E. Rüther

Nocturnal myoclonus syndrome (periodic movements in sleep) related to central dopamine D2-receptor alteration.

The nocturnal myoclonus syndrome (NMS) consists of stereotyped, repetitive jerks of the lower limbs that occur during sleep or wakefulness. NMS is often related with restless-legs syndrome (RLS) and can cause severe sleep disturbances and daytime sleepiness. The efficacy of dopamine agonists in the treatment points to a dopaminergic dysfunction in NMS. We investigated the central dopamine D2-receptor occupancy with [123I] labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) ([123I]IBZM) and single photon emission tomography (SPET) in 20 patients with NMS and in 10 healthy controls. In most of the patients with NMS there was a lower [123I]IBZM binding in the striatal structures compared to controls. The results indicate that NMS is related to a decrease of central D2-receptor occupancy.

Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.

Chronic alcohol consumption can induce brain atrophy, whereby the exact mechanism of brain damage in alcoholics remains unknown. There is evidence that chronic alcoholism is associated with hyperhomocysteinemia. Homocysteine is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxic and oxidative injury in vitro and in vivo. The present volumetric magnetic resonance imaging study included 52 chronic alcoholics and 30 non-drinking healthy controls. Patients were active drinkers and had an established diagnosis of alcohol dependence. We investigated the influence of different variables on the hippocampal volume of patients suffering from chronic alcoholism. We observed that pathological raised levels of plasma homocysteine showed the most significant correlation to hippocampal volume reduction (P<0.001, multiple regression analysis). Raised plasma levels of homocysteine are associated with hippocampal (brain) atrophy in alcoholism.

Isoform Pattern of 14‐3‐3 Proteins in the Cerebrospinal Fluid of Patients with Creutzfeldt‐Jakob Disease

Abstract : Two‐dimensional polyacrylamide gel electrophoresis of CSF has been used in the diagnosis of Creutzfeldt‐Jakob disease (CJD). One of the two diagnostic protein spots was identified as isoform(s) of the 14‐3‐3 family of abundant brain proteins. This has led to the development of one‐dimensional 14‐3‐3 sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot, which is currently used to support the diagnosis of CJD. In the present study employing western blot analysis, we have identified the panel of 14‐3‐3 isoforms that appear in the CSF of 10 patients with CJD compared with 10 patients with other dementias. The results clearly show that the 14‐3‐3 isoforms β, γ, ε, and η are present in the CSF of patients with CJD and can be used to differentiate other dementias. 14‐3‐3η also gave a baseline signal in all patients with other dementias, including six patients with Alzheimers disease. The presence of 14‐3‐3η in the CSF of a patient with herpes simplex encephalitis was particularly noteworthy. This study has determined that isoform‐specific 14‐3‐3 antibodies against β, γ, and ε should be considered for the neurochemical differentiation of CJD from other neurodegenerative diseases.

Early traumatic life events, parental rearing styles, family history of mental disorders, and birth risk factors in patients with social anxiety disorder

AbstractObjectiveChildhood traumatic experiences, rearing styles, familial mental disorders and birth risk factors have been associated with the development of social anxiety disorder.MethodPatients with social anxiety disorder (n = 50) and healthy controls (n = 120) were investigated using a retrospective interview with 203 questions.ResultsThe frequency of reports of traumatic childhood experiences was significantly higher in patients than in controls, including separation from parents, parents’ marital discord, sexual abuse, familial violence, childhood illness, and other factors. On a 0–10 point ‘severe trauma scale’ patients had significantly higher mean scores (2.0; SD 1.28) than control subjects (0.82; SD 1.1; p < 0.0001).Only 6 (12 %) of the social phobic patients, but 63 (52.5%) of the controls did not report any severe traumatic events at all (χ2= 24.0; p < 0.0001). Compared to controls, patients described their parents’ rearing styles as significantly more unfavourable. Patients reported higher rates of psychiatric disorders in their families in general, in particular anxiety disorders, depression, and suicidality. Birth risk factors did not differ between patients and controls. In a logistic regression model, the highest contribution was noted for familial anxiety disorders. Separation from parents also had a significant, but smaller influence. There was only a trend towards a significant contribution of childhood sexual abuse. Violence in the family, parental rearing styles and birth risk factors did not contribute significantly.ConclusionsThe present data suggest that the aetiology of social anxiety disorder is multifactorial and that familial mental disorders and separation experiences are the most important contributing factors.

Dopamine D2 receptor alteration in patients with periodic movements in sleep (nocturnal myoclonus)

Periodic movements in sleep (PMS) can cause severe sleep disturbances. We investigated the central dopamine D2 receptor density in patients with PMS with123I-IBZM and single photon emission tomography (SPET). In PMS there was a lower123I-IBZMbinding in the basal ganglia compared tothe control group. The results indicate a loss of central D2 receptors in PMS.

Amyloid beta peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing.

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

Validation of amyloid- β peptides in CSF diagnosis of neurodegenerative dementias

Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimers disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-β (Aβ) peptide patterns, using the quantitative Aβ-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Aβ1-38. The main outcome measures were a striking decrease of Aβ1-42 in AD (P=7.4 × 10−19), and most interestingly a pronounced decrease of Aβ1-38 in FTD (P=9.6 × 10−7). Moreover, a novel peptide that most probably represents an oxidized α-helical form of Aβ1-40 (Aβ1-40ox) displayed a highly significant increase in DLB (P=3.7 × 10−3) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Aβ peptide abundances (Aβ1-X%) was clearly superior to absolute CSF Aβ levels. Aβ1-42% and Aβ1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Aβ1-40ox% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Aβ1-38 levels as measured by the Aβ-SDS-PAGE/immunoblot and MSD, respectively. CSF Aβ peptides may reflect disease-specific impact of distinct neurodegenerative processes on Aβ peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

Plasma homocysteine is a predictor of alcohol withdrawal seizures.

An adaptive consequence of prolonged ethanol consumption is a compensatory up-regulation of NMDA receptors in certain brain areas. Taking into account that homocysteine and its breakdown products (i.e. homocysteic acid) are putative neurotransmitters and agonists at the NMDA receptor, the aim of this study was to assess the influence of levels of homocysteine on alcohol withdrawal seizures. Six patients with chronic alcoholism who suffered from withdrawal seizures had significantly higher levels of homocysteine on admission (84.7 ± 29.8 μmol/l) than patients (n = 26) who did not develop seizures (30.2 ± 23.2 μmol/l; U = 8.0, p = 0.0007). Furthermore, seizure patients had significantly lower levels of folate and significantly higher blood alcohol concentrations. Using a logistic regression analysis, withdrawal seizures were best predicted by a high homocysteine level on admission (p < 0.01; odds ratio = 1.05). Homocysteine levels on admission may be a useful screening method to identify patients at risk for withdrawal seizures.

Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa

SummaryA double-blind randomized crossover study of 0.125 mg Pergolide (Lilly®) at bedtime versus 250 mg L-Dopa + Carbidopa (Roche®) was conducted in 16-day phases in 11 patients with idiopathic restless legs syndrome. Two patients reported a partial and 9 patients a complete relieve of motor restlessness while receiving Pergolide. Only 1 patient experienced an improvement of restlessness after L-Dopa. The patients showed polysomnographically a mean decrease in NMS cluster disturbed time by 45% from control on L-Dopa (p < 0.025) and by 79% from control on Pergolide (p < 0.001). In addition, Pergolide increased the total sleep time compared to L-Dopa (p < 0.05). In conclusion, the dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS.

Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS)

Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [123I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) to D2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [123I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by a nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [123I]IBZM SPET technique in conclusion offers an interesting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies.