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$522 Poster Session P4: Molecular Mechanisms of Neurodegeneration - Enzyme Activities
further adjusted for presence of anxiety or depression, benzodiazepines, alcohol use and history of stroke. Finally, we studied the percentage of genetic variance explained by vascular factors. Results: Heritability was highest for estimated intelligence (h a 0.54;se 0.12;p < 0.0001). For immediate and delayed recall, h a was 0.28 (se 0.11;p = 0.001), and for verbal fluency 0.32 (se 0.14;p = 0.004). For performance on Stroop card HI, h 2 was 0.41 (se 0.12;p < 0.0001). For performance on Block Design and the trail making test h a was lower (0.11 and 0.16;p = 0.1). After adjustment for hypertension or diabetes mellitus, h a increased with 3% for immediate and delayed recall, and remained unchanged for other tests, thus giving no evidence that vascular factors explain familial clustering. Conclusion: We found strongest evidence for genes underlying cognitive function for the domains intelligence, memory, color-word interference and verbal fluency. The underlying genes most likely concern Alzheimer-related pathology, as there is no evidence for vascular factors explaining familial clustering.
~ - 6 - ~ G E N E T I C ANALYSIS OF STROKE AND DEMENTIA IN TWO SWEDISH FAMILIES
Sofie Ingvast*, Elin Blom, Marie Hedlund, Vilmantas Giedraitis, Anna Glaser, Lars Lannfelt. Uppsala University, Uppsala, Sweden. Contact e-mail: [email protected]
Background: Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), occurring in 25% of dementia cases. Executive dysfunction is commonly seen in VaD, but unlike AD, memory impairment can be mild or may not even be present. VaD is defined as the loss of cognitive function resulting from ischemic, ischemic- hypoxic, or hemorrhagic brain lesions as a result of cerebrovascular disease and cardiovascular pathologic changes. Objective(s): The purpose of this project is to identify genes and mutations that cause stroke and dementia with relatively late onset. The family material consists of two families, which include 42 individuals from the middle of Sweden. Both families show an autosomal dominantly inherited disease distinguished by cerebral haemorrhages and ischemic strokes. Methods: Initially we used a candidate gene approach where known mutations in genes, which have been linked to cerebrovascnlar disease, were investigated. Individuals from the two families were sequenced for notch3, cystatin C, tan, BRI, a-synuclein, gelsolin and APP but without finding any mutations segregating with the disease. No evidence of the involvement of these genes was found we performed a whole- genome scan, including 340 microsatellite markers evenly distributed over the entire genome with a genetic distance of approximately 10 cM. Linkage analysis using parametric and non-parametric methods (Genehunter 2.1) was performed. Results: We are currently analysing chromosomal regions were haplotypes are shared between affected individuals within each family and where a common, overlapping chromosomal region is implicated in both families. Mutation screening of candidate genes within implicated regions has been initiated. Regions identified from the genome scan will be further investigated in the search of candidate genes. Conclusions: Due to the similar disease pattern in the two families we expect the same genetic factor to be segregating with VaD in the two families.
• MOLECULAR STUDY OF DEMENTIA WITH NEUROFILAMENT INCLUSIONS
Parastoo Momeni* 1, Nigel Cairns 2, Robert Perry 1 Evelyn Jaros l, Andrew B. Singleton 3, John Hardy 3. 1NIH, Bethesda, MD, USA; 2University of Pennsylvania School of Medicine, Philadelphia, PA, USA; 3 N1H/NIA, Bethesda, MD, USA. Contact e-mail: [email protected]
Neurofilament inclusion disease is a novel neurodegenerative disease char- acterized progressive early-onset dementia, focal atrophy of frontal and temporal lobe and intraneural, cytoplasmic neurofilament inclusions. These inclusions are mostly immunopositive for the heavy and light subunits of neurofilament protein and negative for tau and ct-synuclein. In this study we performed detailed mutation analysis of neurofilament heavy, -medium, -light, c~-internexin and SOD-lgenes in four neuropathologically diagnosed patients. We report here a total of 39 sequence variants in 4 patients and
40 controls. Twenty-four of these changes are novel and four nucleotide alterations occur exclusively in patients. We also present data describing gene dosage analysis of the neurofilament genes in these patients.
