Diagnostic validity of biomarkers in Parkinson's Disease: systematic review and meta-analysis / Validad diagnóstica de biomarcadores en la enfermedad de Parkinson: una revisión sistemática y metaanálisis / Validade diagnóstica de biomarcadores na doença de Parkinson: revisão sistemática e meta-análise

ABSTRACT Objective: To identify biomarkers for Parkinson's disease, cerebrospinal fluid, blood, saliva, and urine. Method: The studies were collected from the Cochrane, LILACS, PubMed, SCOPUS, WEB OF SCIENCE, OpenGrey, ProQuest and Google Scholar databases starting from May 3, 2016 and updated on March 20, 2017. Twenty-two studies were evaluated, by the Quality Assessment Tool for Diagnostic Accuracy Studies and Review Manager 5.3. Results: Evidence shows that serum antibodies can be used as highly specific and accurate biomarkers for the diagnosis of Parkinson's disease at the outset. Biomarkers in the cerebrospinal fluid are related to increased motor severity, postural instability, gait abnormality, and cognitive impairment. Conclusion: Serum and cerebrospinal antibodies can be used as diagnostic biomarkers at the onset of the disease.

RESUMEN Objetivo: Identificar los biomarcadores para la enfermedad de Parkinson, el líquido cefalorraquídeo, la sangre, la saliva y la orina. Método: Los estudios fueron recolectados en las bases de datos Cochrane, LILACS, PubMed, SCOPUS, WEB OF SCIENCE, OpenGrey, ProQuest y Google Scholar, a partir del 3 de mayo de 2016 y actualizados el 20 de marzo de 2017. Se seleccionaron 22 estudios, evaluados por la Quality Assessment Tool for Diagnostic Accuracy Studies y el Review Manager 5.3. Resultados: La evidencia muestra que los anticuerpos séricos pueden ser utilizados como biomarcadores altamente específicos y precisos para el diagnóstico de la enfermedad de Parkinson en su inicio. Los biomarcadores en el líquido cefalorraquídeo están relacionados con el aumento de la severidad motora, la inestabilidad postural, el disturbio de la marcha y la declinación cognitiva. Conclusión: Los anticuerpos séricos y cefalorraquídeos pueden utilizarse como biomarcadores de diagnóstico al inicio de la enfermedad.

RESUMO Objetivo: Identificar os biomarcadores para a doença de Parkinson, no líquido cefalorraquidiano, sangue, saliva e urina. Método: Os estudos foram coletados nas bases de dados Cochrane, LILACS, PubMed, SCOPUS, WEB OF SCIENCE, OpenGrey, ProQuest e Google Scholar, a partir de 3 de maio de 2016 e atualizados em 20 de março de 2017. Foram selecionados 22 estudos, avaliados pelo Quality Assessment Tool for Diagnostic Accuracy Studies e o Review Manager 5.3. Resultados: A evidência mostra que os anticorpos séricos podem ser usados como biomarcadores altamente específicos e precisos para o diagnóstico da doença de Parkinson em seu início. Os biomarcadores no líquido cefalorraquidiano estão relacionados ao aumento da severidade motora, à instabilidade postural, ao distúrbio da marcha e ao declínio cognitivo. Conclusão: Os anticorpos séricos e cefalorraquidianos podem ser utilizados como biomarcadores de diagnóstico no início da doença.

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease / Os níveis circulantes de fatores neurotróficos não estão alterados em pacientes com doença de Parkinson

ABSTRACT There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.

RESUMO Há evidências de que alteracões nas ações exercidas por fatores neurotróficos (FNs) estejam associadas à fisiopatologia da doença de Parkinson (DP). O presente estudo foi conduzido para avaliar os níveis plasmáticos de FNs e suas possíveis associações com sintomas clínicos na DP. Para este fim, 40 pacientes com DP e 25 controles foram submetidos à avaliação clínica e coleta de sangue periférico. Os níveis plasmáticos do fator neurotrófico derivado do cérebro (BDNF), pro-BDNF, neurotrofina 3, neurotrofina 4, fator de crescimento do nervo, fator neurotrófico derivado da glia e fator neurotrófico ciliar foram avaliados por ensaio de imunoadsorção enzimática. Não houve diferença significativa entre pacientes com DP e controles quanto aos níveis plasmáticos dos FNs avaliados. Além disso, não encontramos associação entre os níveis dos FNs e duração da doença, grau de comprometimento motor ou funcional, desempenho cognitivo e gravidade dos sintomas depressivos. Em conclusão, embora os FNs possam desempenhar papéis relevantes na fisiopatologia da DP, os níveis circulantes dessas moléculas não estão necessariamente alterados em pacientes com DP.

Association of Parkinson's disease with altered serum levels of lead and transition metals among South Indian subjects.

