- Email: [email protected]
Epidemiology of cognitive impairment and depressive symptoms in patients with Parkinson's disease
Poster Presentations P1 rates and to examine if rates are increasing in younger persons. This has important public health implications since alcohol related dementia is preventable and better awareness is therefore needed. Finally, persons with this diagnosis need defined care pathways to ensure that they receive adequate care and do not fall between the gaps.
P1-053
EPIDEMIOLOGY OF COGNITIVE IMPAIRMENT AND DEPRESSIVE SYMPTOMS IN PATIENTS WITH PARKINSON’S DISEASE
Irena Rektorova1, Martin Bares1, Robert Jech2, Katerina Farnikova3, Ivan Rektor1, Jan Roth2, Evzen Ruzicka2, Petr Kanovsky3, Karel Chroust4, Tomas Pavlik4, 11st Department of Neurology, Masaryk University and St Anne’s Hospital, Brno, Czech Republic; 2Department of Neurology, 1st Medical Faculty Charles University, Prague, Czech Republic; 3Department of Neurology, Medical Faculty Palacky University, Olomouc, Czech Republic; 4Institute for Biomedical Analysis, Masaryk University, Brno, Czech Republic. Contact e-mail: [email protected] Background: Dementia and depression in Parkinson’s disease (PD) have drawn attention since they impact on patients’ quality of life. We studied cognitive performance and depressive symptoms of PD as measured by Montreal Cognitive Assessment (MOCA) and Montgomery and Asberg Depression Rating Scale (MADRS), based on the results from a national, multicenter, epidemiological E.W.O study (Epidemiology of Wearing-Off symptoms in PD patients treated with L-dopa for 10 years) Methods: Data analyzed from 217 out of 563 consecutive PD patients (83 women, 34 men); detailed records on medical and drug history, clinicians’ assessment, WOQ-9 questionnaire, NMS30, MADRS, HAMA, MOCA used. Results: The most frequent cognitive deficits included impairment of delayed recall and visuospatial/ executive functions. 43.8 % of patients had MOCA scores < 26. MOCA scores were significantly correlated with patients’ age (p < 0.001, r ¼ -0.308), MADRS scores (p ¼ 0.023, r ¼ -0.155) and NMS30 scores (p ¼ 0.010, r ¼ -0.224). MOCA results were not influenced by the cumulative dose of any class of antiparkinsonian medication. Only 17.1% of patients had MADRS score > 14. Sadness, sleep problems, inner tension, and inability to concentrate were the most frequent depressive symptoms. Patients with the first symptom manifestation on the right side had higher MADRS scores compared to those with the left-sided or bilateral manifestations (results adjusted for current Hoehn and Yahr [H-Y] score; p ¼ 0.015). MADRS scores were significantly influenced only by the H-Y score with two peaks at stage 1 and 3 (p ¼ 0.005), and they significantly correlated with HAMA scores (r ¼ 0.681; p < 0.001), NMS30 scores (r ¼ 0.645; p < 0.001), and MOCA scores. Current intake of DA agonists or its daily dose had no impact on MADRS scores. Conclusions: Using the suggested cut-off scores, MOCA revealed dementia in 43.8%, and MADRS revealed depression in 17% of our patients. Antiparkinsonian medication did not influence MOCA results. We demonstrated a significant effect of laterality of the first motor symptom manifestation, and H-Y score on the MADRS results. The current intake or daily dose of DA agonists had no impact on MADRS.
