- Email: [email protected]
rivastigmine in Parkinson’s disease dementia (PDD)
P.5.d. Dementia and neurological disorders − Neurological disorders (clinical) drug, however, is severely limited by the development of side effect. Levodopa-induced dyskinesias (LID) are involuntary muscle movements that occur as a consequence of chronic levodopa (L-DOPA) treatment. LID are a substantial barrier to effective symptomatic management of Parkinson’s disease (PD), up to 45% of L-DOPA users develop LID within 5 years [1]. Clinical heterogeneity of LID suggests a significant role of endogenous factors in determining their prevalence. Some evidence suggest a relationship between LID and specific genetic changes, such as changes in the genes controlling enzymes responsible for drug and monoamine metabolism, neurotransmitter receptors and proteins involved in oxidative stress or antioxidant function [2−4]. Objective: To investigate contribution of polymorphic variants of CYP2D6 and COMT genes in the development of LID in PD patients. Methods: 212 patients with Parkinson’s disease on levodopa therapy were investigated. Dyskinesias were estimated with use of Abnormal Involuntary Movement Scale (AIMS). DNA extraction and fluorogenic 5 -exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out on 2 SNPs of CYP2D6 (CYP2D6*3, rs35742686; CYP2D6*4, rs3892097) and 7 SNPs of COMT genes (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696). The SPSS software was used for statistical analysis. Results: Patients in our cohort demonstrated typical PD demographics, with a mean age of onset of 60.04±9.46 years, a mean disease duration of 9.79±5.57 years. Dyskinesias were reported in 57 (26.9%) patients. The distribution of genotypes of studied genes corresponded to the Hardy–Weinberg equilibrium. Association of polymorphisms in CYP2D6 gene with side effects was not revealed. We found that rs4680 polymorphism in COMT gene is significantly associated with LID (c2 = 6.048, p = 0.049). Odds ratio for carriers of the genotype AA is 2.14 [95% CI: 1.11– 4.11], which indicates the predisposing effect of this genotype on the development of dyskinesias. Rs4680 is a functional SNP in genes encoding the catechol-O-methyltransferase enzyme, which catabolizes dopamine. A valine to methionine substitution at codon 158 of the COMT gene produces a Met variant that catabolizes dopamine up to four times slower than its Val counterpart. Conclusions: Polymorphisms in the COMT gene play significant role in the therapy response to L-DOPA as well as in various adverse effects. COMT is an extracellular enzyme which inactive variants increase the extracellular concentration of dopamine. This may increase the uptake of dopamine by indirect pathway MSN and therefore increase oxidative stress. We hypothesized that functional single nucleotide polymorphism rs4680 in COMT gene may result in a clinical phenotype contributing to an increased risk of LID. Thus, the polymorphism of gene possessing predisposing effects in development of levodopa induced dyskinesia in PD has been revealed that would allow predicting risk of development of movement disorders. References [1] Rascol, O., Brooks, D.J., Korczyn, A.D, et al. 2000. Study Group: A five–year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or L–DOPA. N Engl J Med 342, 1484–1491. [2] Lu, Y., Mo, C., Zeng, Z., et al. 2013. CYP2D6*4 allele polymorphism increases the risk of Parkinson’s disease: evidence from meta-analysis. PLoS One. 8(12): e84413. [3] Loonen, A.J.M., Ivanova, S.A. 2016. Role of 5-HT2C receptors in dyskinesia. International Journal of Pharmacy and Pharmaceutical Sciences. 8 (1), 5−10.
