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1.  Postmortem Magnetic Resonance Imaging to Guide the Pathological Cut: Individualized, 3D-Printed Cutting Boxes for Fixed Brains 
Interfacing magnetic resonance imaging (MRI) and pathology is critically important for understanding the pathological basis of MRI signal changes in vivo and for clinicopathological correlations. Postmortem MRI is an intermediate step in this process; unfortunately, however, relating the data to standard pathological sections, which are relatively thick and often non-parallel, is both time consuming and insufficiently accurate. The aim of this project was to develop technology to integrate postmortem, high-resolution, whole-brain MRI into the planning and execution of the pathological analysis through precise localization of the target and coordinates of cut. Compared to standard pathological sectioning, the use of an individualized 3D-printed cutting-box, designed based on postmortem MRI of formalin-fixed whole brains, improved the speed, quality, and accuracy of radiological-pathological correlation and, specifically, the histopathological localization of imaging findings. The technology described herein is easily implemented, applicable to any brain disorder, and potentially extendable to other organs. From the point of view of the pathologist this technique can improve localization of small or subtle abnormalities, whereas from the point of view of the radiologist it has the potential to improve understanding of MRI signal changes observed in disease.
doi:10.1097/NEN.0000000000000096
PMCID: PMC4144036  PMID: 25007244
Cutting-box; High-resolution; Postmortem MRI; Pathological-MRI correlations
2.  mNos2 Deletion and Human NOS2 Replacement in Alzheimer Disease Models 
Understanding the pathophysiological mechanisms underlying Alzheimer disease (AD) relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic AD-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide (NO) levels produced by immune activation of the NOS2 gene. Using the APPSwDI+/+/mNos2−/− (CVN-AD) mouse strain, we show a sequence of pathological events leading to neurodegeneration that include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, the early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable in AD and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed to CVN-AD mice, pathological characteristics of this new strain (APPSwDI+/−/huNOS2t +/+g/mNos2−/−) mimicked the pathological phenotypes found in the CVN-AD strain.
doi:10.1097/NEN.0000000000000094
PMCID: PMC4131941  PMID: 25003233
Alzheimer disease; Magnetic resonance spectroscopy; Mouse model; Neuronal loss; NOS2; tau pathology
3.  Conditional Overexpression of Insulin-Like Growth Factor-1 Enhances Hippocampal Neurogenesis and Restores Immature Neuron Dendritic Processes After Traumatic Brain Injury 
Traumatic brain injury (TBI) is associated with neuronal damage or death in the hippocampus, a region critical for cognitive function. Immature neurons within the hippocampal neurogenic niche are particularly susceptible to TBI. Therapeutic strategies that protect immature hippocampal neurons or enhance post-traumatic neurogenesis may be advantageous for promoting functional recovery after TBI. Insulin-like growth factor-1 (IGF-1) promotes neurogenesis in the adult brain, but its effects on neurogenesis after TBI are unknown. We used an astrocyte-specific conditional IGF-1-overexpressing mouse model to supplement IGF-1 in regions of neuronal damage and reactive astrocytosis following controlled cortical impact injury. Although early loss of immature neurons was not significantly attenuated, overexpression of IGF-1 resulted in a marked increase in immature neuron density in the subgranular zone at 10 days post-injury. This delayed increase appeared to be driven by enhanced neuron differentiation rather than increased cellular proliferation. In wild type mice, dendrites of immature neurons exhibited significant decreases in total length and numbers of bifurcations at 10 days post-injury vs. neurons in sham-injured mice. In contrast, the morphology of immature neuron dendrites in brain-injured IGF-1-overexpressing mice was equivalent to that in sham controls. These data provide compelling evidence that IGF-1 promotes neurogenesis following TBI.
doi:10.1097/NEN.0000000000000092
PMCID: PMC4102886  PMID: 25003234
Cellular proliferation; Controlled cortical impact; Dendrites; Doublecortin; Hippocampus; IGF-1; Neuronal differentiation; Traumatic brain injury
4.  Lack of Neuropathy-Related Phenotypes in Hint1 Knockout Mice 
Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that involves primarily motor dysfunction and is usually associated with neuromyotonia, i.e. prolonged muscle contraction resulting from hyperexcitability of the peripheral nerve. Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 were normal in appearance and in behavioral tests or motor performance, although they moved slower and for a smaller fraction of time than wild-type (WT) mice in an open field arena. Muscles, neuromuscular junctions, and nodes of Ranvier are anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at 4 and 13 months of age. Axons were slightly smaller than those in WT mice at 4 months of age, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. Using electromyography, we were unable to detect neuromyotonia, even using supra-physiological stimuli and stressors such as reduced temperature or 3,4 diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia.
doi:10.1097/NEN.0000000000000085
PMCID: PMC4098130  PMID: 24918641
Animal model; Axon degeneration; Charcot-Marie-Tooth disease; Histidine triad nucleotide-binding protein 1; HINT1; Neuromyotonia
5.  Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations 
Supplemental digital content is available in the text.
