Parkinson Phenotype in Aged PINK1-Deficient Mice Is Accompanied by Progressive Mitochondrial Dysfunction in Absence of Neurodegeneration

Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death

An experimental investigation of the effect of age and sex/gender on pain sensitivity in healthy human participants

© 2018 El-Tumi et al. Background: Ageing is associated with alterations of the structure and function of somatosensory tissue that can impact on pain perception. The aim of this study was to investigate the relationship between age and pain sensitivity responses to noxious thermal and mechanical stimuli in healthy adults. Methods: 56 unpaid volunteers (28 women) aged between 20 and 55 years were categorised according to age into one of seven possible groups. The following measurements were taken: thermal detection thresholds, heat pain threshold and tolerance using a TSA-II NeuroSensory Analyzer; pressure pain threshold using a handheld electronic pressure algometer; and cold pressor pain threshold, tolerance, intensity and unpleasantness. Results: There was a positive correlation between heat pain tolerance and age (r = 0.228, P = 0.046), but no statistically significant differences between age groups for cold or warm detection thresholds, or heat pain threshold or tolerance. Forward regression found increasing age to be a predictor of increased pressure pain threshold (B = 0.378, P = 0.002), and sex/gender to be a predictor of cold pressor pain tolerance, with women having lower tolerance than men (B =-0.332, P = 0.006). Conclusion: The findings of this experimental study provide further evidence that pressure pain threshold increases with age and that women have lower thresholds and tolerances to innocuous and noxious thermal stimuli. Significance: The findings demonstrate that variations in pain sensitivity response to experimental stimuli in adults vary according to stimulus modality, age and sex and gender

Altered processing of sensory stimuli in patients with migraine

Migraine is a cyclic disorder, in which functional and morphological brain changes fluctuate over time, culminating periodically in an attack. In the migrainous brain, temporal processing of external stimuli and sequential recruitment of neuronal networks are often dysfunctional. These changes reflect complex CNS dysfunction patterns. Assessment of multimodal evoked potentials and nociceptive reflex responses can reveal altered patterns of the brain's electrophysiological activity, thereby aiding our understanding of the pathophysiology of migraine. In this Review, we summarize the most important findings on temporal processing of evoked and reflex responses in migraine. Considering these data, we propose that thalamocortical dysrhythmia may be responsible for the altered synchronicity in migraine. To test this hypothesis in future research, electrophysiological recordings should be combined with neuroimaging studies so that the temporal patterns of sensory processing in patients with migraine can be correlated with the accompanying anatomical and functional changes

Quality of life of a person with Parkinson's disease and the relationship between the time of evolution and the severity of the disease

Parkinson's disease can cause disability and decrease the quality of life in its sufferers. The aim of this study was to evaluate the quality of life of a group of people with Parkinson's disease and whether a relationship exists between time of evolution and severity of the disease. Secondary analysis was carried out on transversal data collected from 40 individuals with Parkinson's disease registered in the Parkinson's Association of Maringá, in Maringá-PR-Brazil. Measures: three instruments were applied: a socio-demographic questionnaire, the Hoenh and Yahr Scale and the Parkinson's Disease Questionnaire (PDQ-39). According to PDQ-39, men referred to a lower quality of life, although, statistically, there was no significant difference between the two genders. Differences were only observed in the dimensions of "activities of daily living" and "social support", in which men presented higher impairment, and "emotions" and "bodily discomfort", where women showed higher impairment. Furthermore, severity of disease tended to lead to a perception of lower quality of life regarding the dimensions of "activities of daily living" and "cognition", which is relevant to improve clinical guidance and intervention.La enfermedad de Parkinson puede llegar a ser incapacitante y afectar a la calidad de vida de los pacientes. El objetivo de este estudio fue evaluar la calidad de vida de las personas con Parkinson e identificar las relaciones con el transcurso del tiempo y la gravedad de la enfermedad. Los datos fueron recogidos en la ciudad de Maringá-PR-Brasil, con 40 personas indexadas en la "Associação Maringaense de Parkinson", a través de la aplicación de tres instrumentos: cuestionario sociodemográfico, escala de Hoenh e Yahr y PDQ-39. De acuerdo con el PDQ-39, los hombres reportaron peor calidad de vida, aunque no hubo diferencias estadísticas entre los sexos. Las diferencias apenas se observaron en la dimensión "actividades de vida diaria" y "apoyo social", con los hombres presentando una mayor participación y "bienestar emocional" e "incomodidad física" con una más grave entre las mujeres. Por otra parte, la gravedad de la enfermedad mostró una tendencia a empeorar la percepción en la calidad de vida en las dimensiones de las actividades de la vida diaria y cognición, puntos importantes para una mejor orientación e intervención clínica.A doença de Parkinson pode ser incapacitante e prejudicar a qualidade de vida de seus portadores. O objetivo do estudo foi avaliar a qualidade de vida de indivíduos com Parkinson e identificar relações com o tempo de evolução e gravidade da doença. Os dados foram coletados na cidade de Maringá, PR, Brasil, com 40 indivíduos cadastrados na Associação Maringaense de Parkinson, por meio da aplicação de três instrumentos: questionário sociodemográfico, escala de Hoenh e Yahr e PDQ-39. De acordo com o PDQ-39, os homens referiram pior qualidade de vida, embora sem diferenças estatísticas entre os sexos. Diferenças foram observadas apenas na dimensão "atividades de vida diária" e "apoio social", com os homens apresentando maior acometimento e "bem-estar emocional" e "desconforto corporal", com maior comprometimento entre as mulheres. Por outro lado, a gravidade da doença apresentou tendência a pior percepção na qualidade de vida nas dimensões atividades de vida diária e cognição, pontos relevantes para melhor orientação clínica e intervenção

Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics

Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies