Behavioural and psychological syndromes in Alzheimer's disease.

OBJECTIVES: The origins of behavioural and psychological symptoms of dementia are still poorly understood. By focusing on piecemeal behaviours as opposed to more robust syndrome change valid biological correlates may be overlooked. Our understanding of BPSD via the identification of neuropsychiatric syndromes. METHODS: We recruited 435 subjects from old age psychiatry and elderly care memory outpatient clinics fulfilling the criteria for diagnosis of probable Alzheimer's disease. Behavioural and psychological symptoms were assessed using the Neuropsychiatric Inventory. Principal components factor analysis was carried out on the composite scores of the 12 symptom domains to identify behavioural syndromes (factors). Results were confirmed by performing three different rotations: Varimax, Equamax and Quartimax. RESULTS: Four factors were identified (which accounted for 57% of the variance): 'affect' factor-depression/dysphoria, anxiety, irritability/lability and agitation/aggression; 'physical behaviour' factor-apathy, aberrant motor behaviour, sleep disturbance and appetite/eating disturbance; 'psychosis' factor-delusions and hallucinations; 'hypomania' factor-disinhibition and elation/euphoria. These groups were unchanged when different methods of rotation were used. CONCLUSIONS: We report novel observations that agitation/aggression/irritability cluster within a depressive symptom factor and apathy is found within a physical behaviour factor.

Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis.

BACKGROUND: Increasing resistance to standard antibiotics has been demonstrated in CF patients colonised by Pseudomonas aeruginosa. The antibiotic Fosfomycin has a unique mode of action against this organism, and may protect against aminoglycoside mediated renal and ototoxic effects. However, there is little published experience of this drug in IV form, and it is not licensed for use in the UK. METHODS: In combination with other antibiotics, we used Fosfomycin to treat 30 pulmonary exacerbations in 15 adult CF patients colonised by P. aeruginosa, mainly multiresistant strains. All patients gave informed consent. We cultured sputum prior to treatment and measured spirometry, renal function, and symptoms before and after treatment, and recorded any side effects. RESULTS: One patient developed nausea and Fosfomycin treatment was withdrawn. The remaining patients showed clinical resolution of their chest exacerbations (mean FEV1% predicted: pre 41.1 vs. post 49.4, P<0.001). Although there was a statistical increase in plasma urea (pre 3.9 mmol/l vs. post 4.3, P<0.03), this was still within the normal range. Plasma creatinine was unchanged. CONCLUSIONS: This study shows that IV Fosfomycin is well tolerated by adult patients with CF and can be useful in the treatment of those colonised with multiresistant P. aeruginosa.

Photoperiodically induced changes in glutamatergic stimulation of LH secretion in male Syrian hamsters: role of circulating testosterone and endogenous opioids.

In seasonally breeding mammals, the sensitivity of LH secretion to stimulation by the glutamate agonist N-methyl-D-aspartic acid (NMDA) is lower in the sexually active condition than in animals with testicular regression. One experiment determined if this increased sensitivity to NMDA in the reproductively inactive animal reflects reduced circulating testosterone. Responses to NMDA were determined during long days (LD) and short days (SD) in castrated hamsters bearing silastic testosterone implants, designed to maintain constant serum testosterone concentrations throughout a photoperiodically induced seasonal cycle. As expected, no significant effect of NMDA (50 mg/kg BW, sc) on secretion of LH occurred in testosterone-implanted castrate or intact control hamsters when challenged in LD. In contrast, both groups of hamsters responded to this dose of NMDA after 8 weeks exposure to SD, despite the maintenance of high serum testosterone concentrations in the castrate group. Moreover, the increased response to NMDA was not a reflection of lower LH concentrations associated with this photoperiod, because a response to NMDA persisted after removal of implants when endogenous secretion of LH had increased. Thus, the low circulating concentrations of testosterone in male hamsters exposed to an inhibitory SD photoperiod cannot explain the increased response to glutamatergic stimulation in the sexually inactive state. Photoperiod, acting centrally, is the major determinant of the response to activation of NMDA receptors. Other experiments investigated whether the lack of response to glutamatergic stimulation in the LD sexually active state results from endogenous opioid (EOP) tone that inhibits further increases in LH secretion at this stage of the reproductive cycle. If this is so, then pretreatment with an opioid antagonist would reveal or increase the stimulatory effect of NMDA on secretion of LH. Hamsters in LD were pretreated with the opioid antagonist naloxone (NAL; 5 mg/kg BW sc) before NMDA treatment (50 mg/kg BW sc), and blood samples collected 15 min later. Compared with controls, serum LH was significantly elevated in hamsters pretreated with NAL, but NMDA alone did not elevate LH. Surprisingly, LH concentrations in hamsters pretreated with NAL and then injected with NMDA were significantly lower than in hamsters receiving NAL only. Treatment with a submaximal dose of NAL (0.1 mg/kg) did not increase serum LH, nor did it reveal a stimulatory effect of subsequent NMDA treatment. The results demonstrate that the decreased sensitivity to glutamatergic agonists in the sexually active state is not a reflection of masking by inhibitory EOP mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Photoperiod regulates the LH response to central glutamatergic stimulation in the male Syrian hamster.

