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1.  High expression of the stem cell marker nestin is an adverse prognostic factor in WHO grade II-III astrocytomas and oligoastrocytomas 
Journal of neuro-oncology  2014;117(1):183-189.
Infiltrating astrocytomas and oligoastrocytomas of low to anaplastic grade (WHO grades II and III), in spite of being associated with a wide range of clinical outcomes, can be difficult to subclassify and grade by the current histopathologic criteria. Unlike oligodendrogliomas and anaplastic oligodendrogliomas that can be identified by the 1p/19q codeletion and the more malignant glioblastomas (WHO grade IV astrocytomas) that can be diagnosed solely based on objective features on routine hematoxylin and eosin sections, no such objective criteria exist for the subclassification of grade II-III astrocytomas and oligoastrocytomas (A+OA II-III). In this study, we evaluated the prognostic and predictive value of the stem cell marker nestin in adult A+OA II-III (n=50) using immunohistochemistry and computer-assisted analysis on tissue microarrays. In addition, the correlation between nestin mRNA level and total survival was analyzed in the NCI Rembrandt database. The results showed that high nestin expression is a strong adverse prognostic factor for total survival (p=0.0004). The strength of the correlation was comparable to but independent of the isocitrate dehydrogenase 1/2 (IDH 1/2) mutation status. Histopathological grading and subclassification did not correlate significantly with outcome, although the interpretation of this finding is limited by the fact that grade III tumors were treated more aggressively than grade II tumors. These results suggest that nestin level and IDH 1/2 mutation status are strong prognostic features in A+OA II-III and possibly more helpful for treatment planning than routine histopathological variables such as oligodendroglial component (astrocytoma vs. oligoastrocytoma) and WHO grade (grade II vs. III).
doi:10.1007/s11060-014-1376-7
PMCID: PMC4326086  PMID: 24519516
mixed glioma; outcome; prognosis; progression-free survival; low-grade gliomas; anaplastic gliomas
2.  Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene 
Background
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
Results
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Conclusions
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-38
PMCID: PMC4190282  PMID: 25239657
C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
3.  Hippocampal Sclerosis in Dementia, Epilepsy, and Ischemic Injury: Differential Vulnerability of Hippocampal Subfields 
Severe neuronal loss in the hippocampus, that is, hippocampal sclerosis (HS), can be seen in 3 main clinical contexts: dementia (particularly frontotemporal lobar degeneration [FTLD]), temporal lobe epilepsy (TLE), and hippocampal ischemic injury (H–I). It has been suggested that shared pathogenetic mechanisms may underlie selective vulnerability of the hippocampal subfields such as the CA1 in these conditions. We determined the extent of neuronal loss in cases of HS-FTLD (n = 14), HS-TLE (n = 35), and H–I (n = 20). Immunohistochemistry for zinc transporter 3 was used to help define the CA3/CA2 border in the routinely processed human autopsy tissue samples. The subiculum was involved in 57% of HS-FTLD, 10% of H–I, and 0% of HS-TLE cases (p < 0.0001). The CA regions other than CA1 were involved in 57% of HS-TLE, 30% of H–I, and 0% of HS-FTLD cases (p= 0.0003). The distal third of CA1 was involved in 79% of HS-FTLD, 35% of H–I, and 37% of HS-TLE cases (p = 0.02). The distal third of CA1 was the only area involved in 29% of HS-FTLD, 3% of HS-TLE, and 0% of H–I cases (p = 0.019). The proximal-middle CA1 was the only area affected in 50% of H–I, 29% of HS-TLE, and 0% of HS-FTLD cases (p = 0.004). These findings support heterogeneity in the pathogenesis of HS.
doi:10.1097/OPX.0000000000000170
PMCID: PMC4076969  PMID: 24423638
Brain ischemia; Frontotemporal dementia; Frontotemporal lobar degeneration; Hippocampal sclerosis; Mesial temporal sclerosis; Vascular dementia; ZNT3
4.  NHERF1/EBP50 Controls Morphogenesis of 3D Colonic Glands by Stabilizing PTEN and Ezrin-Radixin-Moesin Proteins at the Apical Membrane12 
Neoplasia (New York, N.Y.)  2014;16(4):365-374.e2.