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[4] Cheshire, P., Bertram, K., Ling, H., et al. 2014. Influence of Single Nucleotide Polymorphisms in COMT, MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson’s Disease. Neurodegener Dis. 13(1): 24−28. Disclosure statement: This abstract is supported by the Russian Science Foundation (project no. 14−35–00023)
P.5.d.006 Concomitant administration of quetiapine/ rivastigmine in Parkinson’s disease dementia (PDD) G. Sulejmanpasic-Arslanagic1 ° , S. Bise2 1 University of Sarajevo Clinical Center, Psychiatric clinic, Sarajevo, Bosnia and Herzegovina; 2 Sarajevo Psychiatric Hospital, Clinical, Sarajevo, Bosnia and Herzegovina Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder that affects an estimated tens of millions people worldwide older than 65 years, and the incidence is 2 percent. PD is the second most common neurodegenerative disease after Alzheimer’s disease, with clinical features (e.g., dementia, spontaneous parkinsonism, and attentional impairment). Dementia also occurs commonly in PD, affecting up to 75% of PD patients over the long term. Psychotic disorders (or psychoses) occurs rarely in untreated PD patients, those with comorbid late dementia, depression, or delirium are at the greatest risk [1,2]. Medication therapy has made significant advances and improvements especially over the last 10 years. A number of new treatments and new strategies have emerged and the quality of life for the average sufferer has improved. Atypical antipsychotic drugs are prescribed for elderly patients with symptoms of psychosis and behavioral disturbances. These symptoms often occur in patients with Parkinson’s disease. Hallucinations occur in up to 20 percent of patients with Parkinson’s disease, delusions, paranoia and subcortical dementia also may occur. Quetiapine has shown promise in the treatment of psychosis in elderly patients with Parkinson’s disease. It improves psychosis without exacerbating movement disorders [3]. Impairment of attention and memory in patients with Parkinson’s disease is associated with significantly lower levels of acetylcholine. Inhibition of the breakdown of acetylcholine by blocking the enzymes acetylcholinesterase and butyrylcholinesterase with rivastigmine improves this cholinergic depletion. Thus rivastigmine administration provides established, effective, long-term symptomatic treatment in patients with Parkinson’s disease dementia (PDD) [4]. Aim: The aim was to evaluate clinical efficacy, safety and tolerability of the concomitant use of quetiapine and rivastigmine in PDD patients. Methods: Six elderly male outpatients entered this 12-week single centre study to assess clinical efficacy of quetiapine and rivastigmine in PDD. Subjects were divided in two groups: quetiapine (N = 3) with dose of 300 mg/day and quetiapine/rivastigmine (N = 3) with dose of 150 mg/day and 6 mg/day. Psychiatric, motor and cognitive assessments were administered at baseline and at periodic intervals for 12 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NP), Unified Parkinson’s Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention and memory. Patients were in contact with neurologist as well all the time. Results: The results revealed significant improvements in the 12-weeks BPRDS total score and NPI psychosis subscale scores with significantly greater in quetiapine/rivastigmine group, with
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P.5.d. Dementia and neurological disorders − Neurological disorders (clinical)
no decline in UPDRS total or motor subscale scores. Also significant improvement was in recall scores on cognitive measures. Conclusions: These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD. Quetiapine is also an effective and well-tolerated antipsychotic in this population. Rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms. Concomitant administration of quetiapine/rivastigmine in patients with (PDD) was good tolerated, with no apparent worsening of the parkinsonian symptoms. References [1] Aarsland, D., Andersen, K., Larsen, J.P., Lolk, A.L., Kragh-Sorensen, P., 2003. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 60, 387–392. [2] Cummings, J.L., 1992. Neuropsychiatric complications of drug treatment in Parkinson’s disease, in: Huber, S., Cummings, J.L. (editors), Parkinson’s Disease: Neurobehavioral Aspects. Oxford University Press, New York, pp. 313–327. [3] Fernandez, H.H., Okun, M.S., Rodriguez, R.L., et al., 2009. Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinicalpolysomnography study. Int J Neurosci 119(12), 2196–2205. [4] Lalli, S., Albanese, A., 2008. Rivastigmine in Parkinson’s disease dementia. Expert Rev Neurother 8(8), 1181–1188.
