- Email: [email protected]
Alcohol-related dementia: A common diagnosis in younger persons
Poster Presentations P1
S188
frontal pcorrected ¼ 0.06, temporal pcorrected ¼ 0.04, occipital pcorrected ¼ 0.03). PDMCI showed significantly larger bilateral temporal and occipital, and left frontal horn radial distance relative to PDCN (left: frontal pcorrected ¼ 0.01, temporal pcorrected ¼ 0.01, occipital pcorrected ¼ 0.0004; right: temporal pcorrected ¼ 0.005, occipital pcorrected ¼ 0.03). Between the two PDMCI subtypes nonamnestic PDMCI subjects showed more significant and pronounced (up to 30%, p < 0.01) ventricular enlargement spanning all parts of the lateral ventricle while amnestic PDMCI subjects showed ventricular changes localized to the left occipital horn (up to 20%, p ¼ 0.03). Conclusions: We found subtle but significant hippocampal changes in PDCN and nonamnestic PDMCI as well as extensive enlargement of the lateral ventricles in both PDCN and PDMCI. Hippocampal atrophy and lateral ventricular enlargement show promise as sensitive biomarkers for tracking PD and PDD progression.
P1-050
PROTEASE-SENSITIVE PRIONOPATHY IN A COGNITIVELY NORMAL 93-YEAR-OLD
Nupur Ghoshal1, Nigel J. Cairns1, Gianfranco Puoti2, Pierluigi Gambetti2, John C. Morris1, 1Washington University, St. Louis, MO, USA; 2National Prion Disease Pathology Surveillance Center, Cleveland, OH, USA. Contact e-mail: [email protected] Background: Protease-sensitive prionopathy (PSPr) is a recently described novel prion disease biochemically characterized by abnormal prion protein (PrP) sensitive to proteases resulting in a distinct profile on Western blot. Clinically, cases reported to date have presented with behavioral and psychiatric difficulties with an average age of onset of 62 and with a mean disease duration of 20 months. Most PSPr-affected subjects are homozygous for valine at codon 129 (VV) and have no mutation in the PrP gene. Methods: The individual was clinically examined between 1996-2002, including semi-structured interviews, Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) assessments, and retrospective postmortem dementia interview of surviving family. After death, the brain was examined and processed using standard neuropathologic methods and tau, beta amyloid, and PrP immunostaining. DNA was extracted from frozen brain tissue for sequence analysis. Frozen brain tissue was also used for Western blot analyses. Results: This individual was cognitively intact during her initial assessment (CDR 0; MMSE 30) at age 87 and remained cognitively unchanged until her death at age 93 (CDR 0). As a result, no ancillary studies were conducted including EEG, CSF, and imaging. Furthermore, no neurologic abnormalities associated with prion disease were observed. At autopsy, unfixed brain weight was 1180 grams and noted to have mild frontal atrophy; however, the basal ganglia and cerebellum were unremarkable. Neuronal loss, gliosis, and spongiform change were evident in the deeper cortical layers but were absent in the cerebellum. There was weak PrP immunostaining in the cortex and none in the cerebellum. DNA sequence analysis ruled out the presence of a pathogenic mutation in the coding region of the PrP gene and determined the codon 129 genotype as homozygous for methionine (MM). Western blot analysis confirmed the diagnosis of PSPr. Conclusions: To our knowledge, this is the first description of PSPr in a case lacking clinically detectable dementia and advanced age at the time of death. This case report adds to the growing pathological spectrum of prion diseases. Support: P50 AG005681, P01 AG003991 (NG, NJC, JCM); The Patrick Yobs Gerstmann-StrausslerSheinker Grant (GP); P01 AG014359, CDC UR8/ CCU515004 and the Charles S. Britton Fund (PG)
P1-051
DIETARY FAT AND CHOLESTEROL CAUSES NEURONAL ENDOSOMAL ABNORMALITIES AND BASAL FOREBRAIN CHOLINERGIC NEURODEGENERATION IN WILD-TYPE MICE
Jennifer H. K. Choi1,2, Anne Boyer-Boiteau3, Jose Morales-Corraliza2,4, Stephen D. Ginsberg1,2, Efrat Levy1,2, Paul M. Mathews1,2, 1NYU School of Medicine/Sackler Institute, New York, NY, USA; 2Nathan Kline Institute,