Na+/H+ exchanger 3 regulating factor 1/ezrin-radixin-moesin (ERM)–binding phosphoprotein 50 (NHERF1/EBP50), an adaptor molecule that interacts with the ERM–neurofibromatosis type 2 family of cytoskeletal proteins through its ERM-binding region and with phosphatase and tensin homolog (PTEN) and β-catenin through its PDZ domains, has been recently implicated in the progression of various human malignancies, including colorectal cancer (CRC). We report here that NHERF1 controls gland morphogenesis, as demonstrated in three-dimensional (3D) human intestinal glands developing from a single nonpolarized cell. Starting from the early two-cell developmental stage, NHERF1 concentrates at the cellular interface in a central membrane disc that marks the apical pole delimiting the forming lumen. NHERF1 depletion leads to severe disruption of the apical-basal polarity, with formation of enlarged and distorted cell spheroids devoid of a central lumen. This characteristic and the increased number of mitoses in NHERF1-depleted spheroids, including multipolar ones, mimic high-grade dysplasia lesions observed in CRC progression. NHERF1 ERM-binding or PDZ-domain mutants fail to localize apically and impair gland formation most likely by outcompeting endogenous ligands, with the latter mutant completely aborting gland development. Examination of NHERF1 ligands showed that even if both ezrin and moesin colocalized with NHERF1 at the apical membrane, moesin but not ezrin depletion disrupted morphogenesis similarly to NHERF1. NHERF1 depletion resulted also in membrane displacement of PTEN and nuclear translocation of β-catenin, events contributing to polarity loss and increased proliferation. These findings reveal an essential role of NHERF1 in epithelial morphogenesis and polarity and validate this 3D system for modeling the molecular changes observed in CRC.
doi:10.1016/j.neo.2014.04.004
PMCID: PMC4094837  PMID: 24862762
3D, three-dimensional; CIP, calf intestinal phosphatase; IF, immunofluorescence; CRC, colorectal cancer; ERM, ezrin-radixin-moesin; NF2, neurofibromatosis type 2; NHERF1/EBP50, Na+/H+ exchanger 3 regulating factor 1/ERM-binding phosphoprotein 50; pHH3, phospho-histone H3; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PM, plasma membrane
5.  Globular glial tauopathies (GGT): consensus recommendations 
Acta neuropathologica  2013;126(4):537-544.
Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
doi:10.1007/s00401-013-1171-0
PMCID: PMC3914659  PMID: 23995422
6.  PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase 
Oncotarget  2014;5(3):815-823.
The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling.
PMCID: PMC3996652  PMID: 24553260
PHLPP; NF-κB; IKK; glioma; colorectal cancer
7.  Polyadenylated Messenger RNA in Paired Helical Filament-Immunoreactive Neurons in Alzheimer Disease 
Summary
An antibody raised against isolated paired helical filaments (PHF) was used to identify tangle-bearing (PHF+) neurons in autopsy brain tissue from six Alzheimer disease (AD) patients and six age-matched controls (AMC). A comparison of the levels of polyadenylated messenger RNA [poly(A)+ mRNA] in PHF+ and PHF− neurons of similar cross-sectional area in temporal and parietal lobe and cerebellum from four AD and four AMC brains was made by analysis of in situ hybridization of [3H] polyuridylate [poly(U)] to intracellular poly(A)+ mRNA. In PHF+ neurons, the level of poly(A)+. mRNA was approximately two-thirds that in similar-sized PHF− neurons in either AD or AMC. The level of poly(A)+ mRNA in PHF− neurons in regions of the brain that have more of the histopathologically defined effects in AD was similar to that in regions with less effects.
PMCID: PMC3886638  PMID: 1972628
Paired helical filament; Tangle-bearing neurons; Alzheimer disease; Polyadenylated messenger RNA
8.  Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype 
Neurobiology of aging  2012;33(12):2950.e5-2950.e7.