Abstract
Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6–8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.
doi:10.1097/NEN.0000000000000209
PMCID: PMC4470523  PMID: 26083569
Mitochondrial disease; Pontocerebellar hypoplasia type 6; RARS2; Respiratory chain deficiency
6.  KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas 
Abstract
Up to 20% of patients with pilocytic astrocytoma (PA) experience a poor outcome. BRAF alterations and Fibroblast growth factor receptor 1 (FGFR1) point mutations are key molecular alterations in Pas, but their clinical implications are not established. We aimed to determine the frequency and prognostic role of these alterations in a cohort of 69 patients with PAs. We assessed KIAA1549:BRAF fusion by fluorescence in situ hybridization and BRAF (exon 15) mutations by capillary sequencing. In addition, FGFR1 expression was analyzed using immunohistochemistry, and this was compared with gene amplification and hotspot mutations (exons 12 and 14) assessed by fluorescence in situ hybridization and capillary sequencing. KIAA1549:BRAF fusion was identified in almost 60% of cases. Two tumors harbored mutated BRAF. Despite high FGFR1 expression overall, no cases had FGFR1 amplifications. Three cases harbored a FGFR1 p.K656E point mutation. No correlation was observed between BRAF and FGFR1 alterations. The cases were predominantly pediatric (87%), and no statistical differences were observed in molecular alterations–related patient ages. In summary, we confirmed the high frequency of KIAA1549:BRAF fusion in PAs and its association with a better outcome. Oncogenic mutations of FGFR1, although rare, occurred in a subset of patients with worse outcome. These molecular alterations may constitute alternative targets for novel clinical approaches, when radical surgical resection is unachievable.
doi:10.1097/NEN.0000000000000213
PMCID: PMC4470527  PMID: 26083571
BRAF; Brain tumor; FGFR1; Glioma; Molecular diagnosis; Pilocytic astrocytoma; Prognosis
7.  Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a post mortem study 
Natalizumab, a monoclonal antibody directed against α4 integrins, has to date been associated with 377 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Due to the limited number of histological studies, the interplay between MS and PML lesions has not been investigated.
We report the clinical, radiological and histological findings of a MS patient who developed PML after 32 months of natalizumab monotherapy. Following withdrawal of natalizumab, she received plasma exchange, mefloquine and mirtazapine, but passed away soon thereafter. Post mortem studies were restricted to examination of the brain and spinal cord.
Extensive PML lesions, characterized by the presence of JCV DNA were found in the cerebral white matter and neocortex. Sharply demarcated areas of active PML lesions contained prominent inflammatory infiltrates composed of approximately equal numbers of CD4+ and CD8+ T cells, consistent with an immune reconstitution inflammatory syndrome (IRIS). Conversely, all MS lesions identified were hypocellular, long-standing inactive plaques characterized by myelin loss, relative axonal preservation, and gliosis, and importantly, were devoid of JCV-DNA and active inflammation.
Chronic inactive MS lesions were separate and distinct from nearby PML lesions. Furthermore, IRIS greatly affected the shape and appearance of PML lesions but did not involve MS lesions.
