A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank

Toledo, Jon B.; Deerlin, Vivianna M. Van; Lee, Edward B.; Suh, EunRan; Baek, Young Min; Robinson, John; Xie, Sharon X.; McBride, Jennifer D.; Wood, Elisabeth McCarty; Schuck, Theresa; Irwin, David J.; Gross, Rachel G.; Hurtig, Howard I.; McCluskey, Leo; Elman, Lauren; Karlawish, Jason; Schellenberg, Gerard D.; Chen‐Plotkin, Alice S.; Wolk, David A.; Grossman, Murray; Arnold, Steven E.; Shaw, Leslie M.; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1016/j.jalz.2013.06.003

Cited by 178 publications

(247 citation statements)

References 68 publications

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“…Recruitment of the patients and diagnostic criteria for the groups have been described previously in detail [20, 52, 55]. Demographic and biomarker characteristics of the patients included in the study are shown in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1851-x) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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“…For autopsied patients (n 5 5), neuropathologic assessment was performed on standard tissue regions 12,13 by an experienced neuropathologist (J.Q.T., E.B.L.) using previously described immunohistochemical methods 12 and diagnostic criteria. 13,14 Nonautopsied patients were classified as CBS-non-AD and CBS-AD on the basis of either genetic status or CSF analyses.…”

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confidence: 99%

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome

et al. 2016

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Objective: To use multimodal neuroimaging to evaluate the influence of heterogeneous underlying pathology in corticobasal syndrome (CBS) on the neuroanatomical distribution of disease.Methods: We performed a retrospective evaluation of 35 patients with CBS with T1-weighted MRI, diffusion tensor imaging, and neuropathologic, genetic, or CSF evidence of underlying pathology. Patients were assigned to 2 groups: those with evidence of Alzheimer pathology (CBS-AD) and those without Alzheimer pathology (CBS-non-AD). Group comparisons of CBS-AD and CBS-non-AD assessed clinical features, gray matter (GM) cortical thickness, and white matter (WM) fractional anisotropy.Results: CBS-AD was found in 34% (n 5 12) and CBS-non-AD in 66% (n 5 23) of CBS patients.Clinical evaluations revealed that CBS-non-AD had a higher frequency of asymmetric rigidity compared to CBS-AD, but groups otherwise did not differ in dementia severity, impairments in cognition, or rates of extrapyramidal symptoms. We found frontoparietal GM and WM disease in each group compared to healthy, demographically comparable controls, as well as multimodal neuroimaging evidence of a double dissociation: CBS-non-AD had WM disease in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus relative to CBS-AD, and CBS-AD had reduced temporoparietal GM relative to CBS-non-AD, including the precuneus and posterior cingulate. Conclusions:Patients with CBS have a pathology-mediated dissociation of GM and WM disease.Multimodality neuroimaging may be useful for improving in vivo pathologic diagnosis of CBS. Corticobasal syndrome (CBS) is a neurodegenerative condition characterized by lateralized extrapyramidal features and cortically mediated cognitive dysfunction.1 The underlying pathology of CBS is heterogeneous, and clinical features appear to be insufficient to identify an individual's histopathologic abnormality during life.2,3 The most common neuropathologic causes of CBS include corticobasal degeneration, a 4-repeat form of tau pathology associated with frontotemporal lobar degeneration (FTLD), 4 and Alzheimer disease (AD). 2,5,6 Multimodal neuroimaging studies suggest that AD and FTLD can be dissociated on the basis of gray matter (GM) and white matter (WM) neuroimaging. 7,8 Specifically, GM atrophy was evident in both AD and FTLD in T1-weighted MRI studies, but diffusion tensor imaging (DTI) revealed more WM disease in FTLD than in AD. Additional neuroimaging evidence suggests that tau pathology, the most common form of underlying pathology in CBS, is associated with substantial WM imaging changes 9 and that these findings converge with neuropathologic evidence of WM disease burden in 4-repeat tauopathy.9,10 However, prior evidence of greater WM pathology in FTLD disorders has been based on clinically heterogeneous study samples; therefore, it is not clear whether a dissociation of GM and WM disease is

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“…12 All of the probable bvFTD cases in this cohort have a total tau/ b-amyloid ratio that is not suggestive of an autopsy-confirmed AD profile (i.e., ,0.34), 12 minimizing the possible inclusion of atypical AD cases that can influence clinically derived FTLD cohorts. 13,14 In a subset of patients followed to autopsy (i.e., "definite" bvFTD), neuropathologic examination was performed as previously described 15 using well-established monoclonal antibodies and current neuropathologic criteria (table 1). 3 The final cohort included 81 patients who met probable or definite bvFTD criteria.…”

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confidence: 99%

“…Clinical data, including dates and ages at onset and death, were obtained from the Penn Integrated Neurodegenerative Disease Database, 15 and disease duration was calculated from these values and reported in years. Clinical variables were evaluated for normality using a Kolmogorov-Smirnov test and because of a nonnormal distribution analyzed with MannWhitney U tests.…”

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confidence: 99%

Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia

et al. 2014

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Objective: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD).Methods: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of $1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n 5 20) and TDP-43 proteinopathy (n 5 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n 5 37).Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA1) had a shorter median disease duration (TC/TT 5 5.5 years, CC 5 9.5 years; p 5 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p 5 0.04) but not with TDP-43 proteinopathies (p . 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p . 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG 5 54.5 years, AA 5 58 years; p , 0.01). MOBP RA1 patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p , 0.01). Conclusions:The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD.MOBP RA1 patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings. Neurology ® 2014;83:502-509 GLOSSARY AD 5 Alzheimer disease; ALS 5 amyotrophic lateral sclerosis; bvFTD 5 behavioral-variant frontotemporal dementia; FA 5 fractional anisotropy; FTD 5 frontotemporal dementia; FTLD 5 frontotemporal lobar degeneration; GM 5 gray matter; GMD 5 gray matter density; ILF 5 inferior longitudinal fasciculus; MAPT 5 microtubule-associated protein tau; MOBP 5 myelin-associated oligodendrocyte basic protein; PA 5 protective allele; PSP 5 progressive supranuclear palsy; RA 5 risk allele; RD 5 radial diffusion; SCR 5 superior corona radiata; SLF 5 superior longitudinal fasciculus; SNP 5 single nucleotide polymorphism; STG 5 superior temporal gyrus; TDP-43 5 TAR DNA-binding protein 43; WM 5 white matter.Significant heterogeneity exists in the natural history of behavioral-variant frontotemporal dementia (bvFTD), the most common clinical phenotype in frontotemporal lobar degeneration (FTLD) spectrum pathology. Approximately equal numbers of cases appear to be attributable to the 2 main broad categories of proteinopathies 1,2 : those containing pathologic aggregations of the microtubule-associated protein, tau (i.e., FTLD-tau), 3 and those with inclusions composed of the RNA-b...

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A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank

Cited by 178 publications

References 68 publications

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome

Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia

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