Jolanta Florczak-Wyspiańska

Update on neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) defines a heterogeneous group of progressive neurodegenerative disorders characterized by excessive iron accumulation in the brain, particularly affecting the basal ganglia. In the recent years considerable development in the field of neurodegenerative disorders has been observed. Novel genetic methods such as autozygosity mapping have recently identified several genetic causes of NBIA. Our knowledge about clinical spectrum has broadened and we are now more aware of an overlap between the different NBIA disorders as well as with other diseases. Neuropathologic point of view has also been changed. It has been postulated that pantothenate kinase-associated neurodegeneration (PKAN) is not synucleinopathy. However, exact pathologic mechanism of NBIA remains unknown. The situation implicates a development of new therapies, which still are symptomatic and often unsatisfactory. In the present review, some of the main clinical presentations, investigational findings and therapeutic results of the different NBIA disorders will be presented.

Normal Aging and Dementia

Normal aging begins after 60 years of age. According to Harman, the accumulation of free radicals, which results from weakening of repair and protective mechanisms, takes place in the aging brain. It is believed that especially in the population of the most elderly there is increased incidence of both dementia and depression. The causes of these central nervous system disorders in the aging human body are changes at the molecular level, such as changes in the biochemical parameters, the accumulation of mutations in nuclear and mitochondrial DNA, and epigenetic changes. Biomarkers associated with aging of the brain include accumulated deposits of β-amyloid (Aβ), disturbed cholesterol homeostasis, altered neuroimaging parameters, and impaired glucose metabolism. Genetic factors are also responsible for normal aging, for example, SIRT1, AKT1, and CDKN1A, and among them the longevity genes, such as FOXO3A and CETP. Dementia as well as cognitive decline may be modified by poly-T variants of TOMM40 and APOE alleles via influencing the level of apolipoprotein E (apoE) in the brain and in the plasma as well as by its ability of Aβ clearance. Identifying the molecular factors associated with aging and dementia may help introduce new approaches to preventing geriatric disorders, including depression and dementia.

Analysis of PRKN Variants and Clinical Features in Polish Patients with Parkinson’s Disease

The etiology of Parkinson’s disease (PD) is still unclear, but mutations in PRKN have provided some biological insights. The role of PRKN mutations and other genetic variation in determining the clinical features of PD remains unresolved. The aim of the study was to analyze PRKN mutations in PD and controls in the Polish population and to try to correlate between the presence of genetic variants and clinical features. We screened for PRKN mutations in 90 PD patients and 113 controls and evaluated clinical features in these patients. We showed that in the Polish population 4% of PD patients had PRKN mutations (single or with additional polymorphism) while single heterozygous polymorphisms (S167N, E310D, D394N) of PRKN were present in 21% of sporadic PD. Moreover, 5% PD patients had more than one PRKN change (polymorphisms and mutations). Detected PRKN variants moderately correlated with PD course and response to L-dopa. It also showed that other PARK genes (SNCA, HTRA2, SPR) mutations probably may additionally influence PD risk and clinical features. PRKN variants are relatively common in our Polish series of patients with PD. Analysis of the PRKN gene may be useful in determining clinical phenotype, and helping with diagnostic and prognostic procedures in the future.

Substantia nigra hyperechogenicity in Polish patients with Parkinson’s disease

BACKGROUND Hyperechogenicity of the substantia nigra (SN) measured by transcranial sonography (TCS) is a characteristic feature observed in patients with Parkinsons disease (PD). To our knowledge, no SN hyperechogenicity data are available for Polish population. Moreover most of studies come from few centres, which used the one type of ultrasound device. The main aim of the study was to investigate the association between PD and SN hyperechogenicity measured by sonographic machine, not assessed so far. MATERIALS AND METHODS In this study cross-sectional study SN hyperechogenicity was evaluated in 102 PD patients and 95 control subjects. Midbrain was visualised by Aloka Prosound 7 ultrasound device. SN area measurement, the relation to the clinical features of PD, inter- and intra-observer reliability were evaluated. RESULTS We confirmed that SN echogenicity is significantly increased in PD patients compared to control subjects (p < 0.001). The area under curve for PD patients vs. controls was 0.93. Receiver operating characteristic analysis indicated a cut-offs for SN echogenicity at 0.19 cm² with accuracy equal to 90%, specificity - 86% and sensitivity - 93.7%. The SN hyperechogenicity was not related to PD clinical findings. Reliability was good if an experienced sonographer performed the SN measurements. CONCLUSIONS This study shows that the SN abnormality observed by TCS isa specific feature, which can be helpful in the process of PD diagnosing.