Orangeburg, NY, USA; 3McLean Hospital, Belmont, MA, USA; 4NYU School of Medicine, New York, NY, USA. Contact e-mail: [email protected]. org Background: Cholesterol and metabolic syndrome are risk factors for Alzheimer’s disease pathobiology. Neuronal endocytic defects have been observed at early stages of Alzheimer’s disease and Down syndrome (DS), and can be modulated by cholesterol levels. Methods: Wild-type mice were fed a high fat/cholesterol diet for 4 weeks starting at 8 months of age. We have characterized and quantitated neuronal early endosomes and basal forebrain cholinergic neurons (BFCN) after dietary treatment. In order to evaluate the effect of high fat/cholesterol on nerve growth factor (NGF) retrograde transport to the medial septal nucleus, 125I-NGF was injected into the hippocampus, and its delivery to the medial septal nucleus measured. Results: Rab5 immunolabeling detected altered early endosome morphology in pyramidal neurons of the cingulate cortex revealing that dietary high fat/cholesterol in wild-type mice leads to an increased number of large endosomes per neuron (n ¼ 4.5 6 0.67) when compared to those in mice fed a basal diet (n ¼ 1.7 6 0.35; p ¼ 0.001). A similar endosomal phenotype is observed in a DS mouse model, the Ts[Rb12.1716)]2Cje, as has been reported for the related Ts65Dn DS mouse model. Dystrophic neurites and reduced density of BFCNs, a neurodegenerative phenotype that is known to result from endosomal pathology in Ts65Dn mice, were detected by choline acetyltransferase immunolabeling after 4 weeks of dietary high fat/cholesterol. Preliminary findings indicate defective retrograde transport of NGF, with only w20% as much NGF transported to the basal forebrain 20 hours after injection into the hippocampus in mice on high fat/cholesterol diet. Gene dosage of amyloid precursor protein affects endosome morphology. Accordingly, we have examined the transgenic mouse that over expresses the human London V717I mutation of amyloid precursor protein, and determined that it also has neuronal endosomal alterations, as well as BFCN degeneration. Conclusions: Dietary hyperlipidemia intake alone is sufficient to lead to endosomal pathology and basal forebrain cholinergic neurodegeneration in the brains of wildtype mice through deficits in signaling endosome-mediated NGF trophic support.
P1-052
ALCOHOL-RELATED DEMENTIA: A COMMON DIAGNOSIS IN YOUNGER PERSONS
Adrienne Withall1,2, Brian Draper2, 1The University of New South Wales, Sydney, Australia; 2The Prince of Wales Hospital, Sydney, Australia. Contact e-mail: [email protected] Background: Young (or early) onset dementia is defined as dementia with onset before age 65. Alcohol related dementia typically has an early age of onset and often falls within this category. Little is known about the prevalence and service delivery for alcohol related dementia and disagreement often exists as to whether persons with this diagnosis should be managed within dementia services. Methods: The prevalence and diagnostic subtypes of young onset dementia were studied in the Eastern Sydney Area of Australia, which has a total population of 130,000 persons aged 30-64. A case-finding survey and hospital records search, with capture-recapture methodology, were used. In order to be included patients had to be resident within the area and alive as at 1st June 2008, have an onset of memory, behavioural and/or language symptoms before age 65 and have persistent cognitive impairment for at least 6 months. The dementia diagnosis for identified cases was verified through a medical case note review. Results: One hundred and thirty six young onset dementia patients were identified in the area. Alcohol related dementia was the most common primary diagnosis accounting for 22.1% of cases. Alcohol related dementia was a secondary diagnosis for a further 4% of cases and was usually comorbid with vascular dementia. The rate of alcohol related dementia was 18 per 100,000 population aged 30-64 at risk and the average age at onset was 52 years. This group were often isolated, had complex medical histories and had diverse health system access points. Conclusions: The rate of alcohol related dementia in this study is considerably higher than a previous 2003 UK study which reported a rate of 7 per 100,000 at risk. More research needs to be conducted to verify these
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
S188
frontal pcorrected ¼ 0.06, temporal pcorrected ¼ 0.04, occipital pcorrected ¼ 0.03). PDMCI showed significantly larger bilateral temporal and occipital, and left frontal horn radial distance relative to PDCN (left: frontal pcorrected ¼ 0.01, temporal pcorrected ¼ 0.01, occipital pcorrected ¼ 0.0004; right: temporal pcorrected ¼ 0.005, occipital pcorrected ¼ 0.03). Between the two PDMCI subtypes nonamnestic PDMCI subjects showed more significant and pronounced (up to 30%, p < 0.01) ventricular enlargement spanning all parts of the lateral ventricle while amnestic PDMCI subjects showed ventricular changes localized to the left occipital horn (up to 20%, p ¼ 0.03). Conclusions: We found subtle but significant hippocampal changes in PDCN and nonamnestic PDMCI as well as extensive enlargement of the lateral ventricles in both PDCN and PDMCI. Hippocampal atrophy and lateral ventricular enlargement show promise as sensitive biomarkers for tracking PD and PDD progression.
