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Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions (NCI), glial inclusions (GI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN), surviving neurons, abnormally enlarged neurons (EN), and vacuoles in regions of the frontal and temporal lobe.
Changes in density of histological features across cortical gyri were studied in ten sporadic cases of FTLD-TDP using quantitative methods and polynomial curve-fitting.
Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, NCI, DN, and vacuolation were abundant in the upper laminae and GI, NII, EN, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases, their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated.
Laminar distribution of pathological features in ten sporadic cases of FTLD-TDL is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feed-forward and feed-back cortico-cortical connections may be compromised in FTLD-TDP.
PMCID: PMC3504185  PMID: 22804696
Frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP); FTLD with ubiquitin-positive inclusions (FTLD-U); Transactive response TAR DNA-binding protein of 43 kDa (TDP-43); Neuronal cytoplasmic inclusions (NCI); Laminar distribution
2.  Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities 
The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data however are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development.
We investigated the dorsal anterior cingulate cortex (dACC) in 13 males with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neuron and glial numbers, and glia/neuron (GNI) ratios in both layers II-III and V-VI.
We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neuron numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development.
Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post-mortem histopathological studies and in vivo brain imaging findings in patients.
PMCID: PMC3508088  PMID: 22860626
dysmyelination; oligodendrocytes; white matter; morphology; cytoarchitecture; myelin
3.  Altered expression and splicing of Ca2+ metabolism genes in myotonic dystrophies DM1 and DM2 
Neuropathology and applied neurobiology  2013;39(4):10.1111/j.1365-2990.2012.01289.x.
Myotonic dystrophy types 1 and 2 (DM1 and DM2) are multisystem disorders caused by similar repeat expansion mutations, with similar yet distinct clinical features. Aberrant splicing of multiple effector genes, as well as dysregulation of transcription and translation, have been suggested to underlie different aspects of the complex phenotypes in DM1 and DM2. Ca2+ plays a central role in both muscle contraction and control of gene expression, and recent expression profiling studies have indicated major perturbations of the Ca2+ signaling pathways in DM. Here we have further investigated the expression of genes and proteins involved in Ca2+ metabolism in DM patients, including Ca2+ channels and Ca2+ binding proteins.
We used patient muscle biopsies to analyze mRNA expression and splicing of genes by microarray expression profiling and RT-PCR. We studied protein expression by immunohistochemistry and immunoblotting.
Most of the genes studied showed mRNA up-regulation in expression profiling. When analyzed by immunohistochemistry the Ca2+ release channel ryanodine receptor was reduced in DM1 and DM2, as was calsequestrin 2, a sarcoplasmic reticulum lumen Ca2+ storage protein. Abnormal splicing of ATP2A1 was more pronounced in DM2 than DM1.
We observed abnormal mRNA and protein expression in DM affecting several proteins involved in Ca2+ metabolism, with some differences between DM1 and DM2. Our protein expression studies are suggestive of a post-transcriptional defect(s) in the myotonic dystrophies.
PMCID: PMC3882430  PMID: 22758909
Myotonic dystrophy type 1 (DM1); myotonic dystrophy type 2 (DM2); skeletal muscle; calcium metabolism
4.  Non-amyloid and amyloid prion protein deposits in prion-infected mice differ in blockage of interstitial brain fluid 
Prion diseases are characterized by brain deposits of misfolded aggregated protease-resistant prion protein (PrP), termed PrPres. In humans and animals, PrPres is found as either disorganized non-amyloid aggregates or organized amyloid fibrils. Both PrPres forms are found in extracellular spaces of the brain. Thus, both might block drainage of brain interstitial fluid (ISF). The present experiments studied whether ISF blockage occurred during amyloid and/or non-amyloid prion diseases.
Various-sized fluorescein-labeled ISF tracers were stereotactically inoculated into the striatum of adult mice. At times from 5 min to 77 hours, uninfected and scrapie-infected mice were compared. C57BL/10 mice expressing wild-type anchored PrP, which develop non-amyloid PrPres similar to humans with sporadic CJD, were compared with Tg44+/+ mice expressing anchorless PrP, which develop amyloid PrPres similar to certain human familial prion diseases.
In C57BL/10 mice, extensive non-amyloid PrPres aggregate deposition was not associated with abnormal clearance kinetics of tracers. In contrast, scrapie-infected Tg44+/+ mice showed blockage of tracer clearance and co-localization of tracer with perivascular PrPres amyloid.