P1-054
TARDBP MUTATION FREQUENCY IN SCANDINAVIAN AMYOTROPHIC LATERAL SCLEROSIS PATIENTS 1,2
1
3 1
Caroline Graff , Huei-Hsin Chiang , Peter M. Andersen , Karolinska Institutet, Dept NVS, KI-ADRC, Huddinge, Sweden; 2Karolinska University Hospital, Huddinge, Sweden; 3Umea˚ University, Department of Pharmacology and Clinical Neuroscience, Umea˚, Sweden. Contact e-mail: caroline. [email protected] Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the upper and lower motor neurons. The main symptoms are progressive muscle weakness, atrophy of the muscles, fasciculation and dysphagia. Age at onset is generally above 55 years. ALS is a heterogeneous disease with different clinical, neuropathologic and genetic subgroups. TAR-DNA-binding protein 43 (TDP-43) is a protein identified in the skein like inclusions and Lewy body like inclusions characteristically found in
S189
the motor neurons in ALS patients. Soon after this discovery, mutations in the gene encoding the TDP-43, TARDBP, were detected in ALS patients. To elucidate the impact of TARDBP mutations in ALS patients in Scandinavia, we sequenced 195 Scandinavian ALS patients for TARDBP mutations. Methods: Exon 1-5 and part of exon 6 were sequenced to include all splice variants of TDP-43 using both forward and reverse primer. Results: Four mutations were detected in three patients: Arg90Val, Gly357Arg, Arg361Thr and Ser379Pro. The first two mutations were detected in the same individual. Five other genetic variations were detected in the non-coding regions of TARDBP: four variations in the 3’UTR and one in intron 4. DNA samples from six family members, one with FTD, to the patient carrying the Arg361Thr mutation were available for segregation analysis. The mutation was present in only those patients with ALS and FTD suggesting that Arg361Ser is pathogenic and can cause both ALS and FTD. There were no DNA samples available from family members to those patients with the other genetic variations. Conclusions: TARDBP mutations were present in a frequency of 1.5% in the Scandinavian ALS patients. Furthermore, TARDBP mutations can cause ALS and FTD. P1-055
A GENOME-WIDE SEARCH FOR STOX1 TARGET GENES, A TRANSCRIPTION FACTOR ASSOCIATED WITH ALZHEIMER’S DISEASE
Daan Van Abel1, Marie Van Dijk1, Dennis Y. M. Lo2, Rossa W. K. Chiu2, Fiona M. F. Lun2, Marinus A. Blankenstein1, Cees B. M. Oudejans1, 1Vu Medical Centre, Amsterdam, Netherlands; 2Chinese University of Hong Kong, Hong Kong, China. Contact e-mail: [email protected] Background: STOX1, a transcription factor initially found to be a susceptibility gene for pre-eclampsia in Dutch women has recently been shown to be functionally involved in late-onset Alzheimer’s disease (LOAD). Since not much is known about STOX1 regulation in LOAD, a search for STOX1 target genes and its mechanism of regulation on these genes is necessary. Methods: Here we describe an in-vitro model system in which we use the neuroblastoma cell-line SK-N-SH as representative of human neuronal function in order to find potential STOX1 target genes on a genome wide scale. STOX1 transfection with a STOX1-Halotag fusion protein was used in an antibody-free alternative approach (HaloCHIP) for chromatin immunoprecipitation (CHiP). The precipitated DNA was then used for high-throughput sequencing (CHIP-Seq). Results: Data analysis was done with the program Quantitative Enrichment of Sequence Tags (QuEST) which successfully generated a top 100 list of potential STOX1 promoter binding regions. Interestingly, two of the regions validated with quantitative PCR lie in predicted promoter sites of genes associated with phosphorylation and splicing of Tau in Alzheimer’s disease Conclusions: These data indicate, in addition to previously published results, that STOX1 is involved in regulating important pathways which are Alzheimer’s disease related.
