However, an urgent need to identify novel biomarkers which will capture disease in the early stages and with better specificity remains. High-throughput proteomic and pathway analysis of hippocampal tissue provides a valuable source of disease-related proteins and biomarker candidates, since it represents one of the earliest affected brain regions in AD. RESULTS: In this study 2954 proteins were identified (with at least 2 peptides for 1203 proteins) from both control and AD brain tissues. Overall, 204 proteins were exclusively detected in AD and 600 proteins in control samples. Comparing AD and control exclusive proteins with cerebrospinal fluid (CSF) literature-based proteome, 40 out of 204 AD related proteins and 106 out of 600 control related proteins were also present in CSF. As most of these proteins were extracellular/secretory origin, we consider them as a potential source of candidate biomarkers that need to be further studied and verified in CSF samples. CONCLUSIONS: Our semiquantitative proteomic analysis provides one of the largest human hippocampal proteome databases. The lists of AD and control related proteins represent a panel of proteins potentially involved in AD pathogenesis and could also serve as prospective AD diagnostic biomarkers.

Clinicopathological review of pallidonigroluysian atrophy.

Pallidonigroluysian atrophy is a rare neurodegenerative disease characterized by degeneration of the globus pallidus, substantia nigra, and subthalamic nucleus. Few studies have comprehensively documented the clinical and pathological features of pallidonigroluysian atrophy. A systematic review of all published cases of pallidonigroluysian atrophy in English since 1970 was performed. We also report a new case of pallidonigroluysian atrophy. Twenty-five cases of pathologically proven pallidonigroluysian atrophy were reviewed, 24 from the literature and 1 of our own. Average age of onset was 54.3 ± 14.3 years, and average duration of disease was 7.9 ± 5.8 years. The most common first symptom was gait or balance disturbance. Patients had a diversity of movement disorders, including chorea in 5 cases (20%). Nine cases (36%) had coexistent motor neuron disease. Almost all cases had gliosis, and many cases had iron-positive pigments in the pallidonigroluysian system. Tauopathy was absent to rare in this region. Widespread tau-negative, p62-positive glial inclusions, described in 1 previous case, were also present in our patient. As pallidonigroluysian atrophy has a diversity of clinical presentations, it is best defined neuropathologically. The relative lack of tauopathy and the presence of p62-positive glial inclusions or iron-positive pigments in the pallidonigroluysian region may help to distinguish pallidonigroluysian atrophy from similar disease entities.

The pathological potential of ependymal cells in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a common neurological condition affecting millions of individuals worldwide. Although the pathology of mTBI is not fully understood, ependymal cells present a promising approach for studying the pathogenesis of mTBI. Previous studies have revealed that DNA damage in the form of γH2AX accumulates in ependymal cells following mTBI, with evidence of widespread cellular senescence in the brain. Ependymal ciliary dysfunction has also been observed, leading to altered cerebrospinal fluid homeostasis. Even though ependymal cells have not been extensively studied in the context of mTBI, these observations reflect the pathological potential of ependymal cells that may underlie the neuropathological and clinical presentations of mTBI. This mini review explores the molecular and structural alterations that have been reported in ependymal cells following mTBI, as well as the potential pathological mechanisms mediated by ependymal cells that may contribute to overall dysfunction of the brain post-mTBI. Specifically, we address the topics of DNA damage-induced cellular senescence, dysregulation of cerebrospinal fluid homeostasis, and the consequences of impaired ependymal cell barriers. Moreover, we highlight potential ependymal cell-based therapies for the treatment of mTBI, with a focus on neurogenesis, ependymal cell repair, and modulation of senescence signaling pathways. Further insight and research in this field will help to establish the role of ependymal cells in the pathogenesis of mTBI and may lead to improved treatments that leverage ependymal cells to target the origins of mTBI pathology.

BRCA1 heterozygosity promotes DNA damage-induced senescence in a sex-specific manner following repeated mild traumatic brain injury.

Emerging evidence suggests cellular senescence, as a consequence of excess DNA damage and deficient repair, to be a driver of brain dysfunction following repeated mild traumatic brain injury (rmTBI). This study aimed to further investigate the role of deficient DNA repair, specifically BRCA1-related repair, on DNA damage-induced senescence. BRCA1, a repair protein involved in maintaining genomic integrity with multiple roles in the central nervous system, was previously reported to be significantly downregulated in post-mortem brains with a history of rmTBI. Here we examined the effects of impaired BRCA1-related repair on DNA damage-induced senescence and outcomes 1-week post-rmTBI using mice with a heterozygous knockout for BRCA1 in a sex-segregated manner. Altered BRCA1 repair with rmTBI resulted in altered anxiety-related behaviours in males and females using elevated zero maze and contextual fear conditioning. Evaluating molecular markers associated with DNA damage signalling and senescence-related pathways revealed sex-specific differences attributed to BRCA1, where females exhibited elevated DNA damage, impaired DNA damage signalling, and dampened senescence onset compared to males. Overall, the results from this study highlight sex-specific consequences of aberrant DNA repair on outcomes post-injury, and further support a need to develop sex-specific treatments following rmTBI.