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
doi:10.1016/j.neurobiolaging.2012.07.005
PMCID: PMC3617405  PMID: 22840558
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
9.  Regional changes of cortical mean diffusivities with aging after correction of partial volume effects 
NeuroImage  2012;62(3):1705-1716.
Accurately measuring the cortical mean diffusivity (MD) derived from diffusion tensor imaging (DTI) at the comprehensive lobe, gyral and voxel level of young, elderly healthy brains and those with Alzheimer's disease (AD) may provide insights on heterogeneous cortical microstructural changes caused by aging and AD. Due to partial volume effects (PVE), the measurement of cortical MD is overestimated with contamination of cerebrospinal fluid (CSF). The bias is especially severe for aging and AD brains because of significant cortical thinning of these brains. In this study, we aimed to quantitatively characterize the unbiased regional cortical MD changes due to aging and AD and delineate the effects of cortical thinning of elderly healthy and AD groups on MD measurements. DTI and T1-weighted images of 14 young, 15 elderly healthy subjects and 17 AD patients were acquired. With the parcellated cortical gyri and lobes from T1 weighted image transformed to DTI, regional cortical MD of all subjects before and after PVE correction were measured. CSF contamination model was used to correct bias of MD caused by PVE. Compared to cortical MD of young group, significant increases of corrected MD for elderly healthy and AD groups were found only in frontal and limbic regions, respectively, while there were significant increases of uncorrected MD all over the cortex. Uncorrected MD are significantly higher in limbic and temporal gyri in AD group, compared to those in elderly healthy group but higher MD only remained in limbic gyri after PVE correction. Cortical thickness was also measured for all groups. The correlation slopes between cortical MD and thickness for elderly healthy and AD groups were significantly decreased after PVE correction compared to before correction while no significant change of correlation slope was detected for young group. It suggests that the cortical thinning in elderly healthy and AD groups is a significant contributor to the bias of uncorrected cortical MD measurement. The established comprehensive unbiased cortical MD profiles of young, elderly healthy subjects and AD patients at the lobe, gyral and voxel level may serve as clinical references for cortical microstructure.
doi:10.1016/j.neuroimage.2012.05.082
PMCID: PMC3574164  PMID: 22683383
DTI; Cortex; Mean diffusivity; Aging; Alzheimer's disease; Unbiased; Partial volume effects
10.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases 
Coppola, Giovanni | Chinnathambi, Subashchandrabose | Lee, Jason JiYong | Dombroski, Beth A. | Baker, Matt C. | Soto-Ortolaza, Alexandra I. | Lee, Suzee E. | Klein, Eric | Huang, Alden Y. | Sears, Renee | Lane, Jessica R. | Karydas, Anna M. | Kenet, Robert O. | Biernat, Jacek | Wang, Li-San | Cotman, Carl W. | DeCarli, Charles S. | Levey, Allan I. | Ringman, John M. | Mendez, Mario F. | Chui, Helena C. | Le Ber, Isabelle | Brice, Alexis | Lupton, Michelle K. | Preza, Elisavet | Lovestone, Simon | Powell, John | Graff-Radford, Neill | Petersen, Ronald C. | Boeve, Bradley F. | Lippa, Carol F. | Bigio, Eileen H. | Mackenzie, Ian | Finger, Elizabeth | Kertesz, Andrew | Caselli, Richard J. | Gearing, Marla | Juncos, Jorge L. | Ghetti, Bernardino | Spina, Salvatore | Bordelon, Yvette M. | Tourtellotte, Wallace W. | Frosch, Matthew P. | Vonsattel, Jean Paul G. | Zarow, Chris | Beach, Thomas G. | Albin, Roger L. | Lieberman, Andrew P. | Lee, Virginia M. | Trojanowski, John Q. | Van Deerlin, Vivianna M. | Bird, Thomas D. | Galasko, Douglas R. | Masliah, Eliezer | White, Charles L. | Troncoso, Juan C. | Hannequin, Didier | Boxer, Adam L. | Geschwind, Michael D. | Kumar, Satish | Mandelkow, Eva-Maria | Wszolek, Zbigniew K. | Uitti, Ryan J. | Dickson, Dennis W. | Haines, Jonathan L. | Mayeux, Richard | Pericak-Vance, Margaret A. | Farrer, Lindsay A. | Ross, Owen A. | Rademakers, Rosa | Schellenberg, Gerard D. | Miller, Bruce L. | Mandelkow, Eckhard | Geschwind, Daniel H.
