The dopaminergic neurotransmitter system is associated with aggression and agitation in frontotemporal dementia.

To identify neurochemical correlates of behavioral and psychological signs and symptoms of dementia (BPSD), we set up a prospective study. Patients with probable Alzheimer's disease (AD) (n=181), mixed dementia (MXD) (n=28), frontotemporal dementia (FTD) (n=25) and dementia with Lewy bodies (DLB) (n=24) were included. At inclusion, all patients underwent lumbar puncture, neuropsychological examination and behavioral assessment (battery of behavioral assessment scales). Cerebrospinal fluid (CSF) levels of norepinephrine and of (nor)epinephrine (MHPG), serotonin (5HIAA) and dopamine (DOPAC, HVA) metabolites were determined by HPLC and electrochemical detection. Spearman Rank-Order followed by Bonferroni correction was used for calculating correlations. In FTD patients, CSF norepinephrine levels were positively correlated with dementia severity (r=0.539; p=0.021). CSF DOPAC levels were correlated with BPSD in general (r=0.537; p=0.007), associated caregiver burden (r=0.567; p=0.004) and agitated and aggressive behavior (r=0.568; p=0.004). In a subgroup of FTD patients who did not receive psychotropic pharmacological treatment, a strong correlation between CSF HVA/5HIAA ratios (reflecting serotonergic modulation of dopaminergic neurotransmission) and aggressive behavior (r=0.758; p=0.009) was found. In MXD patients, (verbally) agitated behavior was positively associated with the turnover of norepinephrine (r=0.633; p=0.002). No significant correlations were found in AD and DLB groups. In FTD, increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission is associated with agitated and aggressive behavior respectively. This study demonstrated that neurochemical mechanisms underlying the pathophysiology of BPSD are both BPSD-specific and disease-specific which might have implications for future development of new and more selective pharmacological treatments of BPSD.

Acid metabolites and precursor amino acids of 5-hydroxytryptamine and dopamine in affective and other psychiatric disorders.

Levels of various compounds related to monoamines were assessed in 96 patients with a variety of depressive and nondepressive syndromes. The diagnostic categories were composed retrospectively after examination of International Classification of Diseases (ICD) classifications and all available data in medical reports. All patients underwent the 8-hour probenecid test. Administration of probenecid was partly intravenous (1 g) and partly oral (4 g). In all patients, the cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and probenecid were estimated, while in about half of the patients tryptophan and tyrosine were determined in CSF and serum. When the group is taken as a whole, significant positive correlations are found between the CSF levels of 5-HIAA, HVA and probenecid, between the CSF levels of tryptophan and tyrosine, and between tyrosine levels in serum and CSF. A negative correlation is found between CSF probenecid and serum tryptophan. The group of patients was divided in several ways into various subgroups. Analysis of covariance of clinical and biochemical data indicates no significant biochemical differences between any of the subgroups. This retrospective study lacks supportive evidence that any of the clinical syndromes, including the depressive syndromes, is characterized by specific deficiencies of monoamine neurotransmission.

Cerebrospinal fluid amine metabolites, tryptophan and clinical parameters in depression. Part 2. Psychopathological symptoms.

The group of 33 severely depressed female patients was divided into 3 equally large subgroups, separately according to their CSF 5-HIAA, HVA, tryptophan and total plasma tryptophan, and the severity of 17 operationally defined psychopathological symptoms was compared between the subgroups containing the highest and lowest biochemical values. Nonparametric statistical testing yielded significant results on several symptoms, when the subgroups were formed from CSF 5-HIAA and HVA. There was only one significant symptom difference between subgroups separated by CSF tryptophan and a few other differences by plasma tryptophan level. The results indicate that lumbar CSF metabolites correlate more with certain individual symptoms than with the global severity of depression.