We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify ...the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers.
1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy ...(MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.
To assess severity and progression of self‐perceived dysautonomia and their impact on health‐related quality of life (Hr‐QoL) in multiple system atrophy (MSA), twenty‐seven patients were recruited by ...the European MSA Study Group (EMSA‐SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF‐36), and they were assessed using the 3‐point global disease severity scale (SS‐3) and the Unified MSA Rating Scale (UMSARS). After 6 months follow‐up, the self completed COMPASS Change Scale (CCS), the SF‐36, SS‐3, and UMSARS were obtained. MSA patients showed marked self‐perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow‐up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF‐36 scores. Progression of self‐perceived dysautonomia did not correlate with global disease progression. Hr‐QoL scores were stable during follow‐up. This is the first study to investigate self‐perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This paper reviews the epidemiology, pathophysiology, clinical features and rationale for managing dyskinesias associated with Parkinson’s disease. These are a common clinical problem occurring in up ...to 90 % of patients and more frequently affect those with early-onset. Dyskinesias have a negative impact on quality of life and are an important cause of disability. Their precise etiology is still poorly understood, although it is recognized that dopaminergic pre-synaptic and post-synaptic mechanisms are involved together with extra-dopaminergic factors. The phenomenology of dyskinesias encompasses a variable mixture of two prevalent features: dystonia and chorea. We have studied their time course following a single acute levodopa challenge and have found that dystonia occurs throughout the duration of the on period, whereas choreiform movements occur only at the peak of therapeutic dopaminergic motor responses. This allows a schematic relationship to be drawn between a short duration motor response and the occurrence of dystonia and chorea. There is currently no satisfactory treatment for dyskinesias. Managing the therapeutic window does not provide an adequate solution due to the appearance of a dyskinesia threshold dose that narrows the therapeutic margin. High frequency stimulation of the subthalamic nucleus probably has some specific anti-dyskinetic action, but is limited by the small number of patients who are candidates for this treatment. Research efforts are currently focused on the development of specific anti-dyskinetic medications. Their availability will certainly change the current clinical practice and will widen again the therapeutic window of dopaminergic medications that has now become too narrow.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary Pain and fatigue are part of the phenomenological spectrum of Parkinson's disease (PD). These non-motor symptoms can be as troublesome as motor symptoms, impact activities of daily living, ...and are often underdiagnosed. The recognition of pain and fatigue requires a high degree of clinical suspicion and is facilitated by the use of specific questionnaires and ancillary tests. This workup is highly valuable particularly considering that pain and fatigue in PD may be treatable. We review here the clinical manifestations and management of these non-motor symptoms. Their resolution can be challenging, as there is insufficient evidence concerning effective treatment options.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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