Stephen Tyrer

Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial

BACKGROUND Prevalence of Alzheimers disease in people with Downs syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimers disease. Evidence to support treatment with Alzheimers drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Downs syndrome. METHODS In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Downs syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Downs syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). INTERPRETATION There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Downs syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimers disease are not necessarily effective in this group of patients. FUNDING Lundbeck.

Factors associated with a good response to lithium in aggressive mentally handicapped subjects

Twenty-five (25) mentally handicapped in-patient adults with persistent aggressive behaviour took part in a double-blind crossover trial lasting 5 months comparing the effects of lithium with placebo on aspects of aggressive behaviour. All patients were receiving neuroleptic and/or anticonvulsant drugs which were continued during the trial. Seventeen (17) of the patients showed greater improvement during the lithium phase compared to placebo. Multiple regression analysis was carried out to determine which of 17 background variables were related to outcome. The following factors were associated with a good response to lithium: less than one aggressive episode per week before starting treatment, overactivity, stereotypic behaviour, female sex and epilepsy. No patient became toxic during the investigation although lithium levels were maintained within the therapeutic range (0.5-0.8 mmol/l).

Molecular biology of APO E alleles in Alzheimer's and non-Alzheimer's dementias

Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the epsilon 4 allele has been shown to be a risk factor for late onset Alzheimers disease (AD) where there is an increased frequency of the epsilon 4 allele. The epsilon 4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependent manner, with the epsilon 2 allele having an opposing effect. We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein epsilon 4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased epsilon 4 frequency is also found though a normal epsilon 2 frequency exists, unlike in AD where the epsilon 2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinsons disease with or without dementia, or in Downs syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype. Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the epsilon 2 allele frequency may indicate a genetic difference between AD and LBD. The epsilon 4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.

Self-enhancing confabulation: Revisiting the motivational hypothesis

We report a patient who developed spontaneous confabulation following surgical clipping of an anterior communicating artery aneurysm. An autobiographical memory test was used to measure the emotional valence of the patients self-representations in true and false memories. We found that his confabulations included significantly more positive self-representations than his true memories and that the overall valence of his confabulations was more positive than that of his true memories and than that of the memories of five healthy control participants of the same age and educational attainment. It is proposed that while cognitive dysfunction may explain how confabulations are formed, emotional factors may explain which specific confabulations are constructed.

Influence of the amyloid precursor protein locus on dementia in Down syndrome.

Background: The amyloid precursor protein (APP) locus on chromosome 21 influences the development of Alzheimer disease. Method: The authors investigated the relationship between a tetranucleotide repeat on intron 7 of the APP gene and the age at onset of dementia in Down syndrome (DS). Results: There was a 13-year difference in the age at onset of dementia in DS associated with the number of tetranucleotide repeat alleles in APP. Conclusion: APP is an important locus predicting the age at onset of dementia in people with Down syndrome.

Detection of Lewy bodies in Trisomy 21 (Down's syndrome).

The presence of cortical senile plaques and neurofibrillary tangles sufficient to warrant a neuropathological diagnosis of Alzheimers disease is well established in middle-aged individuals with Trisomy 21 (Downs syndrome). In contrast a relationship between Downs syndrome and Lewy bodies, one of the major neuropathological features of Parkinsons disease, has not been previously reported. In a clinico-neuropathological survey of 23 cases of Downs Syndrome, two patients, aged 50 and 56 years respectively, were found to have Lewy body formation in the substantia nigra in addition to cortical Alzheimer-type pathology. Neither case showed significant substantia nigra neuron loss although locus coeruleus loss was present in both. Since substantia nigra Lewy bodies are a characteristic neurohistological feature of idiopathic Parkinsons disease, their occurrence in cases of Downs syndrome with evidence of Alzheimer-type pathology supports an aetiopathological connection between Parkinsons disease, Alzheimers disease, and Downs syndrome; and suggests that common pathogenic mechanisms may underlie aspects of neuronal degeneration in these three disorders, some of which may relate to aberrant chromosome 21 expression.

