Rett syndrome: a mitochondrial disease?

Six girls between 2 years 9 months and 15 years of age with Rett syndrome were thoroughly investigated. Blood ammonia levels varied between 42 and 123 mumol/L, and serum lactate concentration was slightly elevated in two girls. Electroencephalograms showed a dysrhythmic pattern during wakefulness; during drowsiness and light sleep, bilateral bursts of spike or multispike-and-wave activity were seen in all but the oldest girl. In one of the younger girls, slight cortical atrophy was found on computed tomographic scan. Muscle biopsy was performed on all girls, and electron microscopy revealed abnormal mitochondria. Physical signs such as somatic hypotrophy with extremely small muscle mass, and unsatisfactory weight gain in spite of good appetite are found in Rett syndrome. These attributes, as well as reports of ornithine carbamoyltransferase deficiency, may support a mitochondrial dysfunction. The mitochondrial changes indicate either a mitochondrial mutation or more probably an X-borne modulator gene mutation. Another genetic possibility discussed is the "metabolic interference" of an X-borne allele. Further delineation of such mitochondrial changes may clarify the causal metabolic defect in Rett syndrome.     

Corneal nerve microstructure in Parkinson’s disease

Ocular surface changes and blink abnormalities are well-established in Parkinson’s disease. Blink rate may be influenced by corneal sub-basal nerve density, however, this relationship has not yet been investigated in Parkinson’s disease. This case-control study examined the ocular surface in patients with moderately severe Parkinson’s disease, including confocal microscopy of the cornea. Fifteen patients with moderately severe Parkinson’s disease (modified Hoehn and Yahr grade 3 or 4) and fifteen control participants were recruited. Ophthalmic assessment included slit-lamp examination, blink rate assessment, central corneal aesthesiometry and in vivo corneal confocal microscopy. The effect of disease laterality was also investigated. Of the 15 patients with Parkinson’s disease, ten were male and the mean age was 65.5 ± 8.6 years. The corneal sub-basal nerve plexus density was markedly reduced in patients with Parkinson’s disease (7.56 ± 2.4 mm/mm²) compared with controls (15.91 ± 2.6 mm/mm²) (p < 0.0001). Corneal sensitivity did not differ significantly between the patients with Parkinson’s disease (0.79 ± 1.2 mBAR) and the control group (0.26 ± 0.35 mBAR), p = 0.12. Sub-basal nerve density was not significantly different between the eye ipsilateral to the side of the body with most-severe motor symptoms, and the contralateral eye. There was a significant positive correlation between ACE-R scores and sub-basal corneal nerve density (R² = 0.66, p = 0.02). This is the first study to report a significant reduction in corneal sub-basal nerve density in Parkinson’s disease and demonstrate an association with cognitive dysfunction. These results provide further evidence to support the involvement of the peripheral nervous system in Parkinson’s disease, previously thought to be a central nervous system disorder.     

Parkin,PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson’s disease

Mitochondria are dynamic organelles which are essential for many cellular processes, such as ATP production by oxidative phosphorylation, lipid metabolism, assembly of iron sulfur clusters, regulation of calcium homeostasis, and cell death pathways. The dynamic changes in mitochondrial morphology, connectivity, and subcellular distribution are critically dependent on a highly regulated fusion and fission machinery. Mitochondrial function, dynamics, and quality control are vital for the maintenance of neuronal integrity. Indeed, there is mounting evidence that mitochondrial dysfunction plays a central role in several neurodegenerative diseases. In particular, the identification of genes linked to rare familial variants of Parkinson’s disease has fueled research on mitochondrial aspects of the disease etiopathogenesis. Studies on the function of parkin and PINK1, which are associated with autosomal recessive parkinsonism, provided compelling evidence that these proteins can functionally interact to maintain mitochondrial integrity and to promote clearance of damaged and dysfunctional mitochondria. In this review we will summarize current knowledge about the impact of parkin and PINK1 on mitochondria.     

Mortalin: a protein associated with progression of Parkinson disease?

Parkinson disease (PD) is a progressive neurodegenerative disorder that is considered to affect the brainstem at its early stages and other brain regions, including the limbic system and isocortex, in advanced stages. It has been suggested that PD progression is characterized pathologically by the spreading of Lewy body deposition. To identify novel proteins involved in PD progression, we prepared subcellular fractions from the frontal cortex of pathologically verified PD patients at different stages of disease and Lewy body deposition and from age-matched controls. Protein expression profiles were compared using a robust quantitative proteomic technique called isobaric tagging for relative and absolute quantification in conjunction with mass spectrometry. Approximately 200 proteins were found to display significant differences in their relative abundance between PD patients at various stages and controls. Gene ontology analysis indicated that these altered proteins belonged to many categories (e.g. mitochondrial function and neurotransmission) that were likely critically involved in the pathogenesis of PD. Of those, mortalin, a mitochondrial protein, was decreased in the advanced PD cases and was further validated to be decreased using independent techniques. These results suggest a role for mortalin in PD progression.     

