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In their recent paper, Soderstrom et al1 confirmed their preliminary data suggesting that the CSF HVA:5-HIAA ratio was associated with psychopathic traits and, in particular, violent and aggressive behaviour with childhood onset and adult expression. These findings might indeed reflect changed dopaminergic activity, possibly as a result of serotonergic dysregulation. We hypothesise that their findings might be applicable to other brain disorders characterised by specific behavioural disturbances, including aggression and agitation. Indeed, since several studies have found associations between altered serotonergic neurotransmission and aggression in persons with dementia,2,3 we could propose that the CSF HVA:5-HIAA ratio might be associated with aggression in persons with dementia as well. To test this hypothesis, we performed an interim analysis on 102 out of 302 patients who were included in a prospective and longitudinal study on neurochemical and genetic correlates of behavioural and psychological signs and symptoms of dementia (BPSD). The data presented further support a general application of the interesting findings of Soderstrom et al.1
Patients with various neurodegenerative forms of dementia were included in this prospective study, and were followed up by means of a neuropsychological and behavioural assessment every six months. In any case of death, brain autopsy was performed for neurochemical analysis as well as for neuropathological confirmation of the clinical diagnosis. All subjects and their caregivers gave informed consent to participation in the study, which was approved by the local ethics committee.
At baseline, behaviour was assessed by means of a battery of behavioural assessment scales which included the Behavioural Pathology in Alzheimer’s Disease Rating Scale (Behave-AD) and the Cohen-Mansfield Agitation Inventory (CMAI). Lumbar puncture was performed between 9 and 10 am following overnight bed rest and fasting. The first 11 ml of CSF were collected in several polypropylene vials that were immediately frozen in liquid nitrogen and stored at −80°C. Neurochemical analysis was carried out on the CSF fraction containing 6–7.5 ml by means of high performance liquid chromatography and electrochemical detection according to a modification of a recently described method.4 Routine investigation of the CSF included cell count, total protein and glucose analysis, and agar gel electrophoresis of proteins.
For this interim analysis, HVA and 5-HIIA levels were determined in the CSF of 13 participants with frontotemporal lobe dementia (FTD) and 89 participants with probable Alzheimer’s disease (AD). Spearman Rank Order was used for correlation analysis between the CSF HVA:5-HIAA ratio and BPSD, applying SigmaStat Software (SPSS Science, Erkrath, Germany).
In the AD patient group, no significant correlations were found between the CSF HVA:5-HIAA ratio and Behave-AD clusters, total and global scores, or CMAI clusters (aggressive, physically non-aggressive, and verbally agitated behaviours) and total scores. In persons with FTD, however, the CSF HVA:5-HIAA ratio correlated significantly with the Behave-AD aggressiveness cluster score (r = 0.586; p = 0.033) and with the CMAI verbally agitated behaviour cluster score (r = 0.564; p = 0.041). Despite small sample sizes, effects of treatments were ruled out by comparing the CSF levels of HVA (t test: p = 0.691), 5-HIAA (p = 0.370), and the CSF HVA:5-HIAA ratio (p = 0.157) between six untreated subjects with FTD and seven subjects with FTD who were receiving atypical antipsychotics.
Our preliminary results revealed an association between aggression and the CSF HVA:5-HIAA ratio in participants with FTD but not in those with AD. More refined neurochemical analyses, including the determination of all catecholamines and serotonin in an extended population of FTD patients, are scheduled. These will allow further testing of the hypothesis that altered serotonergic modulation of dopaminergic neurotransmission leads to BPSD and in particular to aggression. Meanwhile, our findings suggest that the association between the CSF HVA:5-HIAA ratio and aggression as observed by Soderstrom et al 1 is not limited to violent and aggressive behaviour with childhood onset and adult expression, but may indicate an underlying pathophysiological mechanism that may be common to aggressive symptomatology in other brain disorders, such as frontotemporal lobe dementia.