Gabriela Stoppe

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.

Sleep-wake cycles and cognitive functioning in schizophrenia.

BACKGROUND Irregular sleep-wake cycles and cognitive impairment are frequently observed in schizophrenia, however, how they interact remains unclear. AIMS To investigate the repercussions of circadian rhythm characteristics on cognitive performance and psychopathology in individuals with schizophrenia. METHOD Fourteen middle-aged individuals diagnosed with schizophrenia underwent continuous wrist actimetry monitoring in real-life settings for 3 weeks, and collected saliva samples to determine the onset of endogenous melatonin secretion as a circadian phase marker. Moreover, participants underwent multiple neuropsychological testing and clinical assessments throughout the study period. RESULTS Sleep-wake cycles in individuals with schizophrenia ranged from well entrained to highly disturbed rhythms with fragmented sleep epochs, together with delayed melatonin onsets and higher levels of daytime sleepiness. Participants with a normal rest-activity cycle (objectively determined by high relative amplitude of day/night activity) performed significantly better in frontal lobe function tasks. Stepwise regression analysis revealed that relative amplitude and age represented the best predictors for cognitive performance (Stroop colour-word interference task, Trail Making Test A and B, semantic verbal fluency task), whereas psychopathology (Positive and Negative Syndrome Scale) did not significantly correlate with either cognitive performance levels or the quality of sleep-wake cycles. CONCLUSIONS Consolidated circadian rhythms and sleep may be a prerequisite for adequate cognitive functioning in individuals with schizophrenia.

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.

Behavioural problems associated with dementia: the role of newer antipsychotics.

Behavioural disorders are a common feature in dementia, especially in the later stages of the disease. The most frequent disorders are agitation, aggression, paranoid delusions, hallucinations, sleep disorders, including nocturnal wandering, incontinence and (stereotyped) vocalisations or screaming. Behavioural disorders, rather than cognitive disorders, are the main reason why caregivers place patients with dementia in a nursing home. However, although behavioural disorders are important, there is still no international agreement with respect to the description and definition of symptoms and syndromes. This also holds true for the wide variety of scales for quantification and measurement of behavioural disorders.Drug therapy should be considered after possible underlying causes such as physical illness, drug adverse effects and environmental Stressors have been ruled out, or specifically addressed, and a behavioural approach has also failed. This article briefly reviews the evidence for non-antipsychotic drug therapies, which include a variety of substances. However, antipsychotics are the group of drugs which have been most frequently studied for the treatment of behavioural syndromes in dementia. Drug responsive symptoms include anxiety, verbal and physical agitation, hallucinations, delusions, uncooperativeness and hostility, whereas wandering, hoarding, unsociability, poor self-care, screaming and other stereotyped behaviour seem to be unresponsive to all drugs.Although the use of classical antipsychotics is limited by extrapyramidal symptoms, anticholinergic adverse effects, sedation and postural hypotension, the newer antipsychotics offer the chance of a better risk : benefit ratio. This article reviews the small amount of data published on the use of the newer antipsychotics, and concludes that risperidone at low dosages (0.5 to 2 mg/day) seems to be especially useful for the treatment of behavioural symptoms in dementia because of its negligible anticholinergic adverse effects. The use of clozapine is limited by its anticholinergic activity, at least in dementia of the Alzheimer and Lewy body types. However, in patients with psychosis arising from Parkinson’s disease it seems to be the drug of choice, and similar activity is likely for olanzapine. There are no published data on other newer drugs, such as sertindole, quetiapine or ziprasidone.Future studies should also address questions of dementia heterogeneity and should compare different drug treatments and treatment combinations.

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.

Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2

Urokinase-type plasminogen activator (uPA) converts plasminogen to plasmin. Plasmin is involved in processing of amyloid precursor protein and degrades secreted and aggregated amyloid-β, a hallmark of Alzheimer disease (AD). PLAU, the gene encoding uPA, maps to chromosome 10q22.2 between two regions showing linkage to late-onset AD (LOAD). We genotyped a frequent C/T single nucleotide polymorphism in codon 141 of PLAU (P141L) in 347 patients with LOAD and 291 control subjects. LOAD was associated with homozygous C/C PLAU genotype in the whole sample (χ2=15.7, P=0.00039, df 2), as well as in all sub-samples stratified by gender or APOE ε4 carrier status (χ2≥ 6.84, P≤0.033, df 2). Odds ratio for LOAD due to homozygosity C/C was 1.89 (95% confidence interval 1.37–2.61). PLAU is a promising new candidate gene for LOAD, with allele C (P141) being a recessive risk allele or allele T (L141) conferring protection.

EFFECTS OF CHRONIC TREATMENT WITH METHADONE AND NALTREXONE ON SLEEP IN ADDICTS

Previous studies have described sleep disturbance secondary to chronic opiate use and abuse. Drug-dependency insomnia is of interest because chronic sleep disturbances can promote depressive symptoms which could lead to a drug relapse. For the first time we compared the polysomnographic parameters of 10 methadone-substituted outpatients and 10 naltrexone-treated outpatients. Methadone (μ-opioid agonist) produced a marked fragmentation of the sleep architecture with frequent awakenings and a decrease in EEG arousals. In comparison with methadone and controls, the naltrexone (μ-opioid antagonist) group showed the shortest sleep latency and the longest total sleep time. These data indicate that μ-agonists and μ-antagonists have different effects on sleep. The implications, especially the involvement of opioid-dopamine interactions on sleep and movements during sleep, are discussed.

Validity, Reliability, and Feasibility of Clinical Staging Scales in Dementia A Systematic Review

New staging systems of dementia require adaptation of disease management programs and adequate staging instruments. Therefore, we systematically reviewed the literature on validity and reliability of clinically applicable, multidomain, and dementia staging instruments. A total of 23 articles describing 12 staging instruments were identified (N = 6109 participants, age 65-87). Reliability was studied in most (91%) of the articles and was judged moderate to good. Approximately 78% of the articles evaluated concurrent validity, which was good to very good, while discriminant validity was assessed in only 25%. The scales can be applied in ±15 minutes. Clinical Dementia Rating (CDR), Global Deterioration scale (GDS), and Functional Assessment Staging (FAST) have been monitored on reliability and validity, and the CDR currently is the best-evidenced scale, also studied in international perspective, and is available in 14 languages. Taking into account the increasing differentiation of Alzheimer’s disease in preclinical and predementia stages, there is an urgent need for global rating scales to be refined as well.

Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease

Mitochondrial transcription factor A (TFAM) is essential for transcription and replication of mammalian mitochondrial DNA (mtDNA). Disturbance of maintenance of mtDNA integrity or mitochondrial function may underlay neurodegenerative disorders such as Alzheimer disease (AD). TFAM, the gene encoding TFAM maps to chromosome 10q21.1, a region that showed linkage to late-onset AD in several study samples. We screened TFAM for single nucleotide polymorphisms (SNPs) and genotyped the G>C SNP rs1937, coding for S12T in mitochondrial signal sequence of TFAM, and the A>G SNP rs2306604 (IVS4+113A>G) in 372 AD patients and 295 nondemented control subjects. There was an association of genotype rs1937G/G with AD in females and an association of a TFAM haplotype with AD both in the whole sample and in females. The findings suggest that a TFAM haplotype containing rs1937 G (for S12) may be a moderate risk factor for AD.