Human Molecular Genetics  2012;21(15):3500-3512.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
doi:10.1093/hmg/dds161
PMCID: PMC3392107  PMID: 22556362
11.  TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease 
Background
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
Results
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Conclusions
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
doi:10.1186/1750-1326-8-19
PMCID: PMC3691612  PMID: 23800361
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
12.  Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies 
Biochemical Journal  2013;453(Pt 1):101-113.
Missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a major cause of PD (Parkinson's disease). Several antibodies against LRRK2 have been developed, but results using these polyclonal antibodies have varied widely leading to conflicting conclusions. To address this challenge, the Michael J. Fox Foundation for Parkinson's Research generated a number of monoclonal antibodies targeting epitopes across the LRRK2 protein. In the present paper, we report optimized protocols and results for ten monoclonal antibodies for immunoblotting, immunohistochemistry, immunoprecipitation and kinase activity assays, in rat, mouse and human brain tissue. Several efficacious antibodies were identified, but results demonstrate that the mouse monoclonal N241A/34 is suitable for most applications, with the best overall rabbit monoclonal antibody being c41-2. These antibodies produced a dominant band of the expected size via immunoblotting and a lack of labelling in tissue derived from LRRK2-knockout animals under optimized conditions. A significant proportion of LRRK2 protein localizes to insoluble fractions and no evidence of truncated LRRK2 protein was detected in any fraction from rodent or human tissues. An assay was developed for the robust detection of LRRK2 kinase activity directly from frozen mouse and human brain tissue, but precipitous declines in activity were observed that corresponded to increasing post-mortem intervals and processing times. Finally, we demonstrate the highest levels of brain-localized LRRK2 in the striatum, but note differential expression patterns between rat and mouse in both striatum and cortex. Anti-LRRK2 monoclonal antibodies that are unlimited in availability together with the proposed standardized protocols should aid in the definition of LRRK2 function in both health and disease.
doi:10.1042/BJ20121742
PMCID: PMC3682752  PMID: 23560750
immunohistochemistry; kinase assay; leucine-rich repeat kinase 2 (LRRK2); Parkinson’s disease; DAB, 3,3′-diaminobenzidine; DMEM, Dulbecco’s modified Eagle’s medium; eGFP, enhanced green fluorescent protein; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HEK, human embryonic kidney; KO, knockout; LRRK2, leucine-rich repeat kinase 2; MEF, mouse embryonic fibroblast; MJFF, Michael J. Fox Foundation for Parkinson’s Research; PD, Parkinson’s disease; PEI, polyethyleneimine; PFA, paraformaldehyde; UTSW, University of Texas Southwestern; VDAC, voltage-dependent anion channel; WT, wild-type
13.  Ataxin-2 repeat-length variation and neurodegeneration 
Human Molecular Genetics  2011;20(16):3207-3212.
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
doi:10.1093/hmg/ddr227
PMCID: PMC3140823  PMID: 21610160
14.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
15.  Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders 
Acta neuropathologica  2010;119(6):689-702.
A sensitive immunohistochemical method for phosphorylated α-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson’s disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer’s disease with Lewy bodies (ADLB) and 17 with Alzheimer’s disease with no Lewy bodies (AD-NLB). The relative densities and frequencies of occurrence of phosphorylated α-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.