P1-050
PROTEASE-SENSITIVE PRIONOPATHY IN A COGNITIVELY NORMAL 93-YEAR-OLD
Nupur Ghoshal1, Nigel J. Cairns1, Gianfranco Puoti2, Pierluigi Gambetti2, John C. Morris1, 1Washington University, St. Louis, MO, USA; 2National Prion Disease Pathology Surveillance Center, Cleveland, OH, USA. Contact e-mail: [email protected] Background: Protease-sensitive prionopathy (PSPr) is a recently described novel prion disease biochemically characterized by abnormal prion protein (PrP) sensitive to proteases resulting in a distinct profile on Western blot. Clinically, cases reported to date have presented with behavioral and psychiatric difficulties with an average age of onset of 62 and with a mean disease duration of 20 months. Most PSPr-affected subjects are homozygous for valine at codon 129 (VV) and have no mutation in the PrP gene. Methods: The individual was clinically examined between 1996-2002, including semi-structured interviews, Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) assessments, and retrospective postmortem dementia interview of surviving family. After death, the brain was examined and processed using standard neuropathologic methods and tau, beta amyloid, and PrP immunostaining. DNA was extracted from frozen brain tissue for sequence analysis. Frozen brain tissue was also used for Western blot analyses. Results: This individual was cognitively intact during her initial assessment (CDR 0; MMSE 30) at age 87 and remained cognitively unchanged until her death at age 93 (CDR 0). As a result, no ancillary studies were conducted including EEG, CSF, and imaging. Furthermore, no neurologic abnormalities associated with prion disease were observed. At autopsy, unfixed brain weight was 1180 grams and noted to have mild frontal atrophy; however, the basal ganglia and cerebellum were unremarkable. Neuronal loss, gliosis, and spongiform change were evident in the deeper cortical layers but were absent in the cerebellum. There was weak PrP immunostaining in the cortex and none in the cerebellum. DNA sequence analysis ruled out the presence of a pathogenic mutation in the coding region of the PrP gene and determined the codon 129 genotype as homozygous for methionine (MM). Western blot analysis confirmed the diagnosis of PSPr. Conclusions: To our knowledge, this is the first description of PSPr in a case lacking clinically detectable dementia and advanced age at the time of death. This case report adds to the growing pathological spectrum of prion diseases. Support: P50 AG005681, P01 AG003991 (NG, NJC, JCM); The Patrick Yobs Gerstmann-StrausslerSheinker Grant (GP); P01 AG014359, CDC UR8/ CCU515004 and the Charles S. Britton Fund (PG)
P1-051
DIETARY FAT AND CHOLESTEROL CAUSES NEURONAL ENDOSOMAL ABNORMALITIES AND BASAL FOREBRAIN CHOLINERGIC NEURODEGENERATION IN WILD-TYPE MICE
Jennifer H. K. Choi1,2, Anne Boyer-Boiteau3, Jose Morales-Corraliza2,4, Stephen D. Ginsberg1,2, Efrat Levy1,2, Paul M. Mathews1,2, 1NYU School of Medicine/Sackler Institute, New York, NY, USA; 2Nathan Kline Institute,
Orangeburg, NY, USA; 3McLean Hospital, Belmont, MA, USA; 4NYU School of Medicine, New York, NY, USA. Contact e-mail: [email protected]. org Background: Cholesterol and metabolic syndrome are risk factors for Alzheimer’s disease pathobiology. Neuronal endocytic defects have been observed at early stages of Alzheimer’s disease and Down syndrome (DS), and can be modulated by cholesterol levels. Methods: Wild-type mice were fed a high fat/cholesterol diet for 4 weeks starting at 8 months of age. We have characterized and quantitated neuronal early endosomes and basal forebrain cholinergic neurons (BFCN) after dietary treatment. In order to evaluate the effect of high fat/cholesterol on nerve