Several epidemiologic studies have suggested an association between the Parkinson’s disease (PD) and exposure to heavy metals, such as lead, iron, copper, manganese, etc. A growing body of evidence suggests that heavy metals stimulate free radical formation in the brain and can lead to neurodegeneration. In the present study, we investigated whether such association exists in PD cases from rural and urban areas in our study population. The plasma levels of copper, iron, manganese and lead in PD cases (n = 150) and controls (n = 170) were determined by inductively coupled plasma mass spectrometry (ICP-MS) and correlated with the oxidative stress markers like malondialdehyde (MDA), protein carbonyl and total glutathione. Results indicated significant increase in the levels of copper (17.73 ± 4.48 vs. 13.0 ± 3.22 ng/ml) and iron (554.4 ± 123.8 vs. 421.7 ± 126.1 ng/ml) in PD cases compared to controls, whereas no significant differences in the levels of manganese and lead were observed. Further, the data based on urban or rural residence showed that plasma copper, iron, manganese levels were comparatively higher in rural subjects, whereas plasma lead levels were significantly higher in urban subjects. Increased plasma iron showed positive correlation with marker of lipid peroxidation (MDA), suggesting that increased iron levels induced oxidative stress in PD. These results substantiated the earlier observations about the role of environmental exposure and metal-induced oxidative stress in the etiology of PD.

Restless legs syndrome in Parkinson's disease: clinical characteristics and biochemical correlations / Síndrome das pernas inquietas na doença de Parkinson: características clínicas e correlações bioquímicas

Restless legs syndrome (RLS) is a neurological disorder that responds to dopaminergic drugs, indicating a common pathophysiology with Parkinson's disease (PD). The prevalence of RLS was estimated in a group of PD patients and its clinical and biochemical characteristics were analysed. Forty-eight patients with PD were evaluated into two groups, with and without RLS. Clinical characteristics assessed in both groups were age, gender, duration of PD, Hoehn and Yahr, and Schwab and England scales. Laboratory variables such as hemoglobin, s-iron, s-ferritin and creatinine were obtained. The prevalence of RLS was 18.75 percent. No significant differences regarding clinical variables and biochemical parameters were observed. The high prevalence of RLS found in PD patients suggests the concept of a common etiological link and it seems that secondary causes did not play a central role in the pathophysiology of RLS in this group of parkinsonian patients.

A síndrome das pernas inquietas (SPI) é um distúrbio sensitivo-motor que responde aos agentes dopaminérgicos, demonstrando uma possível semelhança fisiopatológica com a doença de Parkinson (DP). Foi avaliada a prevalência da SPI em um grupo de pacientes com DP e suas características clínicas e laboratoriais. Quarenta e oito pacientes diagnosticados com DP foram divididos em dois grupos: com e sem SPI. Características clínicas como idade, sexo, duração da DP, escalas de Hoehn e Yahr, e Schwab e England e achados bioquímicos como hemoglobina, ferro sérico, ferritina sérica e creatinina foram obtidos. A freqüência da SPI foi de 18,75 por cento. Não se observaram diferenças estatisticamente significativas quanto às características clínicas e aos achados bioquímicos. A alta prevalência de SPI encontrada em pacientes com DP sugere associação entre essas duas doenças. É provável que causas secundárias não exerçam papel central na fisiopatologia da SPI nesse grupo de pacientes parkinsonianos.

Estudio longitudinal de tres familias con parkinsonismo familiar / Longitudinal study of three families with familial Parkinson's disease

Antecedentes. El parkinsonismo autosómico dominante es una variante de la enfermedad de Parkinson que se transmite por generaciones, manifestándose en edades tempranas. Objetivo. Describir las características clínicas de la enfermedad en familias de Colima con parkinsonismo autosómico dominante y su evolución a través de 18 años. Material y métodos. Se determinó el diagnóstico, evolución y patrón de herencia de la enfermedad. Para seguir su curso longitudinal se utilizó el sistema Unified Parkinson Disease Rating Scale (UPDRS). Se realizó estadística descriptiva con media y porcentajes. Resultados. Se estudiaron tres familias, un total de 51 individuos en 4 generaciones, de 29 ± 22 años, con Parkinsonismo familiar en 37% e inicio de la enfermedad a los 24 ± 9 años. La mayor calificación de UPDRS fue de 175. Se demostró transmisión de la enfermedad con patrón de herencia autosómica dominante. En la familia No. 1 se presentó en 100% de los integrantes de la primera y segunda generación. Conclusiones. Las tres familias tienen inicio temprano y rápida progresión de la enfermedad coincidiendo con las características descritas del parkinsonismo familiar tipo 1 (PARK1), originada por la mutación Ala53Thr en el gen de la alfa-sinucleína.

