Journal of Neuropathology & Experimental Neurology:
In This Issue
An Important Glioma Gene
This is a timely review by Dr Horbinski of BRAF gene alterations in low-grade gliomas. Recently, there has been a burst of literature on the subject, and this review puts it all in comfortable perspective.
see page 2
Essential Tremor Followed by Progressive Supranuclear Palsy
Eleven of 89 patients with long-standing essential tremor (ET) eventually developed either parkinsonism or dementia; all 11 received postmortem diagnoses of progressive supranuclear palsy (PSP). This finding raises questions of whether there is an association between ET and PSP, whether ET patients are at an increased risk of developing PSP, and what proportion of ET patients with presumed Parkinson or Alzheimer disease actually has PSP.
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Oxidative Stress and the Friends It Keaps
Oxidative stress induces cytoprotective products via alteration of the Kelch-like ECH-associated protein 1 (Keap1) and NF-E2-related factor 2 (Nrf2) systems. Tanji et al examined these systems in Alzheimer disease, dementia with Lewy Bodies, Parkinson disease, and amyotrophic lateral sclerosis cases. They found that Keap1 coimmunoprecipitated with the Nrf2 system target p62 in diseased and control brains, and that Keap1 colocalized with p62 in cytoplasmic inclusions in affected CNS tissues in these diseases. Their findings suggest a molecular basis for stress response in the formation of cytoplasmic inclusions in numerous neurodegenerative conditions.
see page 18
EBV and MS Inflammatory Cortical Lesions
Magliozzi et al investigated brain samples from 44 cases of secondary progressive MS (multiple sclerosis) for evidence of EBV (Epstein-Barr virus) infection in infiltrated cortical lesions, most of which had adjacent ectopic meningeal B-cell follicles. They found evidence for EBV infection and cytotoxic activity toward EBV-infected plasma cells in these lesions. Their results suggest that both meningeal and intraparenchymal inflammation may contribute to cortical damage during MS progression, and that intracortical inflammation could be sustained by an EBV-driven immunopathologic response.
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Myelin Lipid Abnormalities in Diffusely Abnormal White Matter (DAWM) in MS
Factors in addition to classic white matter plaques contribute to clinical dysfunction and progression in MS patients. Laule et al correlated postmortem magnetic resonance imaging and histologic and immunohistochemical data on 14 formalin-fixed MS brain samples and determined that DAWM shows prominent reductions in staining for myelin phospholipids. They suggest that there is a major lipid abnormality in DAWM, which exceeds protein loss and is accompanied by axonal degeneration, and that it may be important in MS pathogenesis and progression.
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Synaptic Proteins and Choline Acetyltransferase Loss in Visual Cortex in Dementia With Lewy Bodies
The authors report lower levels of synaptic proteins and choline acetyltransferase in the primary and association visual cortex in patients with dementia with Lewy bodies compared with those in aged control and Alzheimer disease subjects. These findings may be related to changes in functional neuroimaging within the occipital lobe in patients with dementia with Lewy bodies.
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PDGFRA Gain in Low-Grade Diffuse Gliomas
Glioblastomas show amplification of different receptor tyrosine kinase genes (e.g. PDGFRA, MET, EGFR) in different tumor cells within single tumors. Motomura et al report PDGFRA gain in 27 of 166 diffuse astrocytomas, most of which showed IDH1/2 mutations and/or PDGFRA gain. Mean survival of diffuse astrocytoma patients with PDGFRA gain was similar to those with IDH1/2 or TP53 mutations but longer than those with MET gain. The PDGFRA and MET were typically amplified in different tumor cell populations, but tumor cells with coamplification were also focally observed, suggesting intratumoral heterogeneity in these low-grade astrocytomas.
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Neuropathology of Pol-III Disorder
Pol-III–related leukodystrophies are a recently recognized group of leukodystrophies that include the 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism). Vanderver et al report the clinical, neuroimaging, and neuropathologic findings of a patient affected by 4H syndrome with POLR3A mutations. Despite a uniformly hypomyelinating pattern seen on imaging, neuropathologic examination reveals a complex heterogeneous leukodystrophy with prominent neuro-axonal and glial involvement; the pathogenesis of these disorders remains to be elucidated.
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