Lithium in the treatment of mania

Lithium is clearly more effective than placebo in the treatment of mania but the delay in its action requires that alternative drugs be used in the control of the acute episode. This review examines the comparative effects of lithium and neuroleptics and the combination of lithium with (i) haloperidol, (ii) carbamazepine and (iii) L-tryptophan in the treatment of mania. The administration of lithium and carbamazepine together seems to be particularly advantageous in the treatment of manic states refractory to lithium. Features that predict a good response to lithium in mania are described and a brief description of the management of the manic patient given. It is argued that stable premorbid personality is associated with good response in this condition.

The relationship between response to fluoxetine, plasma drug levels, imipramine binding to platelet membranes and whole-blood 5-HT

1) Thirty-four (34) out-patients with major depressive disorder as defined by Research Diagnostic Criteria were treated with fluoxetine in an open study. 2) All patients received 60 mg daily of the drug for between 18 and 21 days. 3) Of the 28 patients who completed the trial 21 showed improvement and 7 of these showed a marked change. 4) The 7 good responders had a higher fluoxetine:norfluoxetine ratio after three weeks treatment than the remaining patients; 6 of these patients were males. 5) All patients, irrespective of response, showed a decrease in imipramine binding and decrease in whole blood 5-hydroxytryptamine (5-HT) during the period of the study. 6) The response to the drug may be related to metabolism of fluoxetine.

Gender differences in the phenotypic expression of Alzheimer's disease in Down's syndrome (trisomy 21).

Twenty-eight individuals with typical Downs syndrome (DS) phenotype (17 males and 11 females; age range: 10-74 years) were investigated for gender differences in the phenotypic expression of Alzheimer-type pathology (ATP). Quantitative neuropathology was performed in the 4 neocortical lobes of the right hemisphere, by counting senile plaques (SP), and neurofibrillary tangles (NFT). ATP was present in 25 middle-aged (> 40 years) individuals (16 males and 9 females). Females had significantly higher (p = 0.03) mean neocortical NFT densities (36.6 per mm2; s.e.m. +/- 6.6) than males (17.9 per mm2; s.e.m. +/- 4.7). None of the females had NFT densities below 10 per mm2, compared with 6 males in whom NFT were either absent or seen in very low densities (< 4 per mm2). Assessment of SP densities in the same cortical regions showed non-significant differences in females (42.4 per mm2; s.e.m. +/- 5.1) compared with males (33.6 per mm2; s.e.m. +/- 2.1). There was clinical evidence of dementia in all the female (8/8) individuals who were prospectively assessed, compared with only 54% (7/13) of males. The male individuals without clinical dementia had absent or low neocortical NFT densities regardless of high SP densities. Female DS cases (mean age: 48.8 years; s.e.m. +/- 1.9) had an earlier onset of dementia than males (mean age: 53.6 years; s.e.m. +/- 1.3; p = 0.05). Female middle-aged DS individuals have an earlier onset, and a more severe form of AD which correlates with higher neocortical NFT rather than SP density.

A double blind randomised controlled clinical trial on the effect of transcutaneous spinal electroanalgesia (TSE) on low back pain

A double blind randomised controlled clinical trial on the effect of transcutaneous spinal electroanalgesia (TSE) on low back pain was carried out in 58 patients attending a Pain Management Unit. Four TSE instruments, two active and two sham, were used and each patient was assigned randomly to one of these. Low back pain was rated by each patient using a visual analogue scale (VAS) immediately before and immediately after a single 20min treatment of TSE and also daily for the week prior to, and the week following, the treatment. No significant difference in mean pain score was detected between the active and sham treated groups immediately after treatment or during the subsequent week. The Hospital, Anxiety and Depression scale (HAD) and the General Health Questionnaire (GHQ) were completed by each patient and there was a positive correlation between the scores achieved on these scales and the mean pain scores in both the active and sham treated groups. A post‐trial problem was the discovery that the specification of the two active TSE machines differed from the manufacturers specification. Thus, the output frequencies were either more (+10%) or less (−17%) while the maximum output voltages were both less (−40% and −20%), respectively. However, additional statistical analysis revealed no significant differences between the results obtained with the two active machines.