doi:10.1097/NEN.0000000000000005
PMCID: PMC4465443  PMID: 24128680
Multiple sclerosis; JC virus; Progressive Multifocal Leukoencephalopathy; natalizumab; immune reconstitution inflammatory syndrome
8.  Oligodendrocyte Loss Over the Disease Course in the Canine Model of the Lysosomal Storage Disease Fucosidosis 
Hypomyelination is a poorly understood feature of many neurodegenerative lysosomal storage diseases including fucosidosis in children and animals. To gain insight into hypomyelination in fucosidosis, we investigated lysosomal storage, oligodendrocyte death, and axonal and neuron loss in central nervous system tissues of fucosidosis-affected dogs aged 3 weeks to 42 months using immunohistochemistry, electron microscopy and gene expression assays. Vacuole accumulation in fucosidosis oligodendrocytes commenced by 5 weeks age; all oligodendrocytes were affected by 16 weeks. Despite progressive vacuolation, mature oligodendrocyte loss by apoptosis (caspase-6 positive) in the corpus callosum and cerebellar white matter stabilized by 16 weeks with no further subsequent loss. Axonal neurofilament loss progressed, however, suggesting that disturbed axon-oligodendrocyte interactions are unlikely to be the primary cause of hypomyelination. A 67% decline in Purkinje cell layer oligodendrocyte numbers coincided with a 67% increase in caspase-6-positive Purkinje cells at 16 weeks suggesting that early oligodendrocyte loss contributes to Purkinje cell apoptosis. Fucosidosis hypomyelination appeared to follow normal spatiotemporal patterns of myelination with greater loss of oligodendrocytes and larger downregulation of CNP, MAL and PLP1 genes at 16 weeks in cerebellum vs. the frontal cortex. These studies suggest that survival of oligodendrocytes in fucosidosis is limited during active myelination although the mechanisms remain unknown.
doi:10.1097/NEN.0000000000000075
PMCID: PMC4117195  PMID: 24806306
Apoptosis; Fucosidosis; Hypomyelination; Lysosomal storage disease; Oligodendrocytes
9.  Ischemia-Reperfusion Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus 
Information is limited regarding the effects of injury on neovascularization in the immature brain. We investigated effects of ischemia on cerebral cortical neovascularization after exposure of fetuses to 30 minutes of cerebral ischemia and 48- (I/R-48) or 72- (I/R-72) hours of reperfusion or sham-control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortical sections included immunostaining for glial fibrillary acidic protein and collagen type IV (Coll IV), a molecular component of the vascular basal lamina, to determine the glial-vascular network in fetal brains, and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non-I/R fetuses. Cell bodies of reactive, proliferating astrocytes along with large end-feet surrounded walls of cerebral cortical microvessels in addition to the thick Coll IV-enriched basal lamina. Morphometric analysis of Non-I/R with I/R-48 and I/R-72 groups revealed increased Coll IV density in I/R-72 cerebral cortical microvessels (p < 0.01), which also frequently displayed a sprouting appearance, characterized by growing tip cells and activated pericytes. Increases in cerebral cortical basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization occurs within 72 hours after ischemia in fetal cerebral cortices.
doi:10.1097/NEN.0000000000000071
PMCID: PMC4122327  PMID: 24806298
Cerebral cortex; Fetus; Ischemia-reperfusion; Neovascularization; Ovine; Sheep
10.  Targeting Vascular Amyloid in Arterioles of Alzheimer Disease Transgenic Mice with Amyloid Beta Protein Antibody-Coated Nanoparticles 
The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that utilizes a monoclonal antibody against fibrillar human amyloid-β42 that is surface-coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) following infusion into the external carotid artery using 3 different approaches. The first 2 approaches utilize a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits utilizing confocal laser scanning microscopy. The third approach utilized high field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles (MIONs) following infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.
doi:10.1097/NEN.0b013e318225038c
PMCID: PMC4428546  PMID: 21760540
Alzheimer disease; Cerebral amyloid angiopathy; Cerebrovascular amyloid; Immunotargeted nanoparticles; Confocal laser scanning microscopy; Magnetic resonance imaging
11.  A Novel GRN Mutation (GRN c.708+6_+9delTGAG) in Frontotemporal Lobar Degeneration with TDP-43-positive Inclusions: Clinicopathologic Report of 6 Cases 
Understanding of frontotemporal lobar degeneration (FTLD), the underlying pathology that is most often linked to the clinical diagnosis of frontotemporal dementia (FTD), is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and rarely TARDBP and FUS) are associated with FTD and the pathologic classification of FTLD has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to one quarter of FTLD cases with TAR DNA-binding protein 43-positive inclusions (FTLD-TDP); there currently are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings of 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.