Since tracer localization and clearance was normal in infected C57BL/10 mice, ISF blockage was not an important pathogenic mechanism in this model. Therefore, ISF blockage is unlikely to be a problem in non-amyloid human prion diseases such as sporadic CJD. In contrast, partial ISF blockage appeared to be a possible pathogenic mechanism in Tg44+/+ mice. Thus this mechanism might also influence human amyloid prion diseases where expression of anchorless or mutated PrP results in perivascular amyloid PrPres deposition and cerebral amyloid angiopathy (CAA).
PMCID: PMC3567241  PMID: 22998478
brain interstitial fluid; cerebral amyloid angiopathy; prion; glycophosphatidylinositol anchor; basement membrane
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelination of white matter, loss of myelin forming oligodendrocytes, changes in the blood-brain-barrier (BBB), and leukocyte infiltration. Myelin basic protein (MBP) is a component of the myelin sheath. Degradation of myelin is believed to be an important step that leads to MS pathology. Transmigration of leukocytes across the vasculature, and a compromised BBB participate in the neuroinflammation of MS. We examined the expression and regulation of the chemokine CCL2 and the cytokine IL-6 in human endothelial cells (EC), a component of the BBB, after treatment with MBP.
EC were treated with full length MBP. CCL2 and IL-6 protein were determined by ELISA. Western blot analysis was used to determine signaling pathways. A BBB model was treated with MBP and permeability was assayed using albumin conjugated to Evan’s blue dye. The levels of the tight junction proteins occludin and claudin-1, and matrix metalloprotease (MMP)-2 were assayed by Western blot.
MBP significantly induced CCL2 and IL-6 protein from EC. This induction was partially mediated by the p38 MAPK pathway as there was phosphorylation after MBP treatment. MBP treatment of a BBB model caused an increase in permeability that correlated with a decrease in occludin and claudin-1, and an induction of MMP-2.
These data demonstrate that MBP induces chemotactic and inflammatory mediators. MBP also alters BBB permeability and tight junction expression, indicating additional factors that may contribute to the BBB breakdown characteristic of MS.
PMCID: PMC3430818  PMID: 22524708
MBP; MMP2; IL-6; CCL2; EAE; blood-brain-barrier; MS
6.  Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation 
Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the coordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioral response following peripheral infection. With normal aging, however, microglia develop a more inflammatory phenotype. For instance, in several models of aging there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with aging is referred to as primed, reactive, or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in aging has behavioral and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared to adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behavior, depressive-like behavior and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits.
PMCID: PMC3553257  PMID: 23039106
Brain; Microglia; Aging; Inflammation; Behavior
7.  Microglia in protein aggregation disorders: friend or foe? 
Microglia cells have been implicated, to some extent, in the pathogenesis of all of the common neurodegenerative disorders involving protein aggregation such as Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. However, the precise role they play in the development of the pathologies remains unclear and it seems that they contribute to the pathological process in different ways depending on the specific disorder. A better understanding of their varied roles is essential if they are to be the target for novel therapeutic strategies.
PMCID: PMC3580295  PMID: 23339288
Microglia; protein aggregates neuroinflammation; cytokines; neurotoxicity; Alzheimer’s; Parkinson’s; ALS
8.  Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer’s disease 
Activated microglia overexpressing interleukin-1 (IL-1) are prominent neuropathological features of Alzheimer’s disease. We used computerized image analysis to determine the number of IL-1α-immunoreactive (IL-1α+) microglia in cytoarchitectonic layers of parahippocampal gyrus (Brodmann’s area 28) of Alzheimer and control patients. For cortical layers I and II, the numbers of IL-1α+ microglia were similar in Alzheimer and control patients. For layers III–VI, the numbers of IL-1α+ microglia were higher than that seen in layers I–II for both Alzheimer and control patients. Moreover, for layers III–VI, the number of IL-1α+ microglia in Alzheimer patients was significantly greater than that in control patients (relative Alzheimer values of threefold for layer III–V and twofold for layer VI; P<0.05 in each case). The cortical laminar distribution of IL-1α+ microglia in Alzheimer patients correlated with the cortical laminar distribution of β-amyloid precursor protein-immunoreactive (β-APP+) neuritic plaques found in Alzheimer patients (r=0.99, P<0.005). Moreover, the cortical laminar distribution of IL-1α+ microglia in control patients also correlated with the cortical laminar distribution of β-APP+ neuritic plaques found in Alzheimer patients (r=0.91, P<0.05). These correlations suggest that pre-existing laminar distribution patterns of IL-1α+ microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of β-APP+ neuritic plaques in Alzheimer patients. These findings provide further support for our hypothesis that IL-1 is a key driving force in neuritic plaque formation in Alzheimer’s disease.
