Building An Integrated Neurodegenerative Disease Database At An Academic Health Center

Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Alzheimer's & dementia: the journal of the Alzheimer's Association (Impact Factor: 12.41). 07/2011; 7(4):e84-93. DOI: 10.1016/j.jalz.2010.08.233
Source: PubMed


It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. These comparative studies rely on powerful database tools to quickly generate data sets that match diverse and complementary criteria set by them.
In this article, we present a novel integrated neurodegenerative disease (INDD) database, which was developed at the University of Pennsylvania (Penn) with the help of a consortium of Penn investigators. Because the work of these investigators are based on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration, it allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used the Microsoft SQL server as a platform, with built-in "backwards" functionality to provide Access as a frontend client to interface with the database. We used PHP Hypertext Preprocessor to create the "frontend" web interface and then used a master lookup table to integrate individual neurodegenerative disease databases. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database.
Using the INDD database, we compared the results of a biomarker study with those using an alternative approach by querying individual databases separately.
We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies on several neurodegenerative diseases.

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    • "The higher the htau score of an individual hippocampus, the higher the pPERK staining score tended to be. Htau scores were obtained from the CNDR Integrated Neurodegenerative Disease Database [33] using antibody PHF-1. "
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    ABSTRACT: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum's (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.
    07/2013; 1(1):31. DOI:10.1186/2051-5960-1-31
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    • "Cases were selected from the Centre for Neurodegenerative Disease Research (CNDR) Brain Bank at The University of Pennsylvania following formal neuropathological diagnosis as previously described (Forman et al., 2006) and in accordance with local institutional review board guidelines. Pathological diagnosis, demographic information and post-mortem interval (Table 1) were obtained from the CNDR integrated neurodegenerative disease database (Xie et al., 2011). We sampled 30 regions of the CNS in 10 cases of Alzheimer's disease, five cases of corticobasal degeneration and five cases of progressive supranuclear palsy to examine regional distributions of acetylated K280-immunoreactive tau pathology. "
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    ABSTRACT: The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.
    Brain 03/2012; 135(Pt 3):807-18. DOI:10.1093/brain/aws013 · 9.20 Impact Factor
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    ABSTRACT: TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.
    Acta Neuropathologica 03/2011; 121(3):373-80. DOI:10.1007/s00401-010-0782-y · 10.76 Impact Factor
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