growth factor (NGF) retrograde transport to the medial septal nucleus, 125I-NGF was injected into the hippocampus, and its delivery to the medial septal nucleus measured. Results: Rab5 immunolabeling detected altered early endosome morphology in pyramidal neurons of the cingulate cortex revealing that dietary high fat/cholesterol in wild-type mice leads to an increased number of large endosomes per neuron (n ¼ 4.5 6 0.67) when compared to those in mice fed a basal diet (n ¼ 1.7 6 0.35; p ¼ 0.001). A similar endosomal phenotype is observed in a DS mouse model, the Ts[Rb12.1716)]2Cje, as has been reported for the related Ts65Dn DS mouse model. Dystrophic neurites and reduced density of BFCNs, a neurodegenerative phenotype that is known to result from endosomal pathology in Ts65Dn mice, were detected by choline acetyltransferase immunolabeling after 4 weeks of dietary high fat/cholesterol. Preliminary findings indicate defective retrograde transport of NGF, with only w20% as much NGF transported to the basal forebrain 20 hours after injection into the hippocampus in mice on high fat/cholesterol diet. Gene dosage of amyloid precursor protein affects endosome morphology. Accordingly, we have examined the transgenic mouse that over expresses the human London V717I mutation of amyloid precursor protein, and determined that it also has neuronal endosomal alterations, as well as BFCN degeneration. Conclusions: Dietary hyperlipidemia intake alone is sufficient to lead to endosomal pathology and basal forebrain cholinergic neurodegeneration in the brains of wildtype mice through deficits in signaling endosome-mediated NGF trophic support.
P1-052
ALCOHOL-RELATED DEMENTIA: A COMMON DIAGNOSIS IN YOUNGER PERSONS
Adrienne Withall1,2, Brian Draper2, 1The University of New South Wales, Sydney, Australia; 2The Prince of Wales Hospital, Sydney, Australia. Contact e-mail: [email protected] Background: Young (or early) onset dementia is defined as dementia with onset before age 65. Alcohol related dementia typically has an early age of onset and often falls within this category. Little is known about the prevalence and service delivery for alcohol related dementia and disagreement often exists as to whether persons with this diagnosis should be managed within dementia services. Methods: The prevalence and diagnostic subtypes of young onset dementia were studied in the Eastern Sydney Area of Australia, which has a total population of 130,000 persons aged 30-64. A case-finding survey and hospital records search, with capture-recapture methodology, were used. In order to be included patients had to be resident within the area and alive as at 1st June 2008, have an onset of memory, behavioural and/or language symptoms before age 65 and have persistent cognitive impairment for at least 6 months. The dementia diagnosis for identified cases was verified through a medical case note review. Results: One hundred and thirty six young onset dementia patients were identified in the area. Alcohol related dementia was the most common primary diagnosis accounting for 22.1% of cases. Alcohol related dementia was a secondary diagnosis for a further 4% of cases and was usually comorbid with vascular dementia. The rate of alcohol related dementia was 18 per 100,000 population aged 30-64 at risk and the average age at onset was 52 years. This group were often isolated, had complex medical histories and had diverse health system access points. Conclusions: The rate of alcohol related dementia in this study is considerably higher than a previous 2003 UK study which reported a rate of 7 per 100,000 at risk. More research needs to be conducted to verify these
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