Mutations of the SNCA gene and alpha-synuclein level in the patients with diseases of the extrapyramidal system

Parkinsons disease (PD) is one of the most common degenerative diseases of the extrapyramidal system and the incidence of this disease increases several times with age. It is believed currently that the cause of PD are environmental and genetics factors. An important genetic factors associated with disclosure of PD are SNCA gene mutations and polymorphisms of the region NACP-Rep1 promoter of SNCA, which may affect on the level of alpha-synuclein (ASN). The aim of the study was analysis of G88C mutation and the NACP-Rep1 region in the promoter of SNCA gene and the study of ASN level. The study was conducted on 78 individuals of the Polish population: 40 patients with diagnosed PD (18W and 22M, the average age 65 years), 4 patients with diagnosed multiple system atrophy (3W and 1M, the average age 59 years), 9 patients with diagnosed parkinsonism (5W and 4M, the average age 55 years) and 25 control volunteers without neurological symptoms and dementia (18W and 7M, the average age 57 years). G88C mutation in the SNCA gene was analyzed by performing PCR-RFLP reaction, polymorphism of the NACP-Rep1 promoter region of SNCA gene was evaluated using PCR reaction and capillary electro-phoresis. The ASN level in blood plasma was determined by ELISA. The result of the conducted studies was the exclusion of the presence of the familiar grounds of PD, which are connected with the G88C mutation in the SNCA gene, both among 53 patients with diseases of the extrapyramidal system and 38 control volunteers. Moreover, it was shown that in the Polish population the allele 0, +1, +2, +3 and the haplotypes 0/+1, 0/+2, +1/+1, +1/+2, +2/+2 and +2/+3 of the SNCA promoter region can appear with a various frequency among patients with analyzed disorders of the extra-pyramidal system. It was also shown that both the al-lele 0 and +1 and the haplotypes +2/+2 and +2/+3 of the promoter region SNCA gene can influence differently the disclosure of PD. It was also proved that level of ASN both among the patients with PD and with parkinsonism depends from the haplotype of the promoter region SNCA gene. The advancement and duration of the disease among patients with PD can have an impact on the level of ASN. It seems that polymorphism of the NACP-Rep1 in the promoter region of SNCA gene influence on the level of ASN among patients with diseases of the ex-trapyramidal system.

Paraneoplastic movement disorders

Abstract Paraneoplastic movement disorders are rare, autoimmune-mediated, nonmetastatic complications of malignant neoplasms. Common paraneoplastic movement disorders include paraneoplastic chorea, dystonia, cerebellar degeneration, different types of encephalitis, opsoclonus-myoclonus syndrome, stiff person syndrome, and neuromyotonia. Syndromes usually develop before tumor diagnosis, have subacute onset, and are associated with serum or cerebrospinal fluid antibodies. Two types of antibodies can be distinguished: antibodies against nuclear and cytoplasmic neuronal antigens (anti-Hu, anti-Ri, anti-Yo, anti-Ma, anti-CV2/CRMP5, anti-Gephrin, and anti-GABATRAP) and antibodies recently identified against cell surface and synaptic proteins (anti-NMDAR, anti-LGI1, and anti-Caspr2). These two types differ from each other in a few important aspects. Antibodies against cell surface and synaptic protein disrupt cell-surface antigens. Clinical symptoms are related to the disruption of antigens and potentially can be reversed by immunotherapy. The association between these antibodies and malignancy is much less consistent. On the other hand, antibodies against nuclear and cytoplasmic neuronal antigens seem to be not pathogenic; however, they most likely indicate a T-cell-mediated immune response against neurons. Due to T-cell-mediated neuronal loss, response to immunotherapy is generally disappointing. Early recognition of all these diseases is crucial because it may lead to the disclosure of occult cancer. This review is focused on paraneoplastic movement disorders with emphasis on clinical presentations, investigational findings, and therapeutic results.

Biothiols and oxidative stress markers and polymorphisms of TOMM40 and APOC1 genes in Alzheimer's disease patients