doi:10.1007/s00401-010-0664-3
PMCID: PMC2866090  PMID: 20306269
Parkinson’s disease; Parkinsonism; Dementia with Lewy bodies; Alzheimer’s disease; Incidental Lewy bodies; α-Synuclein; Spinal cord; Sympathetic nervous system; Peripheral nervous system; Autonomic nervous system; Enteric nervous system; Submandibular gland; Esophagus; Adrenal gland; Heart; Stomach; Gastrointestinal system
16.  TC-99m HMPAO Brain Blood Flow Imaging in the Dementias with Histopathologic Correlation in 73 Patients 
The purpose of this study is to determine the value of Tc-99m HMPAO SPECT in the diagnosis of the dementias. Tc-99m HMPAO was used with a 3-camera scanner to produce 5 sets of sectional images of the brain. Images were further processed using Statistical Parametric Mapping. Diagnosis was made by a physician blinded to the clinical diagnosis. Results in 73 subjects were compared with a neuropathologic study of the brain at autopsy. Data were analyzed for sensitivity, specificity, positive and negative predictive values and accuracy. These results are compared with several other studies performed with Tc-99m HMPAO SPECT with histopathologic correlation. This procedure is widely available and relatively inexpensive and may be of value in patients with dementias and problematic diagnoses. Further, a degree of differential diagnosis between Alzheimer's and Frontotemporal diseases may be effected. The study was approved by our Institutional Review Board.
doi:10.1155/2011/409101
PMCID: PMC3065903  PMID: 21490729
17.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions 
Van Deerlin, Vivianna M. | Sleiman, Patrick M. A. | Martinez-Lage, Maria | Chen-Plotkin, Alice | Wang, Li-San | Graff-Radford, Neill R | Dickson, Dennis W. | Rademakers, Rosa | Boeve, Bradley F. | Grossman, Murray | Arnold, Steven E. | Mann, David M.A. | Pickering-Brown, Stuart M. | Seelaar, Harro | Heutink, Peter | van Swieten, John C. | Murrell, Jill R. | Ghetti, Bernardino | Spina, Salvatore | Grafman, Jordan | Hodges, John | Spillantini, Maria Grazia | Gilman, Sid' | Lieberman, Andrew P. | Kaye, Jeffrey A. | Woltjer, Randall L. | Bigio, Eileen H | Mesulam, Marsel | al-Sarraj, Safa | Troakes, Claire | Rosenberg, Roger N. | White, Charles L. | Ferrer, Isidro | Lladó, Albert | Neumann, Manuela | Kretzschmar, Hans A. | Hulette, Christine Marie | Welsh-Bohmer, Kathleen A. | Miller, Bruce L | Alzualde, Ainhoa | de Munain, Adolfo Lopez | McKee, Ann C. | Gearing, Marla | Levey, Allan I. | Lah, James J. | Hardy, John | Rohrer, Jonathan D. | Lashley, Tammaryn | Mackenzie, Ian R.A. | Feldman, Howard H. | Hamilton, Ronald L. | Dekosky, Steven T. | van der Zee, Julie | Kumar-Singh, Samir | Van Broeckhoven, Christine | Mayeux, Richard | Vonsattel, Jean Paul G. | Troncoso, Juan C. | Kril, Jillian J | Kwok, John B.J. | Halliday, Glenda M. | Bird, Thomas D. | Ince, Paul G. | Shaw, Pamela J. | Cairns, Nigel J. | Morris, John C. | McLean, Catriona Ann | DeCarli, Charles | Ellis, William G. | Freeman, Stefanie H. | Frosch, Matthew P. | Growdon, John H. | Perl, Daniel P. | Sano, Mary | Bennett, David A. | Schneider, Julie A. | Beach, Thomas G. | Reiman, Eric M. | Woodruff, Bryan K. | Cummings, Jeffrey | Vinters, Harry V. | Miller, Carol A. | Chui, Helena C. | Alafuzoff, Irina | Hartikainen, Päivi | Seilhean, Danielle | Galasko, Douglas | Masliah, Eliezer | Cotman, Carl W. | Tuñón, M. Teresa | Martínez, M. Cristina Caballero | Munoz, David G. | Carroll, Steven L. | Marson, Daniel | Riederer, Peter F. | Bogdanovic, Nenad | Schellenberg, Gerard D. | Hakonarson, Hakon | Trojanowski, John Q. | Lee, Virginia M.-Y.
Nature genetics  2010;42(3):234-239.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
doi:10.1038/ng.536
PMCID: PMC2828525  PMID: 20154673
18.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
19.  TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease 
Acta neuropathologica  2010;120(1):43-54.