doi:10.1097/NEN.0000000000000070
PMCID: PMC4109801  PMID: 24709683
Dementia; Familial FTD; FTLD-TDP; GRN; Mutation; Progranulin
12.  Toll-Like Receptors and Ischemic Brain Injury 
Toll-like receptors (TLRs) are master regulators of innate immunity and play an integral role in the activation of the inflammatory response during infections. In addition, TLRs influence the body’s response to numerous forms of injury. Recent data have shown that TLRs play a modulating role in ischemic brain damage after stroke. Interestingly, their stimulation prior to ischemia induces a tolerant state that is neuroprotective. This phenomenon, referred to as TLR preconditioning, is the result of reprogramming of the TLR response to ischemic injury. This review addresses the role of TLRs in brain ischemia and the activation of endogenous neuroprotective pathways in the setting of preconditioning. We highlight the protective role of the interferon-related response and the potential site of action for TLR preconditioning involving the blood-brain-barrier. Pharmacological modulation of TLR activation to promote protection against stroke is a promising approach for the development of prophylactic and acute therapies targeting ischemic brain injury.
doi:10.1097/NEN.0000000000000068
PMCID: PMC4115675  PMID: 24709682
Cerebral ischemia; Ischemic brain injury; Preconditioning; Stroke; Toll-like receptors
13.  Blood-Brain Barrier Dysfunction and Cerebral Small Vessel Disease (Arteriolosclerosis) in Brains of Older People 
The blood-brain barrier (BBB) protects brain tissue from potentially harmful plasma components. Small vessel disease ([SVD], arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and IgG, which are assumed to reflect BBB dysfunction, in deep grey matter (anterior caudate-putamen, [DGM]) and deep subcortical white matter (DWM) in the brains of a well-characterized patient cohort with minimal Alzheimer disease pathology (Braak stage 0-II) (n = 84; age ≥65 years). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and IgG was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that in aged brains plasma extravasation and hence local BBB dysfunction is common but do not support an association with SVD.
doi:10.1097/NEN.0000000000000124
PMCID: PMC4209852  PMID: 25289893
Arteriolosclerosis; Blood-brain barrier; Dementia, Fibrinogen; Leukoaraiosis; Small vessel disease
14.  Age-related Brain Expression and Regulation of the Chemokine CCL4/MIP-1β in APP/PS1 Double Transgenic Mice 
The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease (AD). Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1 E9 (APP/PS1) double transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from non-transgenic littermates or single mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitation-quantitative PCR confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathological progression associated with amyloid deposition in AD.
doi:10.1097/NEN.0000000000000060
PMCID: PMC3977177  PMID: 24607962
Alzheimer disease; ATF3; CCL4/MIP-1β; Epigenetics; Neuroinflammation
15.  Neuronopathy in the Motor Neocortex in a Chronic Model of Multiple Sclerosis 
We provide evidence of cortical neuronopathy in myelin oligodendrocyte glycoprotein-peptid-induced experimental autoimmune encephalomyelitis, an established model of chronic multiple sclerosis (MS). To investigate phenotypic perturbations in neurons in this model, we used apoptotic markers and immunohistochemistry with antibodies to NeuN and other surrogate markers known to be expressed by adult pyramidal layer V somas, including annexin V, encephalopsin and Emx1. We found no consistent evidence of chronic loss of layer V neurons but detected both reversible and chronic decreases in the expression of these markers in conjunction with evidence of cortical demyelination and pre-synaptic loss. These phenotypic perturbations were present in but not restricted to neocortical layer V. We also investigated inflammatory responses in the cortex and subcortical white matter of the corpus callosum (CC) and spinal dorsal funiculus and found that those in the cortex and CC were delayed compared to those in the spinal cord. Inflammatory infiltrates initially included T cells, neutrophils and Iba1-positive microglia/macrophages in the CC, whereas only Iba1-positive cells were present in the cortex. These data indicate that we have identified a new temporal pattern of subtle, phenotypic perturbations in neocortical neurons in this chronic MS model.
doi:10.1097/NEN.0000000000000058
PMCID: PMC4229074  PMID: 24607968
Corticospinal neurons; Motor strip; Multiple sclerosis; Neuronopathy
16.  Drosha Inclusions Are New Components of Dipeptide-Repeat Protein Aggregates in FTLD-TDP and ALS C9orf72 Expansion Cases 
Supplemental digital content is available in the text.