BACKGROUND: Familial Parkinson's is a variant of Parkinson's disease (PD) transmitted generationally with an early onset. OBJECTIVE: Describe the clinical disease characteristics and its 18 year evolution among families in Colima presenting familial PD. MATERIALS AND METHODS: We determined disease diagnosis, evolution and hereditary pattern. The UPDRS system was used to follow the longitudinal course of the disease. Descriptive statistics were carried out using means and percentages. RESULTS: Three families were studied, with a total of 51 subjects aged 29 +/- 22 years spanning 4 generations. Thirty-seven percent of studied subjects displayed familial PD, with disease onset at 24 +/- 9 years of age. The highest UPDRS value was 175. Disease transmission with a dominant autosomic heredity pattern was shown. One hundred percent of first and second generation members from family number 1 displayed the disease. CONCLUSIONS: The three families displayed early onset PD and rapid progression, coinciding with described characteristics of type 1 familial Parkinsonism (PARK1). This disease is caused by the Ala53Thr mutation of the alpha-synuclein gene.

Free radical toxicity and antioxidants in Parkinson's disease.

Erythrocyte lipid peroxidation, oxidative hemolysis, erythrocyte antioxidant enzymes, viz. superoxide dismutase, glutathione reductase, glutathione peroxidase, catalase and plasma antioxidants, viz. vitamin A, vitamin E, vitamin C and ceruloplasmin have been determined by spectrophotometric methods in 15 patients with Parkinson's disease (PD) and in 50 controls. Lipid peroxidation, oxidative hemolysis and plasma ceruloplasmin were significantly higher in PD patients as compared to normals. Erythrocyte antioxidants in PD patients were not significantly different from the controls. However, plasma vitamin C in PD patients was significantly lower than the controls. It is concluded that these patients are under oxidative stress which points to a possible involvement of free radicals in PD.

Tryptophan and tyrosine catabolic pattern in neuropsychiatric disorders.

Catabolism of tryptophan and tyrosine in relation to the isoprenoid pathway was studied in neurological and psychiatric disorders. The concentration of trytophan, quinolinic acid, kynurenic acid, serotonin and 5-hydroxyindoleacetic acid was found to be higher in the plasma of patients with all these disorders; while that of tyrosine, dopamine, epinephrine and norepinephrine was lower. There was increase in free fatty acids and decrease in albumin (factors modulating tryptophan transport) in the plasma of these patients. Concentration of digoxin, a modulator of amino acid transport, and the activity of HMG CoA reductase, which synthesizes digoxin, were higher in these patients; while RBC membrane Na+-K+ ATPase activity showed a decrease. Concentration of plasma ubiquinone (part of which is synthesised from tyrosine) and magnesium was also lower in these patients. No morphine could be detected in the plasma of these patients except in MS. On the other hand, strychnine and nicotine were detectable. These results indicate hypercatabolism of tryptophan and hypocatabolism of tyrosine in these disorders, which could be a consequence of the modulating effect of hypothalamic digoxin on amino acid transport.

Endogenous alkaloids in the brain of rats loaded with tyrosine/tryptophan & in the serum of patients of neurodegenerative & psychiatric disorders.

Since binding sites for morphine, nicotine and strychnine exist in the brain, it is possible that they may have some role in neuronal function. The presence/variation in the levels of these alkaloids in the brain of rats fed tryptophan and tyrosine, and in the serum of patients with some neurodegenerative and psychiatric disorders were studied. Brain of rats loaded with tyrosine (500 mg/kg b wt X 14 days) showed increased amounts of morphine, while that from animals loaded with tryptophan (in the same dose) showed presence of strychnine and increased amounts of nicotine. Strychnine is being reported in mammalian brain for the first time. Serum of patients with epilepsy, Parkinson's disease (PD) and manic depressive psychosis (MDP) was also examined for the presence of these alkaloids. Serum of control subjects did not show the presence of any of these alkaloids, while that of all 3 patients groups contained strychnine. Morphine was present only in the serum of patients of MDP. Nicotine was present in trace amounts in the serum of all these patients. Presence of these alkaloids in the serum of patients of neurodegenerative and psychiatric disorders is being reported for the first time, to the best of our knowledge.

Role of norharman, harman and ceruloplasmin in the aetiopathogenesis of Parkinson's disease

Determination of serum levels of Norharman, Harman and Ceruloplasmin of 39 patients with PD and 54 age and sex matched control subjects was done. The study aimed to identify the possible role of these biochemical indices in the etiopathogenesis of PD. The study clarified that most of the PD patients [59%] had moderate degree of illness. The most frequent presenting signs were in the following order: Resting tremors and bradykinesia in 97.4% of cases for each, loss of upper limb swinging during walking in 94.9%, mask facies in 92.3%, rigidity in 84.6%, postural abnormalities and speech disorders in 71.8% for each. Highly significant increase of serum levels of Harman and Norharman and highly significant decrease of Ceruloplasmin level were found among PD patients compared with the control group. The study added more support to the possible roles of the biochemical substances in the etiopathogenesis of Parkinson's disease through defects in the enzymes that regulate potential nigral neurotoxins [Norharman and Harman] or by the deficiency of one of the major plasma antioxidants [Ceruloplasmin]