Eduard Auff

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

Double-blind trial of botulinum A toxin for the treatment of focal hyperhidrosis of the palms.

We performed a randomized double‐blind study within‐group comparison in 11 patients to study the effect of subcutaneous injections of botulinum A toxin in focal hyperhidrosis of the palms. A total dose of 120 mU (mouse units) of botulinum A toxin (Dysport®) was injected into six different sites on one palm, whereas the other was injected with sterile saline. Objective quantification of sweat production was performed using digitized ninhydrin‐staincd sheets. Three weeks after treatment, the mean reduction of sweat production in the botulinum A toxin‐treated palms was 26% (P<0·001). after 8 weeks 26% (P= 0·002) and after 13 weeks 31% (P<0·001).Subjective assessment of sweat production by the patients using a visual analogue scale showed a 38% improvement in the botulinum A toxin‐treated palms at 3 weeks (P=0·002). 40% at 8 weeks (P=0·002) and 38% at 13 weeks (P= 0·002). Neither the objective measurement nor the subjective rating showed a statistically significant reduction of sweating in the placebo‐treated palms. Three patients reported reversible minor weakness of powerful handgrip after injection at the toxin‐treated site, lasting between 2 and 5 weeks.

Variant in the sequence of the LINGO1 gene confers risk of essential tremor

We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 x 10(-9), odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse [corrected] knockout models highlights the potential role of LINGO1 in the pathophysiology of ET [corrected]We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 × 10−9, odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse knockout models highlights the potential role of LINGO1 in the pathophysiology of essential tremor.

Long‐term antidyskinetic efficacy of amantadine in Parkinson's disease

Several randomized placebo‐controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinsons disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LIDs) wear off after about 9 months of treatment. This randomized placebo‐controlled parallel‐group study was performed to assess the long‐term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year‐ were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patients diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1–4.03) at baseline to 4.28 (95% CI, 3.1–5.4) at three‐week follow‐up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1–4.4) to follow‐up 3.6 (95% CI, 2.3–4.8) in patients staying on amantadine. These findings argue for long‐term antidyskinetic efficacy of amantadine in PD patients with LIDs.

Neurological rehabilitation of severely disabled cardiac arrest survivors. Part II. Life situation of patients and families after treatment.

BACKGROUND About half of out-of-hospital cardiac arrest survivors experience secondary anoxic brain damage. Neurological outcome can be influenced by rehabilitative treatment approaches, but the nature and severity of persistent disabilities remain unclear. The aim of the study was to explore persistent neuropsychiatric symptoms, global function and life situation of these patients, and to evaluate quality of life in families. METHODS 25 months after inpatient rehabilitation, 12 individuals (mean age=51 years; ten M: two F) attended a cross-sectional interdisciplinary follow-up assessment with their carers. Function was investigated by clinical rating scales, neuropsychological standard tests, and clinical psychological inventories. Family members were asked about quality of life and satisfaction with social support. RESULTS All patients had deficits in at least one or more cognitive areas such as orientation, memory, alertness, and awareness. Three different clinical syndromes were observed: very severe intellectual and physical impairment, (two), mild to moderate dementia, (five), and amnesic syndrome, (five). Prevalence of multiple disabilities, was high. A striking discrepancy was found between self and proxy rating of disabilities (P<0.01). Family members faced dramatically altered life situations after CA; 60% of spouses suffered from psychosomatic problems, 50% complained of lack of social support. CONCLUSION Despite optimal in-hospital treatment, severe anoxic brain damage resulted in permanent cognitive decline, impaired awareness and self care ability. Families felt isolated, and more than half need more support to prevent burn out.

A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A.

Objective: Botulinum toxin type A (BTXA) is used to treat neurologic disorders associated with increased muscle tone. Its use is often associated with pain relief. Methods: A possible direct analgesic effect of BTXA on C and Aδ fibers was studied on 16 healthy volunteers receiving 30 U BTXA into one forearm and pure saline into the other. To exclude the secondary effect due to muscular tone reduction, BTXA was injected intradermally. Thermal sensory testing of heat pain (threshold and tolerance) and neuroselective current sensory testing of current pain threshold/tolerance were performed at baseline and 3, 14, and 28 days after treatment. Thereafter, on day 28, capsaicin was administered simultaneously into both forearms to evaluate a possible peripheral effect and central effect on pain processing and on the axon reflex flare. Results: The authors observed no significant difference in any of the perception outcome measures between BTXA and placebo pretreated areas. Flare areas as a result of the release of neuropeptides after capsaicin application showed no differences. Conclusions: The results suggest that pain reduction after BTXA treatment is mediated through its effect on muscle tone rather than a direct analgesic effect.