P1-056
GENETIC VARIATION WITHIN APP PROCESSING GENES CORRELATES WITH CEREBROSPINAL FLUID APP CLEAVAGE PRODUCT LEVELS IN ALZHEIMER PATIENTS AND COGNITIVELY NORMAL SUBJECTS
Lynn M. Bekris1, Nichole Galloway2, Ge Li1, Douglas R. Galasko3, Charles DeCarli4, Martin R. Farlow5, Chris M. Clark6, Joseph F. Quinn7,8, Jeffrey A. Kaye8, Gerard D. Schellenberg6, James B. Leverenz1, Peter Seubert9, Debby W. Tsuang1, Elaine R. Peskind1, Chang E. Yu2, 1 University of Washington, Seattle, WA, USA; 2VA Puget Sound Health Care System, Seattle, WA, USA; 3University of California, San Diego, CA, USA; 4 University of California, Davis, CA, USA; 5Indiana University, Indianapolis, IN, USA; 6University of Pennsylvania, Philadelphia, PA, USA; 7Portland VA Medical Center, Portland, OR, USA; 8Oregon Health and Science University, Portland, OR, USA; 9Elan Pharmaceuticals, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Amyloid precursor protein (APP) post-translational processing involves cleavage by b-secretase to produce an APPb fragment which
P1-053
EPIDEMIOLOGY OF COGNITIVE IMPAIRMENT AND DEPRESSIVE SYMPTOMS IN PATIENTS WITH PARKINSON’S DISEASE
Irena Rektorova1, Martin Bares1, Robert Jech2, Katerina Farnikova3, Ivan Rektor1, Jan Roth2, Evzen Ruzicka2, Petr Kanovsky3, Karel Chroust4, Tomas Pavlik4, 11st Department of Neurology, Masaryk University and St Anne’s Hospital, Brno, Czech Republic; 2Department of Neurology, 1st Medical Faculty Charles University, Prague, Czech Republic; 3Department of Neurology, Medical Faculty Palacky University, Olomouc, Czech Republic; 4Institute for Biomedical Analysis, Masaryk University, Brno, Czech Republic. Contact e-mail: [email protected] Background: Dementia and depression in Parkinson’s disease (PD) have drawn attention since they impact on patients’ quality of life. We studied cognitive performance and depressive symptoms of PD as measured by Montreal Cognitive Assessment (MOCA) and Montgomery and Asberg Depression Rating Scale (MADRS), based on the results from a national, multicenter, epidemiological E.W.O study (Epidemiology of Wearing-Off symptoms in PD patients treated with L-dopa for 10 years) Methods: Data analyzed from 217 out of 563 consecutive PD patients (83 women, 34 men); detailed records on medical and drug history, clinicians’ assessment, WOQ-9 questionnaire, NMS30, MADRS, HAMA, MOCA used. Results: The most frequent cognitive deficits included impairment of delayed recall and visuospatial/ executive functions. 43.8 % of patients had MOCA scores < 26. MOCA scores were significantly correlated with patients’ age (p < 0.001, r ¼ -0.308), MADRS scores (p ¼ 0.023, r ¼ -0.155) and NMS30 scores (p ¼ 0.010, r ¼ -0.224). MOCA results were not influenced by the cumulative dose of any class of antiparkinsonian medication. Only 17.1% of patients had MADRS score > 14. Sadness, sleep problems, inner tension, and inability to concentrate were the most frequent depressive symptoms. Patients with the first symptom manifestation on the right side had higher MADRS scores compared to those with the left-sided or bilateral manifestations (results adjusted for current Hoehn and Yahr [H-Y] score; p ¼ 0.015). MADRS scores were significantly influenced only by the H-Y score with two peaks at stage 1 and 3 (p ¼ 0.005), and they significantly correlated with HAMA scores (r ¼ 0.681; p < 0.001), NMS30 scores (r ¼ 0.645; p < 0.001), and MOCA scores. Current intake of DA agonists or its daily dose had no impact on MADRS scores. Conclusions: Using the suggested cut-off scores, MOCA revealed dementia in 43.8%, and MADRS revealed depression in 17% of our patients. Antiparkinsonian medication did not influence MOCA results. We demonstrated a significant effect of laterality of the first motor symptom manifestation, and H-Y score on the MADRS results. The current intake or daily dose of DA agonists had no impact on MADRS.