Alzheimer’s disease (AD) is a progressive disease, with frequently observed improper biothiols turnover, homocysteine (Hcy) and glutathione (GSH). GSH protects cells from oxidative stress and may be determined by 8-oxo-2’-deoxyguanosine (8-oxo2dG) level and its repair enzyme 8-oxoguanine DNA glycosylase (OGG1). The presence of unfavorable alleles, e.g., in APOE cluster, TOMM40 or APOC1 is known to facilitate the dementia onset under oxidative stress. The aim of the study was to analyze rs1052452, rs2075650 TOMM40 polymorphisms, rs4420638 APOC1, and their correlation with Hcy, GSH, 8-oxo2dG, OGG1 levels in plasma of AD patients and controls. We recruited 230 individuals: 88 AD, 80 controls without (UC), 62 controls with (RC) positive family history of AD. The TOMM40 genotype was determined by HRM and capillary electrophoresis, while APOC1 by HRM. The concentrations of OGG1, 8-oxo2dG were determined by ELISA, whereas Hcy, GSH by HPLC/EC. We showed that over 60% of AD patients had increased Hcy levels (p<0.01 vs. UC, p<0.001 vs. RC), while GSH (p<0.01 vs. UC), 8-oxo2dG (p<0.01 vs. UC, p<0.001 vs. RC) were reduced. Minor variants: rs10524523-L, rs4420638-G, rs2075650-G were significantly overrepresented in AD. For rs4420638-G, rs2075650-G variants, the association remained significant in APOE E4 non-carriers. The misbalance of analyzed biothiols, and 8-oxo2dG, OGG1 were more pronounced in carriers of major variants: rs10524523-S/VL, rs4420638-A, rs2075650-A. We showed, for the first time, that APOC1 and TOMM40 rs2075650 polymorphisms may be independent risk factors of developing AD, whose major variants are accompanied by disruption of biothiols metabolism and inefficient removal of DNA oxidation.

THE APOE GENE CLUSTER POLYMORPHISMS AND OXIDATIVE STRESS FACTORS IN PATIENTS WITH ALZHEIMER’S DISEASE

P3-221 LONGITUDINAL ASSOCIATION BETWEEN PHOSPHATIDYLCHOLINES, NEUROIMAGING MEASURES OF ALZHEIMER’S DISEASE PATHOPHYSIOLOGY, AND COGNITION IN THE MAYO CLINIC STUDY ON AGING Danni Li, Clinton E. Hagen, David S. Knopman, Clifford R. Jack, Jr,, Ronald C. Petersen, Michelle M. Mielke, University of Minnesota, Minneapolis, MN, USA; Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA. Contact e-mail: dannili@ umn.edu

Mitochondrial Respiration in Intact Peripheral Blood Mononuclear Cells and Sirtuin 3 Activity in Patients with Movement Disorders

Objective Mitochondrial dysfunction is considered a unifying pathophysiological explanation for movement disorders. Sirtuin 3 (SIRT3) exhibits deacetylase activity and antioxidant properties. The aim of the study was to analyze the mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and the SIRT3 activity in patients with movement disorders. Methods Mitochondrial respiration was analyzed in intact PBMCs using the ROUTINE, LEAK, electron transfer system (ETS), and residual oxygen consumption (ROX) protocol by means of high-resolution respirometry. The SIRT3 expression and PBMC activity were measured using fluorometry. Ultrasound measurements of the echogenicity of the substantia nigra and the diameter of the 3rd ventricle were also performed. Results Patients with movement disorders exhibited a lower ROUTINE respiration than controls (P = 0.0237). Reduced oxygen fluxes in the LEAK (P = 0.033) and ROX (P = 0.0486) states were observed in patients with movement disorders compared with controls. Decreased ROUTINE respiration (P = 0.007) and oxygen flux in the LEAK state (P = 0.0203) were observed in patients with PD with substantia nigra hyperechogenicity compared with controls. Decreased SIRT 3 deacetylase activity was found in patients with movement disorders. Conclusion Impaired mitochondrial respiration in intact PBMCs was associated with inhibited SIRT3 activity and neurodegeneration measures evaluated using ultrasound in patients with PD.

Yellow fever vaccine-associated neurotropic disease (YEL-AND) – A case report

Yellow fever (YF) is a mosquito-borne viral hemorrhagic fever, which is a serious and potentially fatal disease with no specific antiviral treatment that can be effectively prevented by an attenuated vaccine (YEL). Despite the long history of safe and efficacious YF vaccination, sporadic case reports of serious adverse events (SAEs) have been reported, including yellow fever vaccine-associated neurotropic disease (YEL-AND). YEL-AND usually appears within one month of YF vaccination, manifesting as meningoencephalitis, Guillain-Barré syndrome (GBS) or acute disseminated encephalomyelitis (ADEM). We report a case of YEL-AND with meningitis presentation in a 39-year-old Caucasian man without evidence of significant risk factors, which was confirmed by the presence of the YF virus and specific immunoglobulin G (IgG) antibodies in the cerebrospinal fluid (CSF). In conclusion, we should stress the importance of balancing the risk of SAEs associated with the vaccine and the benefits of YF vaccination for each patient individually.