P.5.d.007 Clinical features of GBA associated Parkinson’s disease K. Senkevich1,2 ° , M. Beletskaia2 , A. Kudrevatykh1 , E. Gracheva1 , A. Emelyanov2 , I. Miliukhina1 , S. Pchelina2 1 Institute of Experimental Medicine, Neurology department, Saint-Petersburg, Russia; 2 First Pavlov’s State Medical University of SaintPetersburg, Laboratory of molecular genetics, Saint-Petersburg, Russia Introduction: Parkinson’s disease (PD) is one of the most common neurodegenerative disease caused by the interaction of genetic and environmental factors. Homozygous mutations in the glucocerebrosidase gene (GBA) lead to the development of autosomal recessive lysosomal storage disorder − Gaucher disease. Heterozygous mutations in the GBA gene are high risk factor for PD development in all populations [1,2]. Patients with Gaucher disease and heterozygous GBA mutation carriers, with no prior history of PD scored significantly lower on cognitive assessments (MOCA and MMSE) than controls [3]. Furthermore, GBA mutations in PD patients were estimated as risk factor for cognitive impairment compared to sporadic Parkinson’s disease (sPD) [4]. Moreover, motor- and cognitive decline and increased mortality in patients with GBA-associated PD (GBA-PD) were shown [5]. There is a number of scales to evaluate specific deficits, in our investigation we used the most common ones. Aim: To identify clinical features of PD in carriers of GBA mutations. Materials and Methods: The study included 7 patients with GBA-PD (L444P n = 5, E326K n = 1, N370S n = 1) and 19 patients with sPD without mutations in the GBA gene. GBA mutations (N370S, L444P) and polymorphic variant E326K were screened using PCR and restriction analysis. Diagnosis of PD was defined according to UK Brain Bank Criteria. Assessments were performed in the dopaminergic ON state. Severity of motor symptoms were assessed with Unified Parkinson’s disease Rating Scale (UPDRS-III) and SCOPA-motor. Disease stage was categorized by
the modified Hoehn and Yahr Scale (H&Y). Cognitive function was tested using the Montreal Cognitive Assessment (MoCA), mini mental state examination (MMSE) and Frontal assessment battery (FAB). To evaluate anxiety, depression and other mood disturbances we used Sheehan disability scale (SDS), The Beck’s Depression Inventory (BDI-II), neuropsychiatric inventory (NPI) and hospital anxiety and depression scale (HADS). For estimation of sleep disorders we used RBD Screening Questionnaire. To determine other non-motor symptoms we used PD-NMS questionnaire. Data analyses were performed by Mann–Whitney U-test in SPSS 15.0 (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL, USA). Results: The following clinical features of GBA-PD were compared between two groups: disease onset, cognitive dysfunction, motor and non-motor dysfunctions. In patients with GBA-PD we showed earlier onset of the disease [54 (46−61) years] compared to sPD [62 (50−75) years] (p = 0.045), more frequent development of anxiety and depression by Sheehan scale (p = 0.032) and the HADS (p = 0.004), the results by NPI scale significantly increased, but did not reach statistical significance. Conclusion: GBA-PD is characterized with early onset and high risk of anxiety and depression development. We didn’t find differences between in the cognitive decline in above mention groups, as were shown in previous articles. Moreover, we revealed statistical differences in anxiety and depression using Sheehan scale and the HADS but not BDI-II. This raises the question of the need to assess the sensitivity and specificity for neuropsychiatric scales in patients with PD. This group of patients requires a special approach in the supervision and selection of therapy. References [1] Sidransky, E., Lopez, G. 2012. The link between the GBA gene and parkinsonism. Lancet Neurology 11, 986–998. [2] Emelyanov, A., Boukina, T., Yakimovskii, A., Usenko, T., Drosdova, A., Zakharchuk, A., Andoskin, P., Dubina, M., Schwarzman, A., Pchelina, S., 2012. Glucocerebrosidase gene mutations are associated with Parkinson’s disease in Russia. Movement Disorders 27, 158–159. [3] McNeill, A., Duran, R., Proukakis, C., Bras, J., Hughes, D., Mehta, A., Hardy, J., Wood, N.W., Schapira, A.H., 2012. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Movement Disorders V 27, 526–532. [4] Malec-Litwinowicz, M., Rudzi´nska, M., Szubiga, M., Michalski, M., Tomaszewski, T., Szczudlik, A., 2014. Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients. Neurologia i Neurochirurgia Polska 48, 258–261. [5] Brockmann, K., Srulijes, K., Pflederer, S., Hauser, A.K., Schulte, C., Maetzler, W., Gasser, T., Berg, D., 2015. GBA associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Movement Disorders 30, 407–411.
P.5.d.008 Chemobrain or cognitive dysfunction after chemotherapy in a patient with concurrent bipolar spectrum disorder M. Nascimento1 , C. Oliveira2 ° , S. Batista3 , T. Maia4 1 Hospital Professor Doutor Fernando Fonseca- EPE, Psychiatry, Amadora, Portugal; 2 Centro Hospitalar Psiqui´atrico de Lisboa, MESMO/ SETA, Lisboa, Portugal; 3 Centro Hospitalar do Algarve- EPE, Faro, Portugal; 4 Hospital Professor Doutor Fernando FonsecaEPE, Portugal Introduction: Chemobrain or cognitive impairment related to chemotherapy is a well-established consequence of oncological treatment especially in breast-cancer survivors [1]. It is estimated to appear in 10 − 40% of patients subject to chemotherapy [2].