Abstract
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are 2 neurodegenerative disorders that share clinical, genetic, and neuropathologic features. The presence of abnormal expansions of GGGGCC repeats (G4C2 repeats) in a noncoding region of the Chromosome 9 open reading frame 72 (C9orf72) gene is the major genetic cause of both FTLD and ALS. Transcribed G4C2 repeats can form nuclear RNA foci and recruit RNA-binding proteins, thereby inhibiting their normal function. Moreover, through a repeat-associated non-ATG translation mechanism, G4C2 repeats translation leads to dipeptide-repeat protein aggregation in the cytoplasm of neurons. Here, we identify Drosha protein as a new component of these dipeptide-repeat aggregates. In C9orf72 mutation cases of FTLD-TDP (c9FTLD-TDP) and ALS (c9ALS), but not in FTLD or ALS cases without C9orf72 mutation, Drosha is mislocalized to form neuronal cytoplasmic inclusions in the hippocampus, frontal cortex, and cerebellum. Further characterization of Drosha-positive neuronal cytoplasmic inclusions in the hippocampus, frontal cortex, and cerebellum revealed colocalization with p62 and ubiquilin-2, 2 pathognomonic signatures of c9FTLD-TDP and c9ALS cases; however, Drosha inclusions rarely colocalized with TDP-43 pathology. We conclude that Drosha may play a unique pathogenic role in the onset or progression of FTLD-TDP/ALS in patients with the C9orf72 mutation.
doi:10.1097/NEN.0000000000000182
PMCID: PMC4362478  PMID: 25756586
ALS; C9orf72; Dipeptide-repeat protein; Drosha; FTLD; TDP-43
17.  Arx is required for specification of the zona incerta and reticular nucleus of the thalamus 
Mutations in the aristaless-related homeobox (ARX) gene result in a spectrum of structural and functional nervous system disorders including lissencephaly, movement disorders, intellectual disabilities, and epilepsy. Some patients also have symptoms indicative of hypothalamic dysfunction, however, little is known about the role of ARX in diencephalic development. To begin evaluating diencephalic defects we examined the expression of a panel of known genes and gene products that label specific diencephalic nuclei in two different Arx mutant mouse lines. Male mice engineered to have a polyalanine expansion mutation (Arx(GCG)7/Y) revealed no expression differences in any diencephalic nucleus when compared to wildtype littermates. In contrast, mice null for Arx (Arx−/Y) lost expression of specific markers of the thalamic reticular nucleus (TRN) and zona incerta (ZI), while retaining expression in other thalamic nuclei and in the hypothalamus. Tyrosine hydroxylase, a marker of the ZI’s dopaminergic A13 sub-nucleus, was among those lost, suggesting a requirement for Arx in normal TRN and ZI development, and for A13 dopaminergic fate, specifically. Since the ZI and A13 regions make connections to several hypothalamic nuclei, such mis-specification may contribute to the “hypothalamic dysfunction” observed in some patients.
doi:10.1097/NEN.0000000000000048
PMCID: PMC4038102  PMID: 24487799
Arx; zona incerta; thalamic reticular nucleus; A13; dopaminergic fate; diencephalon
18.  Clinicopathological Outcomes of Prospectively Followed Normal Elderly Brain Bank Volunteers 
Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively-assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were female, median age of study entry was 83.5 years (range 67 to 99), and median duration from first visit until death was 4.3 years (range 0-10). At autopsy a clinico-neuropathological diagnosis was made in 30 cases (25%). Clinicopathological diagnoses included 20 (17%) with Alzheimer's disease (AD), 7 (6%) with vascular dementia, 4 (3%) with progressive supranuclear palsy, (1; 0.8%) with dementia with Lewy bodies, (1; 0.8%) with corticobasal degeneration and (1; 0.8%) with multiple system atrophy. Of those 87 subjects (73%) still clinically normal at death, 33 (38%) had extensive AD pathology (pre-clinical AD), 17 (20%) had incidental Lewy bodies and 4 (5%) had incidental pathology consistent with progressive supranuclear palsy. Diagnoses are not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.
doi:10.1097/NEN.0000000000000046
PMCID: PMC4066814  PMID: 24487796
Alzheimer's disease; progressive supranuclear palsy; vascular dementia; Parkinson's disease; dementia with Lewy bodies; pathology; epidemiology
19.  Visualization of HTLV-1–Specific Cytotoxic T Lymphocytes in the Spinal Cords of Patients With HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis 
Supplemental digital content is available in the text.