PMCID: PMC3833591  PMID: 9775393
Alzheimer’s disease; β-amyloid precursor protein; cerebral cortical layers; interleukin-1; microglia
9.  Nuclear Carrier and RNA Binding Proteins in Frontotemporal Lobar Degeneration associated with Fused in Sarcoma (FUS) pathological changes 
Neuropathology and applied neurobiology  2012;10.1111/j.1365-2990.2012.01274.x.
We aimed to investigate the role of the nuclear carrier and binding proteins, transportin-1 (TRN1) and transportin-2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing’s Sarcoma protein (EWS) in inclusion body formation in cases of Frontotemporal Lobar Degeneration (FTLD) associated with Fused in Sarcoma protein (FTLD-FUS).
Eight cases of FTLD-FUS (5 cases of atypical FTLD-U (aFTLD-U), 2 of Neuronal Intermediate Filament Inclusion Body Disease (NIFID) and 1 of Basophilic Inclusion Body Disease (BIBD)) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. 10 cases of FTLD associated with TDP-43 inclusions served as reference cases.
The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD.
Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.
PMCID: PMC3479345  PMID: 22497712
Frontotemporal Lobar degeneration; Fused in Sarcoma; TDP-43; transportins; TATA-binding protein-associated factor 15; Ewing’s sarcoma protein
10.  Human brain weight is correlated with expression of the ‘housekeeping genes’ beta-2-microglobulin (β2M) and TATA-binding protein (TBP) 
Many variables affect mRNA measurements in post mortem human brain tissue. Brain weight has not hitherto been considered to be such a factor. This study investigated whether there is any relationship between brain weight and mRNA abundance.
We investigated quantitative real-time RT-PCR data for five ‘housekeeping genes’ using the 104 adult brains of the Stanley Microarray Consortium series. Eleven datasets were analysed, from cerebellum, hippocampus, and anterior cingulate cortex. We used a specified sequence of correlations, partial correlations, and multiple regression analyses.
Brain weight correlated with the ‘raw’ (i.e. non-normalised) data for two mRNAs, β2-microglobulin (β2M) and TATA-binding protein (TBP), measured in cerebellum and hippocampus respectively. In hippocampus, the geometric mean of three housekeeping gene transcripts also correlated with brain weight. The correlations were significant after adjusting for age, sex and other confounders, and the effect of brain weight was confirmed using multiple regression. No correlations with brain weight were seen in the anterior cingulate cortex, nor for the other mRNAs examined.
The findings were not anticipated; they need replication in another brain series, and a more systematic survey is indicated. In the interim, we suggest that quantitative gene expression studies in human brain should inspect for a potential influence of brain weight, especially since the affected transcripts are commonly used as reference genes for normalisation purposes in studies of neurological and psychiatric disorders. The relationship of brain weight with β2M mRNA may reflect the roles of MHC class I genes in synapse formation and plasticity.
PMCID: PMC3789120  PMID: 20831744
Brain size; Gene expression; Messenger RNA; Schizophrenia, Real-time PCR
The pathology of Alzheimers's disease (AD) is characterized by the presence of amyloid plaques (APs), neurofibrillary tangles (NFTs), degenerating neurons, and an abundance of reactive astrocytes and microglia. We aim to examine the association between glia maturation factor (GMF) expression, activated astrocytes/microglia, APs, and NFTs in AD affected brain regions.
Brain sections were stained with Thioflavin-S to study AD pathology and sequentially immunolabeled with antibodies against GMF, glial fibrillary acidic protein (GFAP, marker for reactive astrocytes), and Ionized calcium binding adaptor molecule 1 (Iba1, marker for activated microglia) followed by visualization with avidin-biotin peroxidase complex.
Our double immunofluorescence labeling with cell-specific markers demonstrated the glial localization of GMF. The immunohistochemical data showed that APs and NFTs are associated with increased expression of GMF in reactive glia of AD brains compared to non-AD controls.