High-resolution ultrasound changes of the vagus nerve in idiopathic Parkinson’s disease (IPD): a possible additional index of disease

Neurological Sciences - Histopathological studies revealed degeneration of the dorsal motor nucleus of the vagus nerve (VN) early in the course of idiopathic Parkinson’s disease (IPD)....     

Skin nerve α-synuclein deposits in Parkinson’s disease and other synucleinopathies: a review

Clinical Autonomic Research - The in vivo diagnosis of synucleinopathies is an important research aim since clinical diagnostic criteria show low accuracy. The skin innervation, especially the...     

The relevance of gender in Parkinson’s disease: a review

Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson’s disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.     

Is there a typical pattern of brain SPECT imaging in Alzheimer's disease?

The identification of new nosological forms such as Lewy body disease (LBD) requires a re-evaluation of the patterns observed in brain functional imaging in the various forms of dementia. We studied 60 demented patients, divided into three groups and fulfilling the clinical criteria for Alzheimer's disease (AD), LBD and frontotemporal dementia (FTD), using Tc-HMPAO and a brain-dedicated SPECT system. After normalisation we applied a cut-off at two levels according to previously established criteria. We reaffirmed the already established data concerning FTD (mainly a bilateral frontal decrease) and for LBD (a severe diffuse decrease in the frontal regions and also in the posterior association cortex). In contrast, the decrease in AD was strictly limited to the parieto-occipital cortex, irrespective of the severity of the cognitive decline. We hypothesise that the major simplification concerning the pattern observed in AD can be explained by the fact that patients suffering from LBD have previously been included in the groups of AD patients.     

Variations of mitochondrial DNA polymerase γ in patients with Parkinson’s disease

Parkinson’s disease is associated with mitochondrial dysfunction. The POLG1 gene encodes DNA-polymerase γ, which is responsible for the replication of mitochondrial DNA. Mutations in POLG1 cause neurodegenerative diseases such as progressive external ophthalmoplegia and Alpers syndrome. In this study, we investigated if mutations in POLG1 had any correlation with Parkinson’s disease. Subjects consisted of Finnish patients with early-onset Parkinson’s disease (EOPD, N = 441) or late-onset Parkinson’s disease (LOPD, N = 263). The POLG1 gene was screened for nine previously known mutations. Two patients were compound heterozygotes with respect to putatively pathogenic alleles. Twenty-eight patients harbored a heterozygous missense mutation, but the allele frequencies did not differ from those of the controls. Interestingly, the frequency of affected siblings was 4.6-fold higher (95 % confidence interval; 1.09, 19.5) among the patients with EOPD and with heterozygous POLG1 mutations than among patients without mutations. Clinically the patients with or without POLG1 mutations did not differ from each other. Our findings provide two lines of evidence suggesting a role for POLG1 mutations in Parkinson’s disease: (1) identification of patients with compound heterozygous mutations in POLG1, and (2) higher frequency of affected siblings among the EOPD patients with heterozygous POLG1 mutations than among EOPD patients without mutations.     

Parkinson’s disease: a multi-faceted disease

Journal of Neurology -     

Effects of stimulus-response compatibility in Parkinson’s disease: a psychophysiological analysis

Summary. The present study investigated the mechanisms underlying stimulus-response compatibility effects in Parkinson’s disease patients and matched controls. Since basal ganglia are involved in the selection and inhibition of competing responses we examined whether basal ganglia dysfunction in Parkinson’s disease leads to greater interference effects compared to the control subjects. Reaction times and lateralized movement-related cortical potentials (lateralized readiness potential: LRP) were recorded in two modified Eriksen flanker tasks. Both groups were influenced by compatibility conditions; interference was seen as enhanced reaction time and error rate, as well as incorrect early LRP and delayed late LRP in incongruent trials. Altogether, behavioral and electrophysiological measures showed the interference to be rather smaller for the patients than for the controls. In contrast, facilitation did not differ among groups. Hence the claim that Parkinson’s disease patients are more influenced than controls by interfering directional stimuli appears not always valid.