PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer\u27s disease.

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer\u27s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition

NHERF1/EBP50 is an organizer of polarity structures and a diagnostic marker in ependymoma

NHERF1/EBP50, an adaptor protein required for epithelial morphogenesis, has been implicated in the progression of various human malignancies. NHERF1-deficient mice have intestinal brush border structural defects and we report here that they also have disorganized ependymal cilia with development of non-obstructive hydrocephalus. Examination of mouse and human brain tissues revealed highest NHERF1 expression at the apical plasma membrane of ependymal cells. In ependymal tumors, NHERF1 expression was retained in polarized membrane structures, such as microlumens, rosettes and canals, where it co-localized with some of its ligands, such as moesin and PTEN. Analysis of a comprehensive panel of 113 tumors showed robust NHERF1 labeling of microlumens in 100% of ependymomas, subependymomas, and pediatric anaplastic ependymomas, and in 67% of adult anaplastic ependymomas. NHERF1 staining was present in 35% of ependymoma cases that lacked reactivity for EMA, the routine immunohistochemical marker used for ependymoma diagnosis. NHERF1 labeling of microlumens was either absent or rarely seen in other types of brain tumors analyzed, denoting NHERF1 as a reliable diagnostic marker of ependymal tumors. Anaplastic foci and a subset of adult anaplastic ependymomas showed complete absence of NHERF1-labeled polarity structures, consistent with a loss of differentiation in these aggressive tumors. These data highlight a role for NHERF1 in ependymal morphogenesis with direct application to the diagnosis of ependymal tumors. Keywords: NHERF1/EBP50 Ependymoma Hydrocephalus Polarity Moesin PTE

Angiocentric glioma mimicking encephalomalacia

Angiocentric glioma is a rare low-grade neoplasm of the central nervous system which typically presents with medication-refractory seizures in children and young adults. On magnetic resonance imaging, angiocentric glioma is classically T1 hypointense and T2/FLAIR hyperintense. We present the case of a 40-year-old male who had been followed by our institution for 17 years for management of epilepsy. Initial and repeat brain imaging showed an apparent region of cystic encephalomalacia in the right frontal lobe. In an attempt to control his seizures, the lesion was resected. Grossly, the cut surface of the specimen was characterized by multiple small cystic spaces. Microscopically, the lesion was composed of an infiltrative population of glial cells variably arranged in perivascular “pseudorosettes,” nodules, and subpial “palisades.” The final diagnosis was angiocentric glioma. This is the second reported case of an angiocentric glioma mistaken for encephalomalacia. Keywords: Angiocentric glioma, Encephalomalacia, Seizures, Low-grade gliom

Cerebral Amyloid Angiopathy Presenting with Synchronous Bilateral Intracerebral Macrohemorrhages

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid proteins in the cerebrovasculature, which can lead to intracerebral hemorrhage. Intracerebral hemorrhage in CAA often presents with microhemorrhages and, less frequently, with more devastating macrohemorrhages. We present a case of CAA-related synchronous bilateral intracerebral macrohemorrhage which, to our knowledge, has yet to be reported in the literature, and postulate its relationship to antiplatelet therapy and transient elevations in blood pressure

LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases

Autophagic vacuolar cardiomyopathy is an underrecognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ-induced and colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use 3 cases of CQ-induced or HCQ-induced cardiomyopathy and 1 HCQ-treated control case to show that the same two markers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ-induced or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosed patients, thus increasing the likelihood of favorable clinical outcomes

LC3 and p62 as Diagnostic Markers of Drug-induced Autophagic Vacuolar Cardiomyopathy

Autophagic vacuolar cardiomyopathy is an under recognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for  malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic  markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ- and  colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use three cases of CQ- or HCQ-induced cardiomyopathy and one HCQ-treated control case to show that the same twomarkers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ- or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosedpatients, thus increasing the likelihood of favorable clinical outcomes

LC3 and p62 as Diagnostic Markers of Drug-induced Autophagic Vacuolar Cardiomyopathy

Autophagic vacuolar cardiomyopathy is an under recognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for  malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic  markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ- and  colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use three cases of CQ- or HCQ-induced cardiomyopathy and one HCQ-treated control case to show that the same twomarkers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ- or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosedpatients, thus increasing the likelihood of favorable clinical outcomes

Distinctive MRI Features of Pediatric Medulloblastoma Subtypes

OBJECTIVE: We hypothesized that the apparent diffusion coefficient (ADC) and other MRI features can be used to predict medulloblastoma histologic subtypes, as defined by the World Health Organization (WHO) in WHO Classification of Tumours of the Central Nervous System. MATERIALS AND METHODS: A retrospective review of pediatric patients with medulloblastoma between 1989 and 2011 identified 38 patients with both pretreatment MRI and original pathology slides. The mean and minimum tumor ADC values and conventional MRI features were compared among medulloblastoma histologic subtypes. RESULTS: The cohort of 38 patients included the following histologic subtypes: 24 classic medulloblastomas, nine large cell (LC) or anaplastic medulloblastomas, four desmoplastic medulloblastomas, and one medulloblastoma with extensive nodularity. The median age at diagnosis was 8 years (range, 1-21 years) and the median follow-up time was 33 months (range, 0-150 months). The mean ADC (× 10(-3) mm(2)/s) was lower in classic medulloblastoma (0.733 ± 0.046 [SD]) than in LC or anaplastic medulloblastoma (0.935 ± 0.127) (Mann-Whitney test, p = 0.004). Similarly, the minimum ADC was lower in classic medulloblastoma (average ± SD, 0.464 ± 0.056) than in LC or anaplastic medulloblastoma (0.630 ± 0.053) (p = 0.004). The MRI finding of focal cysts correlated with the classic and desmoplastic subtypes (Fisher exact test, p = 0.026). Leptomeningeal enhancement positively correlated with the LC or anaplastic medulloblastoma subtype and inversely correlated with the classic medulloblastoma and desmoplastic medulloblastoma subtypes (p = 0.04). Ring enhancement correlated with tumor necrosis (p = 0.022) and with the LC or anaplastic medulloblastoma histologic subtype (p \u3c 0.001). CONCLUSION:The LC or anaplastic medulloblastoma subtype was associated with increased ADC and with ring enhancement, the latter of which correlated with tumor necrosis. These features could be considered in the evaluation of high-risk medulloblastoma subtypes