Neuropsychological, MRI and EEG findings after very mild traumatic brain injury

Neuropsychological performance, magnetic resonance imaging (MRI) and electroencephalography (EEG) were investigated in 12 consecutive patients with very mild traumatic brain injury (MTBI) (Glasgow coma score 15) within 24 hours and 6 weeks after injury. The data were compared to 14 control subjects. There was a significant impairment in neuropsychological performance (verbal memory, arithmetic abilities and psychomotor reaction time) at onset and after 6 weeks, whereas verbal fluency and non-verbal memory test revealed no significant differences matching the control values. In MRI scans, three patients showed traumatic lesions (slight epidural haematoma, haemorrhagic contusions and white matter lesions indicating diffuse axonal injury). In the EEG recordings, no generalized slowing or focal changes were found. Structural and functional impairment can be identified using neuroimaging and neuropsychological examination, even in very MTBI patients.

Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene

Mutations in the valosin-containing protein (VCP) on chromosome 9p13-p12 were recently found to be associated with hereditary inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). We identified a novel missense mutation in the VCP gene (R159H; 688G>A) segregating with this disease in an Austrian family of four affected siblings, who exhibited progressive proximal myopathy and Paget disease of the bone but without clinical signs of dementia.

Circadian secretion pattern of melatonin in de novo Parkinsonian patients: evidence for phase-shifting properties of l-dopa

SummaryAim of this study was the characterization of the circadian melatonin profile in de novo Parkinson patients (N=9, age 60.0±3.2 years, mean ± SEM) and the comparison of these profiles with those of controls and Parkinson patients treated with I-dopa/decarboxylase inhibitor (l-dopa/DCI). We collected 14 venous blood samples during a period of 24 hours and measured the serum melatonin levels by a radioimmuno assay. De novo Parkinson patients displayed the nocturnal melatonin peak (acrophase) at the same time as controls and significantly later than l-dopa/DCI treated patients (1:54±15.6 min [average clock time ± SEM in minutes] vs. 1:45±15.6 min vs. 0:13±40.8 min). The amount of secreted melatonin did not differ among the three groups. Stage and duration of Parkinsons disease did not correlate with the amount of secreted melatonin. Patients of the tremor subgroup, however, secreted more melatonin than patients presenting only with rigidity and akinesia. The phase advance in Parkinson patients treated with l-dopa/DCI is possibly due to a central nervous dopaminergic effect elicited by l-dopa administration and not inherent to Parkinsons disease per se.

Sleep disorders and depression in patients with Parkinson's disease

Objectives– Sleep disorders and depression are frequent in patients with Parkinsons disease (PD). However, the exact prevalence and the causality are still unknown. Patients and methods– We interviewed 56 consecutive PD patients and 59 age‐matched healthy controls concerning sleep disorders and depression. Sleep Disorders Questionnaire (SDQ) and Zung Depression Scale (ZDS) were used as standardized valid and reliable psychometric tests. Results– Patients with PD had significantly higher values in the clinical‐diagnostic scale narcolepsy (P=0.01), correlating with the l‐dopa dose (P=0.007). Concerning sleep apnea (P=0.49), psychiatric sleep disorder (P=1.00) and periodic limb movement disorder (P=0.12), no significant difference could be identified. PD patients showed significantly higher depression scores than healthy control subjects (P=0.01), increasing with the duration of PD (P=0.04). Conclusion– The significant higher narcolepsy score in PD patients must be seen due to dopaminergic medication and PD‐specific neurodegeneration and immobility rather than due to narcolepsy. This leads to the conclusion that extreme caution is advised when carrying out the SDQ and interpreting the results in various persons and patient groups with motor problems. The strong association of depression, disease severity and sleep disorders in PD patients underlines the importance of identifying and treating both conditions in these patients.