This is the first report that shows GMF, a mediator of CNS inflammation, is expressed in the brain regions affected in AD and that GMF is mainly localized in reactive astrocytes surrounding APs/NFTs. The distribution of GMF-immunoreactive cells in and around Thioflavin-S stained APs and NFTs suggests involvement of GMF in inflammatory responses through reactive glia and a role of GMF in AD pathology.
PMCID: PMC3290752  PMID: 22035352
Glia maturation factor (GMF); Alzheimer's disease (AD); Neuropathology; Neuroinflammation; Reactive glia; Amyloid plaques (APs); Neurofibrillary tangles (NFTs); Tau-protein
12.  Activation status of integrated stress response pathways in neurones and astrocytes of HIV-associated neurocognitive disorders (HAND) cortex 
Combined anti-retroviral therapy (cART) has led to a reduction in the incidence of HIV-associated dementia (HAD), a severe motor/cognitive disorder afflicting HIV(+) patients. However, the prevalence of subtler forms of neurocognitive dysfunction, which together with HAD are termed HIV-associated neurocognitive disorders (HAND), continues to escalate in the post-cART era. The microgliosis, astrogliosis, dendritic damage, and synaptic and neuronal loss observed in autopsy cases suggest an underlying neuroinflammatory process, due to the neurotoxic factors released by HIV-infected/activated macrophages/ microglia in the brain, might underlie the pathogenesis of HAND in the post-cART era. These factors are known to induce the integrated stress response (ISR) in several neurodegenerative diseases; we have previously shown that BiP, an indicator of general ISR activation, is upregulated in cortical autopsy tissue from HIV-infected patients. The ISR is composed of three pathways, each with its own initiator protein: PERK, IRE1α and ATF6.
To further elucidate the specific ISR pathways activated in the central nervous system of HAND patients, we examined the protein levels of several ISR proteins, including ATF6, peIF2α and ATF4, in cortical tissue from HIV-infected patients.
The ISR does not respond in an all-or-none fashion in HAND, but rather demonstrates a nuanced activation pattern. Specifically, our studies implicate the ATF6 pathway of the ISR as a more likely candidate than the PERK pathway for increases in BiP levels in astrocytes.
These findings begin to characterize the nature of the ISR response in HAND and provide potential targets for therapeutic intervention in this disease.
PMCID: PMC3708539  PMID: 21883374
astrocyte; ATF6; ER stress response; HAND; HIV; neurone
13.  Insights Gained from Modeling High-Grade Glioma in the Mouse 
High grade gliomas (HGG) are devastating primary brain tumors with universally poor prognoses. Advances toward effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumor initiation, progression, and phenotype, the influence of tumor microenviroment, and the analysis of cell types that can give rise to glioma. HGGs are a highly heterogeneous group of tumors, and the complexity of diverse mutations within common signaling pathways as well as the developmental and cell-type context of transformation contribute to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely approximate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing.
PMCID: PMC3312987  PMID: 22035336
14.  Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to REM sleep behaviour disorder 
Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during REM sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurons in a neighbouring nucleus, the locus coeruleus (LC).
This retrospective study, utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 AD and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurons of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry.
Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD.
Whether decreases in brainstem cholinergic neurons in LBD contribute to RBD is uncertain, but our findings indicate these neurons are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.
PMCID: PMC3218297  PMID: 21696423
α-synuclein; cholinergic; Lewy body; laterodorsal tegmentum; locus coeruleus; pedunculopontine nucleus; REM behaviour disorder; tau
15.  S100β as a novel and accessible indicator for the presence of monocyte-driven encephalitis in AIDS 
The pathogenesis of HIV/SIV encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood brain barrier. Heretofore, it has not been possible to easily determine if an individual has HIVE/SIVE before post mortem examination.
We have examined serum levels of the astroglial protein S100β in SIV-infected macaques and show that it can be used to determine which animals will have SIVE. We also checked for correlations with inflammatory markers such as CCL2/ MCP-1, IL-6 and C Reactive Protein (CRP).
We also found that increased S100β protein in serum correlated with decreased expression of the tight junction protein zonula occludens-1 on brain microvessels. Further, the decrease in zonula occludens-1 expression was spatially related to SIVE lesions and perivascular deposition of plasma fibrinogen. There was no correlation between encephalitis and plasma levels of IL-6, MCP-1/CCL2 or CRP.