The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies.
doi:10.1007/s00401-010-0681-2
PMCID: PMC2903745  PMID: 20361198
Primary progressive aphasia; Frontotemporal dementia; Alzheimer disease; FTLD-TDP; TDP-43 proteinopathy; Hippocampal sclerosis
20.  Unified Staging System for Lewy Body Disorders: Correlation with Nigrostriatal Degeneration, Cognitive Impairment and Motor Dysfunction 
Acta neuropathologica  2009;117(6):613-634.
The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type α-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of 10 brain regions from 417 subjects stained immunohistochemically for α-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson’s disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer’s disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson’s Disease Rating Scale Part 3. Additionally there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases.
doi:10.1007/s00401-009-0538-8
PMCID: PMC2757320  PMID: 19399512
Parkinson’s disease; parkinsonism; dementia with Lewy bodies; Alzheimer’s disease; incidental Lewy bodies; α-synuclein; olfactory bulb; amgydala; limbic; brainstem; neocortex
21.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration 
Acta Neuropathologica  2007;114(1):5-22.
The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U sub-type. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.
doi:10.1007/s00401-007-0237-2
PMCID: PMC2827877  PMID: 17579875
Frontotemporal dementia; Semantic dementia; Progressive non-Xuent aphasia; Frontotemporal lobar degeneration; Motor neuron disease; Tauopathy; Ubiquitin; TDP-43 proteinopathy; Progranulin; Valosin-containing protein; Charged multivesicular body protein 2B; Neuronal intermediate filament inclusion disease; Neuropathologic diagnosis
22.  Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders 
Acta neuropathologica  2008;117(2):169-174.
Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the unified Parkinson's Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.
doi:10.1007/s00401-008-0450-7
PMCID: PMC2631085  PMID: 18982334
Parkinson's disease, surgery; Deep brain stimulation; Gene therapy; Transplantation; Dementia with Lewy bodies, diagnosis, therapy, clinical trial; α-Synuclein, Lewy bodies, incidental Lewy body disease; Biopsy; Olfactory bulb
23.  Response to Parkinnen et al. and Jellinger 
Acta neuropathologica  2008;117(2):217.
doi:10.1007/s00401-008-0464-1
PMCID: PMC2637655  PMID: 20126279
24.  Molecular Characterization of Novel Progranulin (GRN) Mutations in Frontotemporal Dementia 
Human mutation  2008;29(4):512-521.
Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
doi:10.1002/humu.20681
PMCID: PMC2756561  PMID: 18183624
Frontotemporal dementia; FTD; granulin; progranulin; GRN; PGRN
25.  Neuroanatomical Profile of Polyglutamine Immunoreactivity in Huntington Disease Brains 
A pathologic hallmark of Huntington disease (HD) is the presence of intraneuronal aggregates of polyglutamine-containing huntingtin protein (Htt) fragments. Monoclonal antibody 1C2 is a commercial antibody to normal human TATA-binding protein that detects long stretches of glutamine residues. Using 1C2 as a surrogate marker for mutant Htt, we immunostained 19 HD cases, 10 normal controls, and 10 cases of frontotemporal degeneration with ubiquitinated inclusions as disease controls. In the HD cases there was consistent 1C2 immunoreactivity in the neocortex, striatum, hippocampus, lateral geniculate body, basis pontis, medullary reticular formation, and cerebellar dentate nucleus. The normal and disease controls demonstrated 1C2 immunoreactivity only in the substantia nigra, locus coeruleus, and pituitary gland. Staining of 5 HD cases and 5 normal controls revealed a less consistent and less diagnostically useful morphologic immunoreactivity profile. These results indicate that widespread 1C2 immunoreactivity is present in diverse central nervous system areas in HD and that in the appropriate setting 1C2 staining can be a useful tool in the postmortem diagnosis of HD when neuromelanin-containing neuronal populations are avoided.
doi:10.1097/NEN.0b013e318198d320
PMCID: PMC2756075  PMID: 19225411
1C2; Frontotemporal degeneration with ubiquitinated inclusions; inclusions; Huntington disease; Immunohistochemistry; Neuromelanin; Polyglutamine

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