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[4] Cheshire, P., Bertram, K., Ling, H., et al. 2014. Influence of Single Nucleotide Polymorphisms in COMT, MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson’s Disease. Neurodegener Dis. 13(1): 24−28. Disclosure statement: This abstract is supported by the Russian Science Foundation (project no. 14−35–00023)
P.5.d.006 Concomitant administration of quetiapine/ rivastigmine in Parkinson’s disease dementia (PDD) G. Sulejmanpasic-Arslanagic1 ° , S. Bise2 1 University of Sarajevo Clinical Center, Psychiatric clinic, Sarajevo, Bosnia and Herzegovina; 2 Sarajevo Psychiatric Hospital, Clinical, Sarajevo, Bosnia and Herzegovina Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder that affects an estimated tens of millions people worldwide older than 65 years, and the incidence is 2 percent. PD is the second most common neurodegenerative disease after Alzheimer’s disease, with clinical features (e.g., dementia, spontaneous parkinsonism, and attentional impairment). Dementia also occurs commonly in PD, affecting up to 75% of PD patients over the long term. Psychotic disorders (or psychoses) occurs rarely in untreated PD patients, those with comorbid late dementia, depression, or delirium are at the greatest risk [1,2]. Medication therapy has made significant advances and improvements especially over the last 10 years. A number of new treatments and new strategies have emerged and the quality of life for the average sufferer has improved. Atypical antipsychotic drugs are prescribed for elderly patients with symptoms of psychosis and behavioral disturbances. These symptoms often occur in patients with Parkinson’s disease. Hallucinations occur in up to 20 percent of patients with Parkinson’s disease, delusions, paranoia and subcortical dementia also may occur. Quetiapine has shown promise in the treatment of psychosis in elderly patients with Parkinson’s disease. It improves psychosis without exacerbating movement disorders [3]. Impairment of attention and memory in patients with Parkinson’s disease is associated with significantly lower levels of acetylcholine. Inhibition of the breakdown of acetylcholine by blocking the enzymes acetylcholinesterase and butyrylcholinesterase with rivastigmine improves this cholinergic depletion. Thus rivastigmine administration provides established, effective, long-term symptomatic treatment in patients with Parkinson’s disease dementia (PDD) [4]. Aim: The aim was to evaluate clinical efficacy, safety and tolerability of the concomitant use of quetiapine and rivastigmine in PDD patients. Methods: Six elderly male outpatients entered this 12-week single centre study to assess clinical efficacy of quetiapine and rivastigmine in PDD. Subjects were divided in two groups: quetiapine (N = 3) with dose of 300 mg/day and quetiapine/rivastigmine (N = 3) with dose of 150 mg/day and 6 mg/day. Psychiatric, motor and cognitive assessments were administered at baseline and at periodic intervals for 12 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NP), Unified Parkinson’s Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention and memory. Patients were in contact with neurologist as well all the time. Results: The results revealed significant improvements in the 12-weeks BPRDS total score and NPI psychosis subscale scores with significantly greater in quetiapine/rivastigmine group, with
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no decline in UPDRS total or motor subscale scores. Also significant improvement was in recall scores on cognitive measures. Conclusions: These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD. Quetiapine is also an effective and well-tolerated antipsychotic in this population. Rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms. Concomitant administration of quetiapine/rivastigmine in patients with (PDD) was good tolerated, with no apparent worsening of the parkinsonian symptoms. References [1] Aarsland, D., Andersen, K., Larsen, J.P., Lolk, A.L., Kragh-Sorensen, P., 2003. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 60, 387–392. [2] Cummings, J.L., 1992. Neuropsychiatric complications of drug treatment in Parkinson’s disease, in: Huber, S., Cummings, J.L. (editors), Parkinson’s Disease: Neurobehavioral Aspects. Oxford University Press, New York, pp. 313–327. [3] Fernandez, H.H., Okun, M.S., Rodriguez, R.L., et al., 2009. Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinicalpolysomnography study. Int J Neurosci 119(12), 2196–2205. [4] Lalli, S., Albanese, A., 2008. Rivastigmine in Parkinson’s disease dementia. Expert Rev Neurother 8(8), 1181–1188.