Together these data indicate that SIVE lesions are associated with vascular leakage that can be monitored by S100β protein in the periphery. The ability to simply monitor the development of SIVE will greatly facilitate studies of the neuropathogenesis of AIDS.
PMCID: PMC3234337  PMID: 21696421
16.  Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival 
Atypical (WHO grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Postoperative radiotherapy (RT) may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array CGH to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumors show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample.
86 completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow up was obtained. Utilizing a dual-colour interphase FISH assay, 1q gain was assessed using BAC probes directed against 1q25.1 and 1q32.1.
The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas.
These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.
PMCID: PMC3563294  PMID: 21988727
meningioma; atypical; pathology; classification; genetics
To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP).
We quantified the neuronal cytoplasmic inclusions (NCI), glial inclusions (GI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN), surviving neurons, abnormally enlarged neurons (EN), and vacuoles in regions of the frontal and temporal lobe using a phosphorylation independent TDP-43 antibody in thirty-two cases of FTLD-TDP comprising sporadic and familial cases, with associated pathology such as hippocampal sclerosis (HS) or Alzheimer’s disease (AD), and four neuropathological subtypes using TDP-43 immunohistochemistry. Analysis of variance (ANOVA) was used to compare differences between the various groups of cases.
These data from FTLD-TDP cases demonstrate quantitative differences in pathological features between: (1) regions of the frontal and temporal lobe, (2) upper and lower cortex, (3) sporadic and progranulin (GRN) mutation cases, (4) cases with and without AD or HS, and (5) between assigned subtypes.
The data confirm that the dentate gyrus is a major site of neuropathology in FTLD-TDP and that most laminae of the cerebral cortex are affected. GRN mutation cases are quantitatively different from sporadic cases while cases with associated HS and AD have increased densities of dystrophic neurites (DN) and abnormally enlarged neurons (EN) respectively. There is little correlation between the subjective assessment of subtypes and the more objective quantitative data.
PMCID: PMC3206199  PMID: 21696412
Frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP); Density; Neuronal cytoplasmic inclusions (NCI); Neuronal intranuclear inclusion (NII)
18.  Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates 
Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal, and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging (MRI) usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum (CSP), signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces, and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology, and pathogenesis of CTE and Alzheimer’s disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP, and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia.
PMCID: PMC3166385  PMID: 21696410
chronic traumatic encephalopathy; traumatic brain injuries; boxing; contact sports; Alzheimer’s disease; frontotemporal dementia; amyotrophic lateral sclerosis
19.  Intravenous Administration of Human ES-derived Neural Precursor Cells Attenuates Cuprizone-induced CNS Demyelination 
Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination.
C57Bl/6 mice were fed cuprizone (0.2%) for two weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional two weeks of dietary cuprizone treatment, CNS tissues were analyzed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC).
Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES-NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, GFAP. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC-treated mice.
These findings indicated that systemically-administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and (c) the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells.
PMCID: PMC3252213  PMID: 21276029
embryonic stem cell; microglia; demyelination; differentiation; oligodendrocyte
20.  A case of Gerstmann-Sträussler-Scheinker disease with a novel six octapeptide repeat insertion 
PMCID: PMC3135713  PMID: 21426368
Amyloid; Gerstmann-Sträussler-Scheinker (GSS) disease; Neuropathology; Octapeptide repeat insertion (OPRI); Prion protein
21.  Cannabinoid Receptor Expression in HIV Encephalitis and HIV-associated Neuropathologic Comorbidities 
Cannabinoids have been proposed for treating various neurodegenerative disorders and as adjunct therapy for HIV+ patients with neurologic sequelae. The expression of cannabinoid receptors (CB1 and CB2) has been reported in neurodegenerative diseases and in SIV encephalitis, yet the receptor expression in the CNS of HIV+ individuals is not known.
An anti-CB1 antibody and two anti-CB2 antibodies were employed for immunohistochemistry in the cerebral cortex and white matter of HIV encephalitis (HIVE) and HIV-associated comorbidities, as well as control brains (HIV− and HIV+).