P1-054
TARDBP MUTATION FREQUENCY IN SCANDINAVIAN AMYOTROPHIC LATERAL SCLEROSIS PATIENTS 1,2
1
3 1
Caroline Graff , Huei-Hsin Chiang , Peter M. Andersen , Karolinska Institutet, Dept NVS, KI-ADRC, Huddinge, Sweden; 2Karolinska University Hospital, Huddinge, Sweden; 3Umea˚ University, Department of Pharmacology and Clinical Neuroscience, Umea˚, Sweden. Contact e-mail: caroline. [email protected] Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the upper and lower motor neurons. The main symptoms are progressive muscle weakness, atrophy of the muscles, fasciculation and dysphagia. Age at onset is generally above 55 years. ALS is a heterogeneous disease with different clinical, neuropathologic and genetic subgroups. TAR-DNA-binding protein 43 (TDP-43) is a protein identified in the skein like inclusions and Lewy body like inclusions characteristically found in
S189
the motor neurons in ALS patients. Soon after this discovery, mutations in the gene encoding the TDP-43, TARDBP, were detected in ALS patients. To elucidate the impact of TARDBP mutations in ALS patients in Scandinavia, we sequenced 195 Scandinavian ALS patients for TARDBP mutations. Methods: Exon 1-5 and part of exon 6 were sequenced to include all splice variants of TDP-43 using both forward and reverse primer. Results: Four mutations were detected in three patients: Arg90Val, Gly357Arg, Arg361Thr and Ser379Pro. The first two mutations were detected in the same individual. Five other genetic variations were detected in the non-coding regions of TARDBP: four variations in the 3’UTR and one in intron 4. DNA samples from six family members, one with FTD, to the patient carrying the Arg361Thr mutation were available for segregation analysis. The mutation was present in only those patients with ALS and FTD suggesting that Arg361Ser is pathogenic and can cause both ALS and FTD. There were no DNA samples available from family members to those patients with the other genetic variations. Conclusions: TARDBP mutations were present in a frequency of 1.5% in the Scandinavian ALS patients. Furthermore, TARDBP mutations can cause ALS and FTD. P1-055
A GENOME-WIDE SEARCH FOR STOX1 TARGET GENES, A TRANSCRIPTION FACTOR ASSOCIATED WITH ALZHEIMER’S DISEASE
Daan Van Abel1, Marie Van Dijk1, Dennis Y. M. Lo2, Rossa W. K. Chiu2, Fiona M. F. Lun2, Marinus A. Blankenstein1, Cees B. M. Oudejans1, 1Vu Medical Centre, Amsterdam, Netherlands; 2Chinese University of Hong Kong, Hong Kong, China. Contact e-mail: [email protected] Background: STOX1, a transcription factor initially found to be a susceptibility gene for pre-eclampsia in Dutch women has recently been shown to be functionally involved in late-onset Alzheimer’s disease (LOAD). Since not much is known about STOX1 regulation in LOAD, a search for STOX1 target genes and its mechanism of regulation on these genes is necessary. Methods: Here we describe an in-vitro model system in which we use the neuroblastoma cell-line SK-N-SH as representative of human neuronal function in order to find potential STOX1 target genes on a genome wide scale. STOX1 transfection with a STOX1-Halotag fusion protein was used in an antibody-free alternative approach (HaloCHIP) for chromatin immunoprecipitation (CHiP). The precipitated DNA was then used for high-throughput sequencing (CHIP-Seq). Results: Data analysis was done with the program Quantitative Enrichment of Sequence Tags (QuEST) which successfully generated a top 100 list of potential STOX1 promoter binding regions. Interestingly, two of the regions validated with quantitative PCR lie in predicted promoter sites of genes associated with phosphorylation and splicing of Tau in Alzheimer’s disease Conclusions: These data indicate, in addition to previously published results, that STOX1 is involved in regulating important pathways which are Alzheimer’s disease related.
P1-056
GENETIC VARIATION WITHIN APP PROCESSING GENES CORRELATES WITH CEREBROSPINAL FLUID APP CLEAVAGE PRODUCT LEVELS IN ALZHEIMER PATIENTS AND COGNITIVELY NORMAL SUBJECTS
Lynn M. Bekris1, Nichole Galloway2, Ge Li1, Douglas R. Galasko3, Charles DeCarli4, Martin R. Farlow5, Chris M. Clark6, Joseph F. Quinn7,8, Jeffrey A. Kaye8, Gerard D. Schellenberg6, James B. Leverenz1, Peter Seubert9, Debby W. Tsuang1, Elaine R. Peskind1, Chang E. Yu2, 1 University of Washington, Seattle, WA, USA; 2VA Puget Sound Health Care System, Seattle, WA, USA; 3University of California, San Diego, CA, USA; 4 University of California, Davis, CA, USA; 5Indiana University, Indianapolis, IN, USA; 6University of Pennsylvania, Philadelphia, PA, USA; 7Portland VA Medical Center, Portland, OR, USA; 8Oregon Health and Science University, Portland, OR, USA; 9Elan Pharmaceuticals, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Amyloid precursor protein (APP) post-translational processing involves cleavage by b-secretase to produce an APPb fragment which