This study investigated central glutamatergic function in relation to photoperiodically-induced changes in the secretion of luteinizing hormone (LH). The experimental approach was to compare the central effects of glutamate agonists on LH secretion in reproductively active hamsters kept in long days (LD) with those in photoinhibited hamsters kept in short days (SD) for 6 weeks and having regressed testes. Agonists were delivered via a cannula into the III ventricle of freely moving hamsters, and blood samples collected 10 to 15 min after the start of the infusion. A high dose (3.0 nmole) of N-methyl-D-L-aspartate (NMDA) induced significant (P<0.01) increases in serum concentrations of LH in hamsters in both photoperiods, though the NMDA-induced increase relative to endogenous LH concentrations was greater in SD than in LD. However, a lower dose of NMDA (0.3 nmole revealed a difference in sensitivity. This dose significantly increased serum LH (P<0.05) in hamsters in SD but had no effect in those in LD. The seasonal difference in response to NMDA was compared with the response to an equimolar dose of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a non-NMDA agonist. This dose of AMPA (0.3 nmole) induced a two-fold increase (P<0.05) in serum concentrations of LH in hamsters in both photoperiods, relative to vehicle-treated controls. In a third experiment the dose-response effects of central AMPA on LH secretion were examined more closely. The sensitivity of LH secretion to stimulation with AMPA did not differ between SD- and LD-housed hamsters. Thus the photoperiod-related difference in sensitivity to stimulation with glutamate agonists is specific for NMDA receptor-mediated activation, rather than a passive reflection of differences in the capacity to secrete GnRH/LH in SD and LD photoperiods. To investigate the site of action of NMDA, the expression of the c-fos immediate-early gene, as assessed by immunocytochemistry for its protein product Fos, was used as a marker of neuronal activation, because previous studies in rodents indicate that a high proportion of GnRH neurons express c-fos at the time of the mid-cycle LH surge. NMDA induced widespread expression of c-fos in many periventricular regions including the medial preoptic area (POA) and ventromedial hypothalamic nucleus. However, dual ICC revealed that in neither photoperiod was Fos present in GnRH-positive neurons 1 h after infusion of 3 nmole of NMDA, despite the increases in LH secretion induced by the infusion. AMPA injected icv at doses which released LH did not enhance expression of c-fos in the hypothalamus. Thus, in the male, enhanced expression of c-fos cannot be detected in GnRH neurons at the time of increased secretion of this hormone induced by glutamate agonists. In conclusion, these results show that both NMDA and non-NMDA glutamatergic pathways potentially regulated LH secretion in the Syrian hamster. The increased sensitivity to NMDA but unaltered sensitivity to AMPA in photoinhibited hamsters in SD is consistent with the view that changes in photoperiod might induce specific alterations in NMDA-mediated pathways that ultimately regulate GnRH neurosecretory activity.