Abstract
Activated human T-lymphotropic virus type-1 (HTLV-1)–specific CD8-positive cytotoxic T lymphocytes (CTLs) are markedly increased in the periphery of patients with HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP), an HTLV-1–induced inflammatory disease of the CNS. Although virus-specific CTLs play a pivotal role to eliminate virus-infected cells, the potential role of HTLV-1–specific CTLs in the pathogenesis of HAM/TSP remains unclear. To address this issue, we evaluated the infiltration of HTLV-1–specific CTLs and the expression of HTLV-1 proteins in the spinal cords of 3 patients with HAM/TSP. Confocal laser scanning microscopy with our unique staining procedure made it possible to visualize HTLV-1–specific CTLs infiltrating the CNS of the HAM/TSP patients. The frequency of HTLV-1–specific CTLs was more than 20% of CD8-positive cells infiltrating the CNS. In addition, HTLV-1 proteins were detected in CD4-positive infiltrating T lymphocytes but not CNS resident cells. Although neurons were generally preserved, apoptotic oligodendrocytes were frequently in contact with CD8-positive cells; this likely resulted in demyelination. These findings suggest that the immune responses of the CTLs against HTLV-1–infected CD4-positive lymphocytes migrating into the CNS resulted in bystander neural damage.
doi:10.1097/NEN.0000000000000141
PMCID: PMC4336315  PMID: 25470342
Apoptosis; Cytotoxic T lymphocyte; Demyelination; HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP); Human T-lymphotropic virus type-1 (HTLV-1)
20.  Activated microglia mediate axo-glial disruption that contributes to axonal injury in multiple sclerosis 
The complex symptoms of chronic multiple sclerosis (MS) are due, in part, to widespread axonal pathology affecting lesioned and non-lesioned areas of the CNS. Here we describe an association between microglial activation and axon/ oligodendrocyte pathology at nodal and paranodal domains in normal appearing white matter (NAWM) of MS and experimental allergic encephalomyelitis (EAE). The extent of paranodal axo-glial (neurofascin-155+/Caspr1+) disruption correlated with the local degree of microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axo-glial alterations were seen in pre-symptomatic EAE, at a time-point characterised by microglia activation prior to the infiltration of immune cells. Disruption of the axo-glial unit in adjuvant immunised animals was reversible and coincided with the resolution of microglial inflammation, whereas paranodal damage and microglial inflammation persisted in chronic EAE. We were able to preserve axo-glial integrity by administering minocycline, which inhibited microglial activation, in actively immunised animals. Therefore, permanent disruption to axo-glial domains in an environment of microglial inflammation is an early indicator of axonal injury that would affect normal nerve conduction contributing to pathology outside of the demyelinated lesion.
doi:10.1097/NEN.0b013e3181f3a5b1
PMCID: PMC4335193  PMID: 20838243
Axon; demyelination; multiple sclerosis; neuroinflammation; neurofascin; sodium channel
21.  Cellular Mechanisms of Toll-Like Receptor-3 Activation in the Thalamus Are Associated With White Matter Injury in the Developing Brain 
Supplemental Digital Content is available in the text.
Abstract
Toll-like receptor-3 (TLR3) has been identified in a variety of intracellular structures (e.g. endosomes and endoplasmic reticulum); it detects viral molecular patterns and damage-associated molecular patterns. We hypothesized that, after white matter injury (WMI) has occurred, localization and activation of TLR3 are altered in gray matter structures in response to damage-associated molecular patterns and activated glia. Therefore, we investigated the subcellular localization of TLR3 and its downstream signaling pathway in postmortem brain sections from preterm infants with and without WMI (7 patients each). We assessed astroglia (glial fibrillary acidic protein–positive), microglia (ionized calcium-binding adaptor molecule-1–positive), and neuronal populations in 3 regions of the thalamus and in the posterior limb of the internal capsule and analyzed TLR3 messenger RNA and protein expression in the ventral lateral posterior thalamic region, an area associated with impaired motor function. We also assessed TLR3 colocalization with late endosomes (lysosome-associated membrane protein-1) and phagosomal compartments in this region. Glial fibrillary acidic protein, ionized calcium-binding adaptor molecule-1, and TLR3 immunoreactivity and messenger RNA expression were increased in cases with WMI compared with controls. In ventral lateral posterior neurons, TLR3 was colocalized with the endoplasmic reticulum and the autophagosome, suggesting that autophagy may be a stress response associated with WMI. Thus, alterations in TLR3 expression in WMI may be an underlying molecular mechanism associated with impaired development in preterm infants.