P.5.d.007 Clinical features of GBA associated Parkinson’s disease K. Senkevich1,2 ° , M. Beletskaia2 , A. Kudrevatykh1 , E. Gracheva1 , A. Emelyanov2 , I. Miliukhina1 , S. Pchelina2 1 Institute of Experimental Medicine, Neurology department, Saint-Petersburg, Russia; 2 First Pavlov’s State Medical University of SaintPetersburg, Laboratory of molecular genetics, Saint-Petersburg, Russia Introduction: Parkinson’s disease (PD) is one of the most common neurodegenerative disease caused by the interaction of genetic and environmental factors. Homozygous mutations in the glucocerebrosidase gene (GBA) lead to the development of autosomal recessive lysosomal storage disorder − Gaucher disease. Heterozygous mutations in the GBA gene are high risk factor for PD development in all populations [1,2]. Patients with Gaucher disease and heterozygous GBA mutation carriers, with no prior history of PD scored significantly lower on cognitive assessments (MOCA and MMSE) than controls [3]. Furthermore, GBA mutations in PD patients were estimated as risk factor for cognitive impairment compared to sporadic Parkinson’s disease (sPD) [4]. Moreover, motor- and cognitive decline and increased mortality in patients with GBA-associated PD (GBA-PD) were shown [5]. There is a number of scales to evaluate specific deficits, in our investigation we used the most common ones. Aim: To identify clinical features of PD in carriers of GBA mutations. Materials and Methods: The study included 7 patients with GBA-PD (L444P n = 5, E326K n = 1, N370S n = 1) and 19 patients with sPD without mutations in the GBA gene. GBA mutations (N370S, L444P) and polymorphic variant E326K were screened using PCR and restriction analysis. Diagnosis of PD was defined according to UK Brain Bank Criteria. Assessments were performed in the dopaminergic ON state. Severity of motor symptoms were assessed with Unified Parkinson’s disease Rating Scale (UPDRS-III) and SCOPA-motor. Disease stage was categorized by
the modified Hoehn and Yahr Scale (H&Y). Cognitive function was tested using the Montreal Cognitive Assessment (MoCA), mini mental state examination (MMSE) and Frontal assessment battery (FAB). To evaluate anxiety, depression and other mood disturbances we used Sheehan disability scale (SDS), The Beck’s Depression Inventory (BDI-II), neuropsychiatric inventory (NPI) and hospital anxiety and depression scale (HADS). For estimation of sleep disorders we used RBD Screening Questionnaire. To determine other non-motor symptoms we used PD-NMS questionnaire. Data analyses were performed by Mann–Whitney U-test in SPSS 15.0 (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL, USA). Results: The following clinical features of GBA-PD were compared between two groups: disease onset, cognitive dysfunction, motor and non-motor dysfunctions. In patients with GBA-PD we showed earlier onset of the disease [54 (46−61) years] compared to sPD [62 (50−75) years] (p = 0.045), more frequent development of anxiety and depression by Sheehan scale (p = 0.032) and the HADS (p = 0.004), the results by NPI scale significantly increased, but did not reach statistical significance. Conclusion: GBA-PD is characterized with early onset and high risk of anxiety and depression development. We didn’t find differences between in the cognitive decline in above mention groups, as were shown in previous articles. Moreover, we revealed statistical differences in anxiety and depression using Sheehan scale and the HADS but not BDI-II. This raises the question of the need to assess the sensitivity and specificity for neuropsychiatric scales in patients with PD. This group of patients requires a special approach in the supervision and selection of therapy. References [1] Sidransky, E., Lopez, G. 2012. The link between the GBA gene and parkinsonism. Lancet Neurology 11, 986–998. [2] Emelyanov, A., Boukina, T., Yakimovskii, A., Usenko, T., Drosdova, A., Zakharchuk, A., Andoskin, P., Dubina, M., Schwarzman, A., Pchelina, S., 2012. Glucocerebrosidase gene mutations are associated with Parkinson’s disease in Russia. Movement Disorders 27, 158–159. [3] McNeill, A., Duran, R., Proukakis, C., Bras, J., Hughes, D., Mehta, A., Hardy, J., Wood, N.W., Schapira, A.H., 2012. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Movement Disorders V 27, 526–532. [4] Malec-Litwinowicz, M., Rudzi´nska, M., Szubiga, M., Michalski, M., Tomaszewski, T., Szczudlik, A., 2014. Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients. Neurologia i Neurochirurgia Polska 48, 258–261. [5] Brockmann, K., Srulijes, K., Pflederer, S., Hauser, A.K., Schulte, C., Maetzler, W., Gasser, T., Berg, D., 2015. GBA associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Movement Disorders 30, 407–411.
P.5.d.008 Chemobrain or cognitive dysfunction after chemotherapy in a patient with concurrent bipolar spectrum disorder M. Nascimento1 , C. Oliveira2 ° , S. Batista3 , T. Maia4 1 Hospital Professor Doutor Fernando Fonseca- EPE, Psychiatry, Amadora, Portugal; 2 Centro Hospitalar Psiqui´atrico de Lisboa, MESMO/ SETA, Lisboa, Portugal; 3 Centro Hospitalar do Algarve- EPE, Faro, Portugal; 4 Hospital Professor Doutor Fernando FonsecaEPE, Portugal Introduction: Chemobrain or cognitive impairment related to chemotherapy is a well-established consequence of oncological treatment especially in breast-cancer survivors [1]. It is estimated to appear in 10 − 40% of patients subject to chemotherapy [2].