• MICROARRAY ANALYSIS OF GENE EXPRESSION IN THE FRONTAL CORTEX OF PATIENTS WITH FRONTOTEMPORAL DEMENTIA
Doris G. Leung .1 , Raphael Gibbs 1, William H. Wood 2, Diane Teichberg 2, John A. Hardy 1 , Kevin G. Becker 2, Amanda J. Myers 1 . 1NIA/NIH/IRP, Bethesda, MD, USA; 2NIA/NIH/IRP, Baltimore, MD, USA. Contact e-mail: leungdl @ mail.nih.gov
Background: Eruntotemporal dementia (FrD) describes a group of neu- rodegenerative diseases distinguished by atrophy of the frontal and anterior temporal lobes. The localization of the disease produces the behavioral- cognitive syndrome associated with FTD, which accounts for 4% of pre- senile dementias. To date, no microarray analyses have been done to evaluate genome-wide expression profiles associated with FTD. Objective(s): To generate a list of differentially expressed genes in brain tissue with fron- totemporal dementia compared to normal controls. Methods: Total RNA's were isolated from frontal cortex tissues of 5 patients with neuropathologic diagnoses of FTD as well as 5 age and gender matched controls. These RNA's were used to synthesize 33P-labeled cDNAs by reverse transcription and hybridized to cDNA microarrays containing 9,600 genes. T-test, SAM (Significance Analysis of Microarrays) and Z-test analyses were utilized to perform a two-class unpaired comparison of FTD and control samples. T-test analyses were performed using a critical p-value of 0.01 with p-values based on a t-distribution and all permutations. No alpha corrections were used for t-distribution T-tests; an adjusted Bonferroni correction was used for permutation-based T-tests. SAM analysis was performed using 100 permutations and a delta of 0.874 to keep the median false discovery rate at 0.00% (or approximately no false significant genes for these data sets and a fold change value of 1.5). Z-tests were performed using a p-value of 0.001, based on a 2-tailed p-value from a normal distribution and a z-ratio >4- 1.5. Genes that showed significant differential expression in all 3 tests were considered. Results: Expression profile analyses generated a composite list of 867 genes that were differentially expressed in FTD vs. controls. The list was further narrowed to 85 genes that had a z-ratio > 1.5. These genes are primarily involved in binding (36.7%), catalytic activity (16.5%), and transcription regulator activity (7.6%). Conclusions: This study has generated a preliminary list of genes that may be differentially expressed in FTD vs. controls. To confirm these findings, analyses using Western blots, quantitative PCR, and other methods are required. These studies may ultimately identify new genes involved in the pathways that produce FTD.
Poster Session P4: Molecular Mechanisms of Neurodegeneration - Enzyme Activities
• OVEREXPRESSION OF CDK-5 INDUCES HYPERPHOSPHORYLATION OF CYTOSKELETAL PROTEINS AND IMPAIRMENT OF AXONAL TRANSPORT IN N2A CELLS
Juan Chen* 1, Honglian Yipeng, Youmei Jianzhi, Li Wang, Feng Wang 2. 1Neuroscience Pathophysiology Department, Neuroscience Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China, China; 2Neuroscience Institute, Wuhan, China. Contact e-mail: xiahui @public. wh.hb.cn
Abstract Accumulation of abnormally hyperphosphorylated "t and neurofil- arnents (NFs) and defect in axonal transport are seen in brains of Alzheimer's disease (AD). Several protein kinases can phosphorylate these proteins, but which kinase can induce the hyperphosphorylafion as well as axonal trans- port impairment is not well known. In this study, we overexpressed cdk-5 in neuroblastoma N2a cells which resulted in a 3.5-fold cdk-5 activation of the