By quantitative image analysis, we observed that CB1 was increased in HIVE brains and those with comorbidities, while CB2 was significantly increased in the white matter of HIVE. Morphologically, CB1 was present in neurons, and both CB1 and CB2 were present in meningeal macrophages and subpial glia in all brains. In HIVE, CB1 was found in white matter microglia and perivascular cells, while CB2 was increased in microglia, astrocytes and perivascular macrophages. Double immunofluorescence with cell-specific markers and immunoblots on primary cultured microglia and astrocytes substantiated the glial localization of the cannabinoid receptors and specificity of the antibodies.
Our study indicates that cannabinoid receptor expression occurs in glia in HIVE brains, and this may have ramifications for the potential use of cannabinoid ligands in HIV-infected patients.
PMCID: PMC3135748  PMID: 21450051
cannabinoid receptor; human; inflammation; microglia; astrocytes; immunohistochemistry
22.  The neurobiology of varicella zoster virus infection 
Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to 1-3 dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death, and the development of an animal model provided by simian varicella virus infection of monkeys.
PMCID: PMC3176736  PMID: 21342215
VZV; neurological disease; latency; apoptosis; animal model
23.  Subcortical TDP-43 pathology occurs infrequently in multiple system atrophy 
Aims and Methods
The α-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological TDP-43 or FUS aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients.
TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe structures and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions.
The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter α-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α-synuclein mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43.
PMCID: PMC3030620  PMID: 20942898
Multiple system atrophy; 43-kDa transactivating responsive sequence DNA-binding protein
24.  Granulovacuolar Degeneration Bodies of Alzheimer’s Disease Resemble Late-stage Autophagic Organelles 
Granulovacuolar degeneration involves the accumulation of large, double membrane-bound bodies within certain neurons during the course of Alzheimer’s disease and other adultonset dementias. Because of the two-layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalled in Alzheimer’s disease.
Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for GVD bodies, was evaluated in hippocampal sections prepared from postmortem Braak stage IV and V Alzheimer’s disease cases using double-label confocal fluorescence microscopy.
GVD bodies colocalized weakly with early-stage autophagy markers LC3 and p62, but strongly with late-stage marker LAMP1 (lysosome-associated membrane protein 1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with CHMP2B (charged multivesicular body protein 2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D.
The resultant immunohistochemical signature suggests that GVD bodies contain late-stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. . The data further suggest that failure to complete autolysosome formation may be an important correlate of GVD body accumulation.
PMCID: PMC3037976  PMID: 20946470
Alzheimer’s disease; granulovacuolar degeneration; autophagy; endocytosis; lysosome
25.  Review: Cerebral microvascular pathology in aging and neurodegeneration 
This review of age-related brain microvascular pathologies focuses on topics studied by this laboratory, including anatomy of the blood supply, tortuous vessels, venous collagenosis, capillary remnants, vascular density, and microembolic brain injury. Our studies feature thick sections, large blocks embedded in celloidin, and vascular staining by alkaline phosphatase (AP). This permits study of the vascular network in three dimensions, and the differentiation of afferent from efferent vessels. Current evidence suggests that there is decreased vascular density in aging, Alzheimer’s disease (AD), and leukoaraiosis (LA), and cerebrovascular dysfunction precedes and accompanies cognitive dysfunction and neurodegeneration. A decline in cerebrovascular angiogenesis may inhibit recovery from hypoxia-induced capillary loss. Cerebral blood flow (CBF) is inhibited by tortuous arterioles and deposition of excessive collagen in veins and venules. Misery perfusion due to capillary loss appears to occur before cell loss in LA, and CBF is also reduced in the normal-appearing white matter. Hypoperfusion occurs early in AD, inducing white matter lesions and correlating with dementia. In vascular dementia, cholinergic reductions are correlated with cognitive impairment, and cholinesterase inhibitors have some benefit. Most lipid microemboli from cardiac surgery pass through the brain in a few days, but some remain for weeks. They can cause what appears to be a type of vascular dementia years after surgery. Donepezil has shown some benefit. Emboli, such as clots, cholesterol crystals, and microspheres can be extruded through the walls of cerebral vessels, but there is no evidence yet that lipid emboli undergo such extravasation.
PMCID: PMC3020267  PMID: 20946471
Alzheimer’s disease; Vascular dementia; Leukoaraiosis; Tortuous vessels; Capillary loss; String vessels; Periventricular venous collagenosis; Cerebrovascular lipid emboli

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