doi:10.1097/NEN.0000000000000172
PMCID: PMC4327391  PMID: 25668563
Interferon regulatory factor-3; Microtubule-associated protein light chain; Toll-like receptor-3; White matter injury
22.  Components of Myelin Damage and Repair in the Progression of White Matter Pathology After Mild Traumatic Brain Injury 
Abstract
White matter tracts are highly vulnerable to damage from impact-acceleration forces of traumatic brain injury (TBI). Mild TBI is characterized by a low density of traumatic axonal injury, whereas associated myelin pathology is relatively unexplored. We examined the progression of white matter pathology in mice after mild TBI with traumatic axonal injury localized in the corpus callosum. Adult mice received a closed-skull impact and were analyzed from 3 days to 6 weeks post-TBI/sham surgery. At all times post-TBI, electron microscopy revealed degenerating axons distributed among intact fibers in the corpus callosum. Intact axons exhibited significant demyelination at 3 days followed by evidence of remyelination at 1 week. Accordingly, bromodeoxyuridine pulse-chase labeling demonstrated the generation of new oligodendrocytes, identified by myelin proteolipid protein messenger RNA expression, at 3 days post-TBI. Overall oligodendrocyte populations, identified by immunohistochemical staining for CC1 and/or glutathione S-transferase pi, were similar between TBI and sham mice by 2 weeks. Excessively long myelin figures, similar to redundant myelin sheaths, were a significant feature at all post-TBI time points. At 6 weeks post-TBI, microglial activation and astrogliosis were localized to areas of axon and myelin pathology. These studies show that demyelination, remyelination, and excessive myelin are components of white matter degeneration and recovery in mild TBI with traumatic axonal injury.
doi:10.1097/NEN.0000000000000165
PMCID: PMC4327393  PMID: 25668562
Axon damage; Demyelination; Neuroinflammation; Oligodendrocyte; Redundant myelin; Remyelination; Traumatic axonal injury
23.  Reduction in Serum Aquaporin-4 Antibody Titers During Development of a Tumor-Like Brain Lesion in a Patient With Neuromyelitis Optica: A Serum Antibody–Consuming Effect? 
Abstract
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a “serum antibody–consuming effect” during lesion formation.
doi:10.1097/NEN.0000000000000173
PMCID: PMC4327561  PMID: 25668569
Aquaporin-4; Brain biopsy; Multiple sclerosis; Neuromyelitis optica; Serum level; Tumor-like lesion
24.  Serotonin Metabolites in the Cerebrospinal Fluid in the Sudden Infant Death Syndrome: In Search of a Biomarker of Risk 
Clinical biomarkers are urgently needed in the sudden infant death syndrome (SIDS) to identify living infants at risk because it because it occurs without occurs without clinical warning. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. Here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared to autopsy controls, as a first step towards their assessment as diagnostic biomarkers of medullary pathology. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high performance liquid chromatography in 57 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude use of 5-HIAA, HVA, Trp or Tyr measurements as CSF biomarkers of 5-HT medullary pathology in infants at risk. They provide, however, important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS.
doi:10.1097/NEN.0000000000000034
PMCID: PMC4287961  PMID: 24423636
5-hydroxyindoleacetic acid; brainstem; dopamine; high performance liquid chromatography; postmortem interval; tryptophan; tyrosine
25.  Neuropathologic Heterogeneity Does Not Impair Florbetapir-PET Postmortem Correlates 
Neuropathologic heterogeneity is often present within Alzheimer’s disease (AD). We sought to determine if amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinicopathologically-defined AD and 17 non-demented cases (ND) with quantitative florbetapir F-18 (18F-AV-45) PET imaging during life and histological β-amyloid quantification and neuropathologic examination were assessed. AD cases were divided on the basis of concurrent pathologies, including those with Lewy bodies (N=21), white matter rarefaction (N=27), severe cerebral amyloid angiopathy (N=11), argyrophilic grains (N=5) and TDP-43 inclusions (N=18). Many cases exhibited more than one type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in six cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p values <0.001). All AD subgroups had significantly greater amyloid measures compared to ND, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with Lewy bodies had significantly decreased SUVr measures compared to AD cases without (p = 0.002); there were no other paired comparison differences. These findings indicate florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
doi:10.1097/NEN.0000000000000028
PMCID: PMC4037918  PMID: 24335535
argyrophilic grains; autopsy; cerebral amyloid angiopathy; Lewy bodies; plaques; TDP-43; vascular dementia